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SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
Current Report
Pursuant to Section 13 or 15(d) of
The Securities Exchange Act of 1934
Date of Report: October 31, 2000
Express Scripts, Inc.
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(Exact Name of Registrant as specified in its Charter)
Delaware 0-20199 43-1420563
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(State or other (Commission File No.) (I.R.S. Employer
jurisdiction of Identification
corporation) No.)
13900 Riverport Drive, Maryland Heights, Missouri 63403
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(Address of Principal Executive Offices) (Zip Code)
Registrant's telephone number, including area code: (314) 770-1666
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(Former name or former address, if changed since last report)
Item 5. Other Events
Reproduced below in full is our 1999 Drug Trend Report dated June 2000.
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express scripts
1999 DRUG TREND REPORT
JUNE 2000
--------------------------------------------------
[EXPRESS SCRIPTS LOGO]
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THE BOTTOM LINE
Per member per year (PMPY) Average Wholesale Price (AWP) prescription
expenditures grew at a significant rate in 1999 -- 17.4 percent. This annual
growth rate surpassed the 1997-1998 rate of 16.8 percent, continuing a trend of
increasing rates of drug outlays seen since 1993, the first year Express Scripts
began monitoring drug trends. PMPY drug costs are projected to grow at an even
higher rate to 17.6 percent in 2000, before gradually slowing to an annual 12.1
percent growth rate in 2004.
Acknowledgements: The authors owe special thanks to the following people who
provided substantial input and comments: Emily Cox, PhD; Sandra Ellis, RPh;
Raulo Frear, PharmD; Jeannie Harty; Shelly Heinle; Brenda Motheral, PhD; Chris
Peterson, PharmD; Regina Thompson and Clinical Services Staff.
<PAGE> 4
INTRODUCTION
BACKGROUND
The significant increases in prescription drug expenditures in the past several
years have been well documented. Many pundits point to drug cost increases as
the primary cause for rising healthcare premiums. Blaine Bos of William M.
Mercer Inc. asserts that prescription drug costs accounted for 15 percent of
total employer health plan costs in 1998 compared with 9 percent in 1993(1). In
its most recent HMO Intercompany Rate Survey, Milliman and Robertson attribute
the 1999 health premium increase of 8.2 percent primarily to rising pharmacy
costs(2). The 2000 Towers Perrin Health Care Survey indicated that increasing
prescription drug cost would be a significant factor in the anticipated
12-percent rise in the cost of large employers' health benefit plans(3). The
Segal Company forecasts that due to an anticipated 18 percent growth in 2000,
drug outlays will account for 15 percent of total health benefit costs for
people under 65 years of age and fully 40 percent for those 65 and older(4). The
1999 annual Hoechst Marion Roussel survey found that prescription drug costs
represented 13.6 percent of total HMO operating costs in 1999, up from 10.4
percent in 1996(5). Empire Blue Cross and Blue Shield asserted that prescription
drug costs represented 15.5 percent of premiums in 1999 compared with 12 percent
just three years before(6).
The magnitude of drug cost increases clearly is responsible for the increasing
importance of drug expenditures in overall healthcare costs. Based on results
from its annual survey of benefit plans of medium and large U.S. companies, the
Hay Group found that prescription drug costs rose 15 percent in 1999(7).
National Health Expenditure data indicate that, after declining from 1990
through 1993, annual percent changes in prescription drug spending increased
every year thereafter, reaching 15.4 percent in 1998(8). Looking to the future,
HCFA staff expect prescription drug expenditures to increase at a double-digit
rate through 2005 but at a steadily declining rate of 12.9 percent to 10.2
percent(9).
The unabated rise in prescription drug costs has placed substantial pressure on
third-party payers and self-funded groups to at least curb the rate of
prescription drug growth. The factors driving the use of more drugs and more
expensive drugs are the same supply-and-demand phenomena discussed in the 1998
Drug Trend Report:
(1) Bloomberg News, Dec. 14, 1999
(2) As quoted in Managed Care Executive Edition, January 2000, p. 3. Respondents
to the 1999 annual Deloitte & Touche/Business Employer Survey on Managed
Care indicated that employers expected health rate increases of 8.7% in
1999, 9.1% in 2000 and 9.6% in 2001, with escalating pharmacy cost cited as
the number one reason for this level of increase. (Business & Health,
December 1999)
(3) Towers Perrin Survey Projects Double-Digit Growth in Health Care Costs in
2000, www.towers.com/towers/news/pr20000110.html
(4) 2000 Segal Health Plan Cost Trend Survey, December 1999
(5) Hoechst Marion Roussel Managed Care Digest Series 1999, p. 7
(6) Rising Costs of Drugs Take a Bigger Share of Health Insurance Outlays,
Jennifer Steinhauer, New York Times, October 29, 1999
(7) The Rise in Health Care Premiums Is Closely Tied To Prescription Drugs Cost,
Michael Carter, the HayGroup
(8) National Health Expenditures, 1998, Table 2, Health Care Financing
Administration, Office of the Actuary, National Health Statistics Group
(9) National Health Expenditures Projections: 1998-2008, Table 12a, Health Care
Financing Administration, Office of the Actuary
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- The introduction of many new, usually more expensive, products into the
market
- New indications for existing drugs
- Consumer expectations that:
- Drugs can be used as a substitute for lifestyle changes, as a way of
enhancing the quality of life and as a "fix" for cosmetic blemishes
- Consumers should have access to all drugs and that the costs of these
drugs should be subsidized ultimately by their employers or health plans
- The effective use of direct-to-consumer (DTC) advertising to stimulate
demand
SUMMARY OF FINDINGS
The 1999 Drug Trend Report is the fourth in the series produced by Express
Scripts. The intent of these reports is to provide our clients with a better
understanding of the dynamics underlying current drug cost increases and future
drug cost trends. The 1999 edition highlights the magnitude and underlying
causes for drug cost trends in the most recent five-year period, in particular
between 1998 and 1999. Among the key findings of this study are:
BETWEEN 1995 AND 1999
- Per Member Per Year (PMPY) Average Wholesale Price (AWP) ingredient costs
grew 79.5 percent
- Drugs introduced since 1995 represent 37.2 percent of this growth
BETWEEN 1998 AND 1999
- PMPY AWP ingredient costs grew by 17.4 percent, from $329.83 to $387.09
- The PMPY AWP growth rates for non-managed care clients and managed care
clients were 18 percent and 16.3 percent, respectively
- Increased use of antihyperlipidemics, antidepressants and gastrointestinal
products accounted for $10.47 of the total $57.26 cost increase
- The introduction of COX-2 antirheumatic drugs represented 8.3 percent, or
$4.77, of the total cost increase
- About half of this increase is attributable to increased costs per
prescription, although this percentage varies across therapy classes
- The inflation rate for common drugs (drugs available in 1998 and 1999) grew
by 5.4 percent, slightly above 1998 levels but more than double the rate
seen in 1997. Whereas inflation accounted for 14.9 percent of the 1996-1997
total cost increase, inflation represented 31.2 percent of the total
1998-1999 cost increase.
2000 THROUGH 2004 PROJECTIONS
- PMPY AWP ingredient costs are projected to increase by:
- 17.6 percent in 2000
- 16.5 percent in 2001
- 13.4 percent in 2002
- 12.5 percent in 2003
- 12.1 percent in 2004
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The most significant factor accounting for the projected decline in the rate of
growth in drug expenditures is the anticipated decrease in price inflation. More
specifically, we expect inflation will grow to 6 percent in 2000 but drop to 4
percent in 2001 and to 2 percent from 2002 to 2004, owing to political pressures
surrounding a possible Medicare prescription benefit and differential
manufacturer pricing in the United States relative to other countries. Moreover,
as payers adopt plan designs encouraging more cost-conscious consumer behavior,
increases in utilization likely will abate. These plan designs also will
encourage the use of less expensive but therapeutically efficacious products and
will be reinforced by physician online prescription writing.
The trend figures cited above reflect past experience and future expectations
about the magnitude of drug cost increases if plan sponsors take no significant
action to curb costs. Plan sponsors that did take aggressive steps saw their
drug cost trend decrease by about half the 1999 PMPY AWP trend, thereby saving
$29 PMPY.
The first section of this report describes the reasons for the 1998-1999 drug
cost growth, followed by our PMPY AWP drug cost forecast for the period from
2000-2004. The final part of this analysis discusses some of the key factors
influencing drug costs in recent years and explains the types of actions plan
sponsors can take to offset growing prescription costs. Two appendices are
included in this report.
- Appendix A includes an analysis of drug cost changes across and within
therapy classes between 1995 and 1999. This appendix highlights some of the
key changes in utilization of specific drugs and drug classes, as well as
pointing out factors that are likely to impact future product mix in these
classes.
- Appendix B presents gender and age group profiles of prescription use across
key therapy classes. This information offers clients a way to better
understand drug usage according to the demographic makeup of their
populations.
METHODS
The analyses contained in the 1999 Drug Trend Report are based on prescription
medications for a large sample of Express Scripts clients. Prescriptions in this
database represent drug usage for a monthly average of 8.8 million members in
1998 and 9.6 million members in 1999. Because of the unique demographics and
drug coverage for Medicaid recipients and Medicare beneficiaries receiving drug
coverage through Medicare + Choice plans, data from those two groups are
excluded from this study. The resulting sample consists of 57 percent
non-managed care commercial members and 43 percent managed care commercial
members. Prescriptions dispensed in inpatient settings and drugs sold
over-the-counter are also excluded from consideration. To ensure comparability
across time periods and across client groups, all cost figures are expressed as
Average Wholesale Price (AWP) ingredient costs (retail "list" price of the
medication). Thus, retail network discounts, mail discounts, dispensing fees and
member financial contributions are not reflected in these data. Overall figures
may not represent actual client experience due to differences in plan design.
Finally, the numbers of prescriptions dispensed through mail service have been
converted to equivalent numbers that would have been dispensed through retail
pharmacies to adjust for differential mail usage rates across Express Scripts
clients.
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[BLANK PAGE]
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TRENDS IN EXPENDITURES FOR PRESCRIPTION DRUGS
In 1999, AWP ingredient costs grew by $57.26 to $387.09 PMPY, a 17.4-percent
increase over the 1998 PMPY cost and a 79.5-percent rise over the 1995 PMPY cost
of $215.63 (see Figure 1).
FIGURE 1: PER MEMBER PER YEAR AWP COSTS 1995-1999
[PER MEMBER PER YEAR AWP COSTS 1995-1999 BAR CHART]
<TABLE>
<CAPTION>
YEAR AWP COSTS
<S> <C>
1995 $215.63
1996 $243.34
1997 $282.48
1998 $329.83
1999 $387.09
</TABLE>
This 17.4-percent drug expenditure growth rate between 1998 and 1999 continues a
pattern of annual increases seen since 1993, the first year Express Scripts
began monitoring drug costs. The 1998-1999 growth rate is almost equally
attributable to rises in utilization and increases in per-prescription costs.
Non-managed care clients experienced higher PMPY cost increases (18 percent)
than managed care clients (16.3 percent). The higher trend for non-managed care
clients is due to substantially greater rises in utilization of common drugs,
8.1 percent as opposed to 4.1 percent for managed care clients, as well as to
the use of more new drugs, 2.2 percent vs. 1.2 percent, respectively. Lower use
of new products for managed care clients is consistent with restrictions that
these clients typically impose. New products are often not on formulary for the
first six-12 months after their introduction into the market. However, the
finding that non-managed care clients experienced almost twice the rate of
growth as managed care clients in the use of common drugs is contrary to the
1996-1997 and 1997-1998 experience. This result may reflect non-managed care
clients catching up with managed care clients that traditionally have had higher
utilization rates. The actual net claim costs trend for Express Scripts clients
ranged from a 5-percent-35-percent rise, depending on how aggressively plan
sponsors chose to implement Express Scripts' recommended cost-management
programs.
Why have prescription drug costs escalated so significantly over the past five
years? To answer this question, growth rates for one-year and five-year periods
were analyzed in terms of: 1) changes in the utilization of "common drugs" --
medications that were available for use between 1995 and 1999; 2) increases in
AWP ingredient costs per prescription of these common drugs; and 3) the
introduction of new products to the market (see Table 1).
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TABLE 1: Components of PMPY AWP Cost Trend 1995-1999*
<TABLE>
<CAPTION>
1995 V 96 1996 V 97 1997 V 98 1998 V 99 1995 V 99
<S> <C> <C> <C> <C> <C>
Inflation 3.3% 2.4% 5.1% 5.4% 16.3%
Units per Rx 1.8% 1.0% 0.6% 0.2% 3.4%
Strength 0.5% 0.6% 0.6% 0.8% 3.9%
Mix 4.2% 4.7% 4.4% 2.3% 10.5%
Utilization 1.4% 4.5% 3.8% 6.2% 9.7%
= Common Drug 11.5% 13.7% 15.2% 15.6% 49.9%
+ New Drugs 1.3% 2.4% 1.6% 1.8% 29.6%
= ALL DRUG 12.9% 16.1% 16.8% 17.4% 79.5%
</TABLE>
* The percentage contribution of each factor does not total the common drug
percentage increase. The calculation takes the base cost for a given year
and multiplies it by one plus the percentage contributed by the first factor
(inflation). The resulting total is then multiplied by the percentage
contributed by the second factor (units per Rx) and so on. The percentage
contribution of the new drugs is then added to the total common drug
percentage increase to yield an all drug percentage increase. The final
results may differ slightly due to rounding.
In the 1998 Drug Trend Report, almost half of the overall 66.6-percent increase
between 1994 and 1998 was attributed to drugs that were introduced in 1995 or
later. Only slightly more than one-tenth of the remaining growth was related to
higher utilization, with roughly nine-tenths caused by factors that affect
prescription cost. Between 1994 and 1998, about 55 percent of the rise in the
cost per prescription was due primarily to inflation and secondarily to
therapeutic mix. A combination of larger numbers of units per prescription and
the use of higher strength drugs contributed the remaining amounts.
In contrast, the 1999 Drug Trend Report suggests a somewhat different pattern.
Drugs introduced since 1996 accounted for slightly more than one-third of the
1995-1999 growth rate of 79.5 percent. In addition, whereas utilization
accounted for about 12 percent of the growth rate attributable to common drugs
between 1994 and 1998, this factor accounted for about 20 percent of the common
drugs increase between 1995 and 1999. No significant differences are discernable
between these two time periods in the contribution of either inflation alone or
inflation and therapeutic mix to the total rates of drug cost increases. (As
described later in the report, wide variations exist across therapy classes in
terms of the relative contribution of utilization and per prescription costs.)
The following sections discuss in more detail how each of the components of cost
trend contributed to cost increases of the combined non-managed and managed
commercial memberships between 1998 and 1999.
CHANGES IN COMMON DRUG COSTS BETWEEN 1998 AND 1999
UTILIZATION OF COMMON DRUGS
The utilization rate of common drugs between 1998 and 1999 rose by more than 50
percent of the rate seen between 1997 and 1998. This is the highest annual rate
seen since Express Scripts began monitoring drug trends in 1993. Utilization of
common drugs grew by 6.2 percent from 7.73 prescriptions PMPY in 1998 to 8.21
PMPY in 1999 (see Figure 2) and accounted for 38.8 percent of the total
1998-1999 cost increase. Changes in usage patterns of common drugs differed
significantly by
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therapeutic drug grouping. To determine the nature of this variable use pattern,
common drugs were categorized into therapy classes -- groups of pharmaceutical
agents that are chemically or therapeutically related. Products were grouped
according to the first two digits of the 14-digit Generic Product Identifier
(GPI) code as classified by First Data Bank. This classification system defines
broad drug groups employed to treat similar medical conditions.
FIGURE 2: UTILIZATION OF COMMON DRUGS
[UTILIZATION OF COMMON DRUGS BAR CHART]
<TABLE>
<CAPTION>
1998 1999
<S> <C> <C>
Number of Rxs PMPY 7.73 8.21
Utilization +6.2%
</TABLE>
Changes in utilization of common drugs between 1998 and 1999 varied widely (see
Table 2). Of the top 25 therapy classes ranked by the number of prescriptions
dispensed in 1999, only three -- non-steriodal anti-inflammatory drugs (NSAIDs),
calcium channel blockers (CCBs) and cephalosporins -- experienced declines in
utilization. In contrast, common drug utilization declined for eight therapeutic
categories between 1996 and 1997 and for six between 1997 and 1998. Four of the
22 therapy classes with increases experienced double-digit utilization growth in
1999. As was true in both 1997 and 1998, the largest percentage increase in
utilization occurred for antihistamines. Prescriptions for common drugs in that
class grew by 18.4 percent to 0.26 PMPY in 1999, slightly above the 17.5-percent
rise seen between 1997 and 1998. These dramatic increases in the use of
antihistamines occurred in non-sedating and low-sedating products. Between 1997
and 1999 the market share for the top three of these products -- Claritin(R),
Allegra(R) and Zyrtec(R) -- grew from 80 percent to 88 percent. Not
coincidentally, according to IMS HEALTH and Competitive Media Reporting, DTC
advertising for just these three products was more than $224 million in 1999,
with the market leader Claritin(R) accounting for $123 million of this total.
Antihyperlipidemics continued to be the second fastest growing class in 1999,
rising 18.1 percent to 0.32 prescriptions PMPY. Increased use of these products
is due not only to evidence showing that their use reduces mortality, but also
to intense marketing, particularly in the form of DTC advertising. IMS HEALTH
and Competitive Media Reporting estimates that in 1999 DTC advertising for
Zocor(R) and Lipitor(R) was $90.5 million. Lipitor(R), introduced in 1997, has
eroded the market share of the other major products in this class, becoming the
market leader with a 43.9-percent share in 1999.
PMPY utilization of common antidepressant drugs continued to grow in 1999,
rising 11.3 percent to 0.46 prescriptions PMPY. As the sixth fastest-growing
class in terms of common drug use, the antidepressant class maintained its
status as the second most-used class of common drugs in 1999. As has been the
case over the past several years, reduction in the stigma associated with
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TABLE 2: Utilization of Common Drugs of Top 25 Therapy Classes 1998-1999
Ranked by 1999 Rxs PMPY
<TABLE>
<CAPTION>
1998 1999
PREVIOUS YEAR SELECTED YEAR
THERAPY CLASS RXs PMPY RXs PMPY % CHANGE
<S> <C> <C> <C>
Antihypertensives 0.47 0.51 8.5%
Antidepressants 0.42 0.46 11.3%
Estrogens 0.41 0.42 4.7%
Narcotic Analgesics 0.35 0.38 8.3%
Cough/Cold 0.32 0.37 12.9%
Gastrointestinals 0.29 0.32 9.7%
Antihyperlipidemics 0.27 0.32 18.1%
Penicillins 0.30 0.30 2.5%
Oral Contraceptives 0.28 0.29 6.8%
Antiasthmatics 0.28 0.29 5.1%
Antidiabetics 0.26 0.28 8.1%
Dermatologicals 0.27 0.27 0.0%
Antihistamines 0.22 0.26 18.4%
Calcium Blockers 0.25 0.25 -0.7%
Diuretics 0.23 0.25 6.8%
Anti-Rheum (NSAIDS) 0.27 0.25 -8.7%
Beta Blockers 0.23 0.24 7.2%
Thyroid 0.19 0.21 8.3%
Macrolides 0.18 0.20 13.2%
Antianxiety Agents 0.17 0.18 3.9%
Cephalosporins 0.16 0.15 -1.4%
Decongestants 0.13 0.14 8.1%
Ophthalmic Products 0.11 0.11 2.3%
Anticonvulsants 0.09 0.11 13.5%
Corticosteroids 0.10 0.10 7.8%
Other 1.49 1.53 2.6%
Total 7.73 8.21 6.2%
</TABLE>
depression, together with greater public awareness of depressive symptoms,
resulted in more people obtaining medical care in the form of drug therapy. In
addition, the availability of easier-to-dose, lower-toxicity, better-tolerated
selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine
reuptake inhibitors (SNRIs) has enhanced the treatment of depression. Increased
utilization of these drugs also reflects new indications for antidepressants.
The use of common antidiabetic drugs increased by 8.1 percent to 0.28 PMPY in
1999 -- a somewhat lower rate of growth compared to the 11.5 percent rise in
1998. The continued rise in the use of this class is attributable to the
emphasis on aggressive management of diabetes, as well as to the availability of
newer oral products such as Glucophage(R), which increased its market share from
21.5 percent in 1998 to 26 percent in 1999.
As in 1998, antihypertensives continued to have the highest utilization in 1999.
This class, consisting of angiotensin converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARBs), vasodilators and combination products,
grew by 8.5 percent in 1999 to 0.51 prescriptions PMPY. This strong growth
pattern will likely continue as the population ages. Most heavily prescribed in
this class were the ACE inhibitors. This growth may be attributed to the
perception that ACE inhibitors have superior efficacy and better side-effect
profiles than other kinds of drug products
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used to treat hypertension. In addition, new indications for use of ACE
inhibitors have added to their increasing popularity. Other classes of cardiac
drugs show mixed results for 1999. The use of calcium channel blockers, for
example, continued to decline, dropping to 0.7 PMPY. Diuretics increased in use
by a modest 6.8 percent, and beta blocker use increased by 7.2 percent.
Diuretics and beta blockers are the recommended first-line agents for
uncomplicated hypertension.
Gastrointestinal (GI) drug use rose by 9.7 percent PMPY in 1999 despite heavy
marketing of several OTC GI products previously available only as prescription
drugs. Most of the rise in prescribed GI drugs came from the use of proton pump
inhibitors (PPIs), Prilosec(R) and Prevacid(R). The manufacturers of these
products have effectively used DTC advertising to help increase their combined
market share from 36.2 percent in 1997 to 55.5 percent in 1999. The cost of DTC
advertising for Prilosec(R) alone was $79.5 million in 1999.
The use of narcotic analgesics grew by 8.3 percent PMPY in 1999. The 1999 common
drug use rate of 0.38 PMPY placed narcotic analgesics as the fourth most widely
used class of drugs. In the past, narcotics were used most often to treat
terminally ill patients and patients with severe, short-term pain such as
post-operative pain. Recently, pain management strategies have become more
aggressive, particularly for non-life threatening conditions, such as lower back
pain. With a growing number of invasive procedures being performed in the
outpatient setting, more narcotic analgesics are being administered in
ambulatory settings. Additionally, more terminally ill patients are living
longer and, therefore, are in need of more pain-killing medications.
Utilization of common drugs in several classes of drugs pertaining to women's
health grew in 1999. Increases were seen in the use of estrogens, thyroid
replacement products, oral contraceptives and miscellaneous endocrine agents.
The utilization of estrogens, commonly used to treat post-menopausal symptoms
and to prevent osteoporosis, grew by 4.7 percent in 1999, maintaining its
position as the third most widely prescribed class of drugs. This modest
increase in utilization may reflect growing awareness of the possible link
between estrogen use and increased risk of breast cancer. Also, the popularity
of newly introduced products like Evista(R), an estrogen-like product classified
as a miscellaneous endocrine, eroded some of the estrogen market. In 1999, PMPY
utilization of thyroid replacement products rose by 8.3 percent, somewhat more
than the 5.5-percent increase that this class experienced between 1997 and 1998.
The growth rate in the use of oral contraceptives was 6.8 percent in 1999. To a
large degree, utilization of oral contraceptives reflects changes in plan design
regarding coverage of oral contraceptives. Additionally, growing political
pressure to mandate the coverage of these drugs is being exerted in many states.
The use of common decongestants, a group consisting primarily of nasal steroids,
rose by 8.1 percent to 0.14 prescriptions PMPY in 1999. These drugs are used to
alleviate allergy symptoms. This class includes many of the popular
antihistamines in combination with decongestants (Claritin(R) D and Allegra(R)
D). DTC advertising for antihistamines may have had an indirect effect on the
utilization of cough and cold products. After declining in use in 1998,
prescriptions for cough and cold products rose 12.9 percent, making it the fifth
fastest growing class.
Use of common drugs in the NSAID class continued to decline in 1999. However,
the reasons for the declines in 1998 and 1999 are probably quite different. In
1998, the decline in common NSAID use was likely due to the availability of OTC
products -- people using OTC products rather than prescription products.
Conversely, the 8.7-percent decrease in common NSAID prescriptions in
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<PAGE> 13
1999 was largely attributable to the introduction of two new cyclo-oxygenase 2
(COX-2) inhibitors, Celebrex(R) and Vioxx(R). These agents, classified as new
drugs in this analysis, have somewhat lower rates of GI distress than older
NSAID products. Introduced in 1999, Celebrex(R) and Vioxx(R) together captured
18.9 percent of the NSAID market.
After growing by only 3.6 percent in 1998, the use of drugs in the macrolide
antibiotic class shot up by 13.2 percent in 1999 to 0.20 prescriptions PMPY. The
continued rise in the use of this drug class resulted from the increased
reliance on macrolides for treating strains of bacteria that are resistant to
other antibiotics, as well as from their role in treating H. pylori infection.
With the growing problem of bacterial resistance, especially S. pneumoniae, many
physicians are initiating therapy with broader spectrum antibiotics, as
evidenced by the modest 2.5-percent increase in PMPY utilization of penicillins
and the 1.4-percent decline in the use of cephalosporins.
Finally, after declining by 0.5 percent between 1997 and 1998, the PMPY use of
common antiasthmatic drugs increased by 5.1 percent in 1999. The continued
relatively stable use of this drug class is somewhat surprising given the
emphasis that has been placed on asthma control in recent years and the central
role that prescription drug therapy plays in that control.
FIGURE 3: PERCENT INCREASE OF COMMON DRUG AWP PER PRESCRIPTION COST CHANGE
ATTRIBUTABLE TO PRICE, UNITS, THERAPEUTIC MIX AND STRENGTH MIX 1998 -
1999
[PERCENT INCREASE OF COMMON DRUG AWP PIE CHART]
<TABLE>
<S> <C>
Units 2%
Price 61.8%
Strength 8.4%
Therapeutic Mix 27.7%
</TABLE>
AWP INGREDIENT COST PER PRESCRIPTION
Overall, increases in the AWP ingredient costs per prescription for common drugs
were responsible for half of overall prescription drug expenditures between 1998
and 1999. However, as noted previously, the relative contributions of
utilization and cost per prescription to cost change vary significantly across
therapy classes. Components of the trend in the cost per prescription for common
drugs are:
- Inflation (AWP price increases per unit moderated by the availability of
less expensive generic equivalents for branded products)
- Therapeutic mix (changes in the mix of chemical entities within and across
therapeutic classes)
- Strength mix (changes in the mix of strengths and dosage forms of existing
chemical entities)
- Units (the number of units dispensed per prescription)
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<PAGE> 14
Inflation (price), the number of units dispensed and the two types of mix
contributed somewhat unevenly on an annual basis over the period examined (see
Table 1 and Figure 3). Between 1998 and 1999 for common drugs, inflation had by
far the greatest effects on the AWP ingredient cost per prescription, followed
by therapeutic mix, number of units per prescription and strength mix. The
contributions of these factors to the overall increase in the AWP per
prescription for common drugs are described below.
INFLATION
Inflation reflects the AWP that manufacturers set for each unit of their
product. The 5.4 percent unit price increase in common drugs between 1998 and
1999 continued a pattern of extraordinarily high increases that began in 1998
when inflation was 5.1 percent. In the period from 1993 through 1997, inflation
ranged from 1 percent-3.3 percent. During this five-year period, prescription
drug inflation was at its lowest point in 1994-1995, a time when healthcare
reform and the potential for government regulation of drug prices were being
hotly debated. After healthcare reform died, the inflation rate rose.
TABLE 3: CPI for Selected Major Categories, 1995-1999
<TABLE>
<CAPTION>
% CHANGE % CHANGE % CHANGE % CHANGE
95-96 96-97 97-98 98-99
<S> <C> <C> <C> <C>
Food 3.3% 2.6% 2.2% 2.1%
Housing 2.9% 2.6% 2.3% 2.2%
Fuels and Other Utilities 3.1% 2.6% -1.8% 0.2%
Household Furnishings and Operations 1.4% 0.6% 1.0% 0.1%
Apparel and Upkeep -0.2% 0.9% 0.1% -1.3%
Transportation 2.8% 0.9% -1.9% 2.0%
Medical Care 3.5% 2.8% 3.2% 3.5%
Prescription drugs 3.4% 2.6% 3.7% 5.7%
Medical Care Services 3.7% 2.9% 3.2% 3.4%
All Commodities 2.6% 1.4% 0.1% 1.8%
All Commodities less Food 2.2% 0.6% -1.0% 1.5%
Durables 1.1% -0.5% -0.9% -1.3%
Nondurables 3.0% 2.0% 0.3% 2.9%
Energy 4.7% 1.3% -7.7% 3.6%
Grand Total of All Items 3.0% 2.3% 1.6% 2.2%
</TABLE>
Source: Consumer Price Index-All Urban Consumers. Washington D.C.: Bureau of
Labor Statistics, [Cited 2000 March 01]. Available from
http://stats.bls.gov/cpihome.htm
To put the magnitude of these inflationary increases in perspective, the
Consumer Price Index (CPI) for selected major expenditure categories was
examined (see Table 3). Although the U.S. Department of Labor defines inflation
somewhat differently than this analysis, the patterns of annual rate increases
since 1995 in prescription drugs are the same -- increasing in 1996, dropping in
1997, then rising again in 1998 and 1999. According to Department of Labor
statistics, the inflation rate for prescription drugs ranked the highest among
the major consumer categories analyzed in both 1998 and 1999. In 1999, the
prescription drug inflation rate was 5.7 percent, with the next highest
inflation rate being medical care at 3.5 percent.
11
<PAGE> 15
Based on Express Scripts data, the 1998-1999 rate of inflation of 5.4 percent
accounted for almost one-third of the overall 17.4-percent trend in PMPY AWP
Cost (see Table 1). An examination of possible factors influencing the 5.4
percent inflation rate was conducted to identify whether the high inflation rate
was specifically and obviously attributable to particular factors or
concentrated in isolated therapeutic classes.
Analysis of Brand and Generics: We found that the inflation increase occurred
among both generic and brand products (see Table 4). The inflation rate for
generic products between 1998 and 1999 was 7 percent, slightly above the
6.9-percent increase experienced between 1997 and 1998. After rising 5.7 percent
between 1997 and 1998, prices for branded products increased 5.8 percent in
1999. The top 50 common branded drugs, ranked by prescriptions filled, had price
increases anywhere from 0 percent-15.6 percent between Dec. 31, 1998 and Dec.
31, 1999 (see Table 5).
The seeming anomaly of a 5.8-percent increase in brand prices and a 7-percent
increase in generic prices resulting in a 5.4-percent increase for all products
reflects the fact that our inflation rate also captures cost changes resulting
from the shift from branded products to their generic equivalents. The move to
generics somewhat moderates the inflation rate because generics are usually less
expensive than their brand equivalents.
Analysis of Key Variables by the Top 25 Therapy Classes: We then explored
whether there was a noteworthy relationship by therapy class between the
percentage of total prescriptions, the percent change in PMPY prescription
utilization, the AWP cost per prescription, or the percent of generic
prescriptions and inflation rate. Figures 4-7 present the inflation rate against
each of these variables. As can be seen, no meaningful relationships were
apparent.
Analysis of Specific Therapy Classes: Additional analyses were conducted for
therapy classes with the largest price increases and for antidepressants. Only
two of these classes (narcotic analgesics and ophthalmic products) were new to
the top-five therapy classes ranked by change in price between 1998 and 1999.
The top-ranking class, thyroid, had a 10.9-percent increase in prescription cost
between 1998 and 1999. The price increase followed the 12.2-percent increase
from 1997-1998. Both the brand and generic products had large increases in
average wholesale price per unit. Synthroid(R), a brand-name product, had a
64.4-percent market share within the thyroid therapeutic class. The manufacturer
of Synthroid(R) increased the AWP per unit of this medication two times from
Dec. 31, 1998-Dec. 31, 1999, resulting in a 9.4-percent increase in the price
per unit. Levoxyl(R), a generic equivalent of Synthroid(R), had a majority of
the 31.6-percent generic market share. The price of Levoxyl(R) was increased
twice during the time period, resulting in a 19.1-percent price increase.
Although the shift in utilization from the expensive brand products to less
expensive generic equivalents helped to mitigate the inflation rate, the large
increase in the price per unit of both the brand and generic products placed the
thyroid class in the first place for price increases at 10.9 percent.
A 10.6-percent price increase moved the narcotic analgesic class from eighth
ranked between 1997 and 1998 to second ranked for change in price between 1998
and 1999. The increase in generic pricing had the greatest impact on the overall
inflation rate in this class. Generic products accounted for 77.5 percent of
narcotic analgesic utilization. Of the 77.5 percent generic market share,
hydrocodone w/acetaminophen had a 46.5 percent share. The manufacturer of the
most commonly used form of hydrocodone w/acetaminophen, which had 17.5 percent
of the market share of this product, had not
12
<PAGE> 16
FIGURE 4: PERCENTAGE CHANGE IN PRICE RANKED BY PERCENT OF 1999 TOTAL Rxs
[PERCENTAGE CHANGE IN PRICE RANKED BY
PERCENT OF 1999 TOTAL Rxs BAR AND LINE CHART]
FIGURE 5: PERCENTAGE CHANGE IN PRICE RANKED BY PERCENTAGE CHANGE IN PMPY Rxs
[PERCENTAGE CHANGE IN PRICE RANKED BY
PERCENTAGE CHANGE IN PMPY Rxs BAR AND LINE CHART]
13
<PAGE> 17
FIGURE 6: PERCENTAGE CHANGE IN PRICE RANKED BY
AWP COST PER Rx
[PERCENTAGE CHANGE IN PRICE RANKED BY
AWP COST PER Rx BAR AND LINE CHART]
FIGURE 7: PERCENTAGE CHANGE IN PRICE RANKED BY
PERCENT OF GENERIC Rxs
[PERCENTAGE CHANGE IN PRICE RANKED BY
PERCENT OF GENERIC Rxs BAR AND LINE CHART]
14
<PAGE> 18
changed the price of this product since Oct. 1, 1997. The second- and
third-ranked hydrocodone w/acetaminophen products, which are produced by the
same manufacturers, had a combined market share of 24.5 percent of the
hydrocodone w/acetaminophen market. The price for the second-ranked product
remained constant, while the third-ranked product increased in price by more
than 60.8 percent between the end of 1998 and the end of 1999. Acetaminophen
w/codeine had 16 percent of the generic market share within the class. The
manufacturer of the most commonly dispensed form of acetaminophen w/codeine,
after increasing the price by 70 percent in 1998, did not increase the price of
their product in 1999. The majority of the generic products within this class
had price increases ranging from 0 percent-66 percent between the end 1998 and
the end of 1999. The shift between brands and their generic equivalents helped
to slightly minimize the impact of these large price increases. In addition to
the large price increases among generics, the most frequently dispensed branded
product, Ultram(R), which ranked second in terms of filled prescription in this
class and held 7.1 percent of the market, had a 9.1 percent increase in price
per unit between Dec. 31, 1998 and Dec. 31, 1999.
The ophthalmic product class moved up from a ranking of 12th in 1998 to third
with a 9.8-percent increase in price between 1998 and 1999. The primary factor
contributing to cost increase within this class was the price increase of brand
products. The brand products, with a 60.1-percent market share within this
class, exhibited an 11.7-percent increase in price (see Table 4). The most
commonly used brand name products within the class -- Xalatan(R), Tobradex(R),
Patanol(R), Alphagan(R), Timoptic-XE(R) and Ciloxan(R) -- had a combined market
share of 34 percent. Among these products, Xalatan(R), Alphagan(R) and
Ciloxin(R) all had one price increase in 1999, each resulting in a total price
increase of less than 6 percent. The other three products, Tobradex(R),
Patanol(R), and Timoptic-XE(R), each had two price increases and at least a
15-percent total price increase in 1999. The generic ophthalmic products, with a
40-percent market share, increased in price by 5.8 percent overall between 1998
and 1999. The same manufacturer of the three most commonly prescribed generic
products in this class -- polymyxin B sulf/trimethopriate, tobramycin sulfate
0.3% and sulfacetamide sodium -- held greater than a 70-percent share of the
generic market for these products in 1999. This manufacturer did not increase
the price of these products in 1999, although sulfacetamide sodium was increased
by 8.3 percent in 1998. Many other generic manufacturers followed the market
leader and did not raise their prices in 1999 either, preferring to hold at
prices increased in 1998 or in previous years.
The unit-price increase for estrogen replacement therapy increased by 8.9
percent between 1998 and 1999. This is subsequent to an 8.7-percent increase
between 1997 and 1998. The increase in price of branded products was a
contributing factor to the overall price increase of this therapeutic class.
Brand products, which had 89.4 percent of the market share within this class,
had a 9.7-percent increase in unit price. Generic products increased in unit
price by only 2.7 percent. Premarin(R) and Prempro(R), which were the two most
commonly prescribed branded products within this class, both had 12.1-percent
increases in the price per unit. Both products are made by the same
manufacturer, which increased the AWP unit price twice for both products between
December 1998 and December 1999. This pattern of multiple increases is
consistent with the pattern seen between December 1997 and December 1998. Only
one estrogen product in the top 10, Estradiol(R) 1mg, had a percentage increase
in price per unit of less than 10 percent. Cenestin(R), which was new to the
market, was priced at $0.52 per unit, just a few pennies below its primary
competitor, Premarin(R). Within the estrogen replacement therapy class, the
shift from brand medications to their less expensive generic equivalents kept
the unit price increase slightly lower overall at 8.9 percent, compared with the
9.7-percent price rise of brand name products.
15
<PAGE> 19
Rounding out the top-five therapy classes in terms of increase in price were the
dermatological products. The 8.4-percent increase in price for dermatological
products was after the 8.1-percent increase between 1997 and 1998. The primary
factor contributing to the increase in the unit price of the dermatological
class was the 8-percent-9-percent overall increase in price of both brand and
generic products. Of the top-15 utilized dermatological products, all but one,
Differin(R) 0.1%, had at least two price changes from Dec. 31, 1998 to Dec. 31,
1999. The acne drugs, Accutane(R) (27.8%), Cleocin T(R) (16.5%) and
Benzamycin(R) (23.5%) all had well-above average price per unit increases in
1999. These increases followed the 18.8-percent, 12.0-percent and 5.8-percent
increases in price, respectively, that each of these products had between the
end of 1997 and the end of 1998. Minimizing the impact of the price increase of
the dermatological products was the shift in the use of brand name products to
their less-expensive generic equivalents.
TABLE 4: Utilization and Price Changes of Top 25 Therapy Classes 1998-1999
Ranked by % Change in Price
<TABLE>
<CAPTION>
PRICE % CHANGE PRICE % CHANGE PRICE % CHANGE
THERAPY CLASS GENERIC PRODUCTS BRANDED PRODUCTS ALL PRODUCTS
<S> <C> <C> <C>
Thyroid 15.1% 11.3% 10.9%
Narcotic Analgesics 20.0% 6.5% 10.6%
Ophthalmic Products 5.8% 11.7% 9.8%
Estrogens 2.7% 9.7% 8.9%
Dermatologicals 9.5% 8.8% 8.4%
Decongestants 9.1% 7.3% 7.3%
Antidiabetics 6.4% 7.4% 6.9%
Diuretics 8.5% 5.5% 6.5%
Antiasthmatics 0.2% 9.9% 6.4%
Antidepressants 31.3% 4.7% 6.2%
Oral Contraceptives 25.6% 5.0% 5.9%
Antianxiety Agents 5.9% 7.2% 5.3%
Anticonvulsants 0.6% 6.2% 4.8%
Antihistamines 11.9% 4.7% 4.7%
Penicillins 0.8% 5.8% 4.2%
Macrolides 1.9% 4.2% 4.1%
Corticosteroids 5.7% 9.2% 4.0%
Cough/Cold 9.8% 5.1% 3.9%
Cephalosporins -1.2% 7.4% 3.6%
Antihypertensives -5.8% 4.8% 3.5%
Gastrointestinals -0.4% 4.6% 3.2%
Antihyperlipidemics 0.0% 3.2% 2.9%
Anti-Rheum (NSAIDS) 2.2% 5.1% 2.8%
Calcium Blockers 2.4% 4.1% 2.7%
Beta Blockers 3.5% 6.1% 2.5%
OTHER 14.8% 6.0% 6.8%
TOTAL 7.0% 5.7% 5.4%
</TABLE>
Given that the antidepressant therapy class was ranked second in both PMPY cost
and PMPY utilization for 1999, closer analysis of the class with a 6.2-percent
increase in unit price was conducted as well. In the antidepressant therapeutic
class, the price increase was attributed to both the unit price increases of
brand and generic products. The branded products, which had 77 percent of the
market share within the class, had a 4.7-percent price increase between 1998
16
<PAGE> 20
and 1999. The SSRI branded products Prozac(R), Zoloft(R), Paxil(R) and Celexa(R)
had 56.1 percent of the market share within this class. Prozac(R), the only SSRI
with multiple increases in price in 1999 and, at 5.6 percent, the largest total
price increase, is the first SSRI scheduled to go off patent in 2001. The
manufacturer may be increasing the price at a significant rate in anticipation
of a loss in revenue due to patent expiration. The manufacturer of Paxil(R)
increased the price of the product once from the end of 1998 to the end of 1999,
resulting in a 4.5-percent increase in unit price. In contrast, Zoloft(R) had an
increase in price per unit of 2.6 percent. Celexa(R), the newest of the SSRI
products, was priced lower than the other SSRI products and subsequently gained
4.8 percent of the market share in 1999. The Celexa(R) price increase was
consistent with the other SSRIs. Another branded antidepressant with significant
price increases was Wellbutrin SR(R). The non-SSRI indicated for depression and
used off-label for smoking cessation had two price increases in 1999, resulting
in a 14.9-percent increase. The unit price for generic products within the class
increased by 31.3 percent. The market share of the most commonly used generic,
amitriptyline HCL, was 9.6 percent in 1999. The top-two manufacturers of
amitriptyline HCL had price increases of 68.1 percent and 243 percent. The large
increase in price per unit caused the average cost per prescription of
amitriptyline HCL to increase by more than 100 percent between 1998 and 1999.
THERAPEUTIC MIX AND STRENGTH MIX
Therapeutic mix is the use of relatively more expensive or less expensive drugs
within and across therapy classes. Strength mix refers to cost impacts caused by
changing to more or less expensive strengths of the same drug or the
introduction of new strengths of existing products. The therapeutic mix trend
among 1999's top-25 classes by utilization was 2.4 percent, lower than the 3.2
percent seen last year. The difference is primarily due to a relative increase
in utilization in classes with less expensive drugs. For instance, two of the
classes with the lowest cost per prescription --cough and cold, and penicillins
-- experienced utilization trend 14.9-percent and 9.1-percent higher,
respectively, than their trend last year. Strength mix, still one of the lowest
contributors to trend, did increase 0.75 percent from 1998 to 1999, marginally
higher than the 0.6-percent contribution from 1997 and 1998. Taken together,
therapeutic and strength mix accounted for 36 percent of the overall 1998-1999
cost increase.
Among the top-25 classes, the largest changes in therapeutic mix occurred in the
antidiabetic and NSAID classes. In 1998, antidiabetics lead all classes with a
10.5-percent increase, largely due to the rise in popularity of Rezulin(R), the
most expensive drug in the class. In 1999, safety concerns that eventually
resulted in Rezulin(R)'s removal from the market and continuing market-share
growth of less expensive antidiabetic agents, such as Glucophage(R), resulted in
a decline of 1.2 percent in therapeutic mix trend. This decline was somewhat
offset by a relatively high strength mix rise of 2.3 percent, primarily due to
the introduction of 1000mg Glucophage(R) tablets in 1999. While less expensive
than Rezulin(R), costs for the new strength of Glucophage(R) were still about
$30 per prescription more than the class average cost.
In contrast to trends affecting antidiabetics, the NSAID class experienced a
dramatic increase in therapeutic mix from a decline of 1.6 percent in 1998 to a
rise of 7.8 percent in 1999. In large part, the increase resulted from growing
use of expensive disease-modifying anti-rheumatic drugs (DMARDs), such as
Arava(R) and Enbrel(R), both introduced late in 1998. Per prescription costs of
Arava(R) were $250, and per prescription costs of Enbrel(R) were slightly over
$1,000. Some plans
17
<PAGE> 21
TABLE 5: Price Changes for Top 50 Common Drugs 1998-1999
<TABLE>
<CAPTION>
# OF PRICE CHANGES
UNIT PRICE ON UNIT PRICE ON PERCENT BETWEEN 12/31/1998
PRODUCT 12/31/1998 12/31/1999 CHANGE AND 12/31/1999
<S> <C> <C> <C> <C>
1 CLARITIN(R)10MG $2.19 $2.24 2.5% 1
2 LIPITOR(R)10MG $1.88 $1.88 0.0% 0
3 ZITHROMAX(R)250MG $6.39 $6.55 2.6% 1
4 PREMARIN(R)0.625MG $0.51 $0.57 12.1% 2
5 PROZAC(R)20MG $2.50 $2.64 5.6% 2
6 PREMPRO(R)0.625-2.5 $0.77 $0.87 12.1% 2
7 PRILOSEC(R)20MG $3.87 $3.99 3.0% 1
8 ORTHO TRI-CYCLEN(R)7-7-7 $0.98 $1.07 9.1% 2
9 PREVACID(R)30MG $3.59 $3.73 3.9% 1
10 GLUCOPHAGE(R)500MG $0.56 $0.65 14.5% 2
11 FLONASE(R)50MCG $2.89 $3.34 15.6% 2
12 ZYRTEC(R)10MG $1.81 $1.86 2.6% 1
13 LIPITOR(R)20MG $2.90 $2.90 0.0% 0
14 ZOLOFT(R)50MG $2.21 $2.27 2.6% 1
15 ALLEGRA(R)60MG $0.92 $0.99 8.0% 1
16 PAXIL(R)20MG $2.23 $2.33 4.5% 1
17 ZOLOFT(R)100MG $2.28 $2.34 2.6% 1
18 PREMARIN(R)1.25MG $0.71 $0.79 12.1% 2
19 CLARITIN-D(R)12 HOUR 120-5MG $1.23 $1.26 2.5% 1
20 BIAXIN(R)500MG $3.26 $3.52 8.0% 2
21 CIPRO(R)500MG $3.99 $4.15 4.0% 1
22 NORVASC(R)5MG $1.29 $1.32 2.6% 1
23 PRAVACHOL(R)20MG $2.17 $2.27 5.0% 1
24 ZESTRIL(R)10MG $0.91 $0.93 1.6% 1
25 WELLBUTRIN SR(R)150MG $1.33 $1.53 14.9% 2
26 TRIPHASIL-28(R)6-5-10 $0.98 $1.02 4.4% 1
27 CLARITIN-D(R)24 HOUR 240-10MG $2.47 $2.53 2.5% 1
28 ZESTRIL(R)20MG $0.98 $0.99 1.6% 1
29 ORTHO-NOVUM(R)7-7-7 $0.98 $1.07 9.1% 2
30 NORVASC(R)10MG $2.17 $2.17 0.0% 0
31 HUMULIN N(R)100U/ML $2.08 $2.29 10.2% 2
32 ULTRAM(R)50MG $0.71 $0.77 9.1% 2
33 AMBIEN(R)10MG $2.03 $2.14 5.1% 1
34 SYNTHROID(R)100MCG $0.28 $0.31 9.4% 2
35 DIFLUCAN(R)150MG $11.24 $11.53 2.6% 1
36 ZOCOR(R)20MG $3.66 $3.81 3.9% 1
37 AUGMENTIN(R)875-125MG $4.54 $4.76 4.9% 1
38 SEREVENT(R)21MCG $4.49 $5.14 14.6% 2
39 PREMARIN(R)0.9MG $0.61 $0.69 12.1% 2
40 K-DUR(R)20MEQ $0.46 $0.50 7.6% 2
41 ALLEGRA-D(R)120-60MG $1.03 $1.11 8.0% 1
42 NASONEX(R)50MCG $2.84 $3.01 6.1% 2
43 TOPROL XL(R)50MG $0.56 $0.58 4.5% 1
44 CELEXA(R)20MG $1.93 $2.02 4.4% 1
45 ORTHO-CYCLEN(R)0.25-0.035 $0.98 $1.07 9.1% 2
46 LO/OVRAL-28(R)0.3-0.03MG $1.05 $1.09 4.4% 1
47 SYNTHROID(R)125MCG $0.33 $0.36 9.4% 2
48 GLUCOTROL XL(R)10MG $0.66 $0.68 2.6% 1
49 SYNTHROID(R)50MCG $0.25 $0.27 9.4% 2
50 ACCUPRIL(R)20MG $0.95 $0.98 3.0% 1
</TABLE>
18
<PAGE> 22
TABLE 6: Mix Changes of Top 25 Therapy Classes 1998-1999
<TABLE>
<CAPTION>
THERAPEUTIC MIX STRENGTH MIX TOTAL MIX
THERAPY CLASS % CHANGE % CHANGE % CHANGE
<S> <C> <C> <C>
Penicillins 7.99% 3.16% 11.16%
Anticonvulsants 8.76% 0.34% 9.10%
Anti-Rheum (NSAIDS) 7.82% -0.40% 7.42%
Narcotic Analgesics 5.56% 1.82% 7.38%
Antiasthmatics 5.01% 0.98% 5.99%
Gastrointestinals 4.78% 0.32% 5.10%
Ophthalmic Products 3.97% -0.05% 3.92%
Dermatologicals 2.94% 0.74% 3.68%
Cephalosporins 1.09% 0.82% 1.91%
Antianxiety Agents 0.26% 1.39% 1.65%
Beta Blockers 1.75% -0.12% 1.64%
Cough/Cold 0.88% 0.72% 1.60%
Estrogens 0.91% 0.40% 1.30%
Corticosteroids 1.24% 0.06% 1.30%
Antidiabetics -1.25% 2.28% 1.03%
Macrolides 0.40% 0.48% 0.88%
Decongestants 1.03% -0.33% 0.69%
Antihyperlipidemics -2.11% 2.78% 0.67%
Calcium Blockers -0.14% 0.77% 0.62%
Antidepressants -0.18% 0.53% 0.35%
Oral Contraceptives 0.06% 0.18% 0.24%
Antihistamines -0.15% 0.28% 0.13%
Antihypertensives -0.39% 0.25% -0.14%
Thyroid 0.14% -0.43% -0.29%
Diuretics -2.42% 0.34% -2.07%
Other 2.76% 0.63% 3.38%
TOTAL 2.28% 0.76% 3.04%
</TABLE>
cover Enbrel(R) under the medical benefit. Despite the fact that both drugs are
generally considered second-line treatment for pain and joint swelling
associated with rheumatoid arthritis (RA), they are showing dramatic growth in
use. Enbrel(R), in particular, has been boosted recently by its approval for the
treatment of juvenile RA in addition to its previous indication for RA in
adults.
Among the top-10 classes of drugs ranked by total mix change in 1999, seven of
them -- penicillins, anticonvulsants, narcotic analgesics, antiasthmatics,
gastrointestinals, ophthalmic products and dermatologicals -- were also among
the top 10 in 1998. In most cases, these trends merely reflect a continued
increase in market share of the same drugs seen last year.
Among penicillins, Augmentin(R) increased market share by 2.5 percent in a class
consisting of approximately 80-percent generics. In addition, while ranking
second in therapeutic mix, penicillins also led all other classes in strength
mix due to the introduction of 200mg and 400mg chewable tablets and suspension
formulations for Amoxil(R) in 1999. The increase in anticonvulsant cost due to
therapeutic mix was driven by a dramatic 5.3-percent rise in the market share of
Neurontin(R). At $114.17 per prescription, Neurontin(R)'s cost was almost twice
the class average. Some of this increased utilization may be due to recent
studies showing Neurontin(R) as effective treatment for severe pain associated
with diabetic nerve damage and with shingles.
19
<PAGE> 23
Similar to the effect of one product on the entire class of anticonvulsants,
narcotic analgesics experienced well above average mix increase due to a higher
market share for OxyContin(R), which was much more expensive than the class
average. While Oxycontin(R) increased by only 0.8 percent, at $190.61 its
average per-prescription price was almost eight times higher than the class
average. Recent efforts by manufacturers to educate prescribers, dispensers and
patients about the use of narcotics in non-terminal, non-institutional pain
management may be responsible for at least part of the increased use of the more
expensive, more powerful narcotics.
In the GI and antiasthmatic classes, newer drugs continue to gain market share
at the expense of older, less expensive therapies. Within the GI class, proton
pump inhibitors (PPIs) increased their market share by 9.3 percent, only
slightly less than the 10.3-percent jump seen last year. Decreasing at the
expense of PPIs were histamine-2 receptor antagonists (H2RAs), which declined by
7.5 percent to 31.6 percent of the GI market. Increases in the antiasthmatic
class were led by one product, Singulair(R), which increased its market share
from 2.2 percent to 6.5 percent. Introduced in 1998, Singulair(R) is one of the
leukotriene modifier agents that control persistent asthma, with the additional
benefit of once-a-day dosing in tablet formulation and an indication for use in
children. Additional newer products, such as Flovent(R) and Serevent(R) --
asthma controllers, not relievers -- also experienced growth but at a slower
rate than Singulair(R).
Ophthalmic products experienced an increase of almost 4 percent due to mix. Two
types of ophthalmic drugs experienced the most market share movement from 1998
to 1999, those to treat glaucoma and allergic conjunctivitis. Among the products
used to treat glaucoma are Xalatan(R), Trusopt(R) and Cosopt(R). Xalatan(R), at
$61.93 per prescription, was slightly less than twice the average price of all
drugs within the class. As the most frequently dispensed brand in this class,
Xalatan(R)'s 1-percent increase in market share had a significant impact on mix.
Trusopt(R) utilization declined while use increased for Cosopt(R), a product
combining the active ingredient in Trusopt(R) with the ophthalmic beta blocker,
timolol. A prescription for Cosopt(R), however, was about $26 more expensive
than one for Trusopt(R) -- not quite as much as separate Trusopt(R) and generic
timolol scripts would cost. The result was a net increase in the cost per script
due to mix. Finally, at 2.3 percent, Patanol(R) increased market share the most
of any drug in the class. Since it is used to treat watery, itchy eyes caused by
allergies, Patanol(R) may be benefiting from the DTC advertising for allergy
medications.
Dermatologicals, the last of the classes in the top 10 for mix in both 1998 and
1999, achieved this status largely because Accutane(R), Dovonex(R) and
Aldara(R), three drugs that cost more than $100 per prescription, all either
increased or maintained their 1998 market share.
UNITS PER RX
Changes in the number of units per prescription accounted for only 0.2 percent
of the increase in cost from 1998 to 1999 (see Table 7). This rate was the
lowest seen since the inception of the Drug Trend Report. One of the factors
driving this component of trend lower was in the antiasthmatic class where there
were sharp declines in the use of relievers, such as beta agonists, and modest
increases in controllers such as inhaled steroids or the newer leukotriene
antagonists.
Among classes experiencing an increase in the units trend were narcotic
analgesics with more than a 2 percent rise. With the increasing emphasis on pain
control as a quality-of-life issue in conditions like fibromyalgia, many drugs
in this class are being used to treat non-terminal pain
20
<PAGE> 24
for longer time periods. As these drugs have made the transition from short-term
to long-term treatment regimens, the number of units per prescription has
increased.
Dermatologicals also showed a relatively high increase in the number of units
per prescription, 2.2 percent, led by two drugs used to treat acne. Both
Accutane(R) and Benzamycin(R) may be showing strong growth partly due to the
more aggressive treatments of acne. The effects of DTC advertising, particularly
with Accutane(R), may also be prompting more individuals to pursue these types
of therapies.
The cough/cold and antihistamine classes have consistently shown above-average
increases in the number of units in each year of the Drug Trend Report. These
classes are dominated by non-sedating antihistamines, either as single agents
or as combination products with decongestants. Patients may not be using an
antihistamine every day, particularly in non-allergy seasons, but they may still
be requesting a full month's supply of that drug.
TABLE 7: Changes in Cost/Rx Due to Changes in Units/Rx 1998-1999,
Top 25 Therapy Classes by Rxs in 1999
<TABLE>
<CAPTION>
THERAPY CLASS % Rxs % CHANGE
<S> <C> <C>
Narcotic Analgesics 4.6% 2.2%
Dermatologicals 3.3% 2.2%
Cough/Cold 4.5% 1.8%
Antihistamines 3.1% 1.5%
Antidiabetics 3.4% 1.3%
Anti-Rheum (NSAIDS) 3.0% 1.0%
Antianxiety Agents 2.2% 0.7%
Gastrointestinals 3.9% 0.6%
Decongestants 1.7% 0.6%
Antidepressants 5.7% 0.4%
Penicillins 3.7% 0.3%
Oral Contraceptives 3.6% 0.2%
Estrogens 5.2% 0.2%
Antihypertensives 6.2% 0.1%
Macrolides 2.4% 0.1%
Calcium Blockers 3.1% 0.0%
Cephalosporins 1.9% -0.3%
Beta Blockers 3.0% -0.4%
Anticonvulsants 1.3% -0.7%
Diuretics 3.0% -0.9%
Antihyperlipidemics 3.9% -1.2%
Thyroid 2.5% 1.4%
Ophthalmic Products 1.4% -1.5%
Corticosteroids 1.3% -2.1%
Antiasthmatics 3.5% 5.6%
Other 18.7% 0.3%
Total 100.0% 0.2%
</TABLE>
NEW DRUGS
As total drug costs have continued to climb over the past few years, the impact
of new drugs can be clearly seen. New drugs introduced since 1992 accounted for
40.8 percent of 1999 cost and 25.4 percent of 1999 prescription use (see Figure
8). In 1999, 35 new drugs and five biologic
21
<PAGE> 25
agents were approved by the FDA, comparable with the introduction of 30 new
drugs and nine biologics in 1998(10). The number of drugs approved in a given
year, however, is only one part of the story. Another important factor is
whether blockbuster drugs were among the products introduced. In 1997 new drugs
accounted for 2 percent of total costs, largely on the strength of Lipitor(R)
and Rezulin(R) (see Figure 9). The contribution of all 1997 new drugs to total
annual costs rose to 6.5 percent in 1999. In this case, the impact of the new
drugs was immediate. Sometimes, though, a drug's true influence is not seen for
a few years due to the timing of the FDA approval. For instance, Enbrel(R) was
not approved until November 1998, thereby having little impact on 1998 costs. In
1999, PMPM costs for Enbrel(R) jumped more than 35 percent, exceeding 1999 costs
of much more celebrated drugs such as Viagra(R). In 2000, new drugs introduced
in 1998, led by potential blockbusters such as Enbrel(R), Celexa(R) and
Singulair(R), may be on course to surpass the impact of drugs that were new in
several previous years.
To help put the importance of both blockbusters and release dates into
perspective, the top-20 drugs of 1999 are presented in Table 8. Drugs introduced
in 1999 accounted for 1.6 percent of the total cost in 1999. This percentage is
slightly above the average over the previous seven years of 1.4 percent for the
percentage of new drug contribution to total annual cost in the year of their
introduction. One drug, Celebrex(R), accounted for 62 percent of the total new
drug cost. In contrast, Lipitor(R) was only able to account for 0.8 percent of
total cost in 1997, the first year it was on the market. Celebrex(R) had great
success in its first year for several reasons. First, as the first COX-2
inhibitor on the market, it offered something new -- pain relief with less GI
discomfort. In contrast, Lipitor(R) entered a market already crowded with
several established products and had to prove that it was better than the
existing products. Secondly, Celebrex(R)was approved on the last day of 1998 --
which means it had a full first year on the market, unlike Lipitor(R), which was
approved Dec. 17, 1996, but not introduced until April 1997.
Two additional insulin-sensitizing agents that are in the same class as
Rezulin(R) were introduced in 1999. These products, Avandia(R) and Actos(R), are
likely to capture much of the market share left by Rezulin(R)'s voluntary
withdrawal. So far these new products have not exhibited the kind of liver
toxicity seen with Rezulin(R). Nevertheless, it will be up to their
manufacturers to restore consumer faith in this class of drugs.
Xenical(R), a new drug to manage obesity, was introduced in 1999. A lipase
inhibitor, Xenical(R) blocks the absorption of dietary fats. This represents a
fundamentally different method of managing obesity than previous anorexiant
drugs, including Redux(R), which work in the brain to reduce appetite. While
Xenical(R) does have some unpleasant side effects, such as partial loss of bowel
control and oily discharge, it has not been shown to have any of the
life-threatening risks that drove Redux(R) from the market.
Two products were brought to market in 1999 to treat disorders at opposite ends
of the sleep spectrum. Provigil(R) is a non-amphetamine product used to treat
the excessive daytime sleepiness of narcolepsy. Sonata(R), a non-benzodiazepine,
is used on a short-term basis to treat insomnia.
In the GI class, Aciphex(R) entered the proton pump inhibitor (PPI) market
previously consisting only of Prilosec(R) and Prevacid(R). Currently Aciphex(R)
has FDA indication for gastric ulcers, duodenal ulcers, gastroesophageal reflux
disease and hypersecretory conditions. However, it does not have an indication
for H. pylori. It was introduced in August 1999, relatively late to make a big
impact
(10) "New Drug Approvals in 1999," Pharmaceutical Research and Manufacturers of
America, January 2000. P1.
22
<PAGE> 26
on 1999 costs. How successful Aciphex(R) will be in the PPI market remains to be
seen. The cost per Aciphex(R) prescription is about $8 less than Prevacid(R),
the least expensive of the established PPIs.
Two other products introduced in 1999 worthy of note are products used to treat
influenza. Relenza(R), an inhaled powder, and the oral capsule Tamiflu(R) are
both antiviral drugs intended to reduce or shorten the symptoms of flu when
taken as directed. The key to their effectiveness is timing. They must be
started within two days after flu symptoms begin. Both entered the market after
mid-year. While 1999 revenue was a significant factor, the ultimate success of
these products will be measured by how accurately patients interpret their
flu-like symptoms and how carefully they take the drug within its narrow window
of effectiveness.
In 1999, two new products were added to the arsenal of drugs available to treat
HIV infection. Ziagen(R) is a nucleoside analogue reverse transciptase inhibitor
indicated for use in combination with other HIV drugs. Agenerase(R), a new
protease inhibitor, offers the advantage of twice-daily dosing, compared with
the three-times-daily dosing for other protease inhibitors. Agenerase(R) is the
first protease inhibitor to crack the top 20 new drug list since Crixivan(R) in
1996.
The new chemical entity Xopenex(R) represents a growing trend among drug
manufacturers to create new products by using only the active components of
existing drugs. Purified from the asthma drug albuterol, Xoponex(R) is currently
available only in a nebulizer formulation, but an oral syrup and an
extended-release tablet are currently in clinical trials. Development of
purified products is likely to produce new variations of such highly used drugs
as Prozac(R) and Claritin(R) in the next few years.
Cenestin(R), a new estrogen replacement therapy, was also introduced in 1999.
Cenestin(R) is a conjugated estrogen product derived from plant sources and
intended to compete directly with Premarin(R). Obtained from the urine of
pregnant mares, Premarin(R) currently garners about 46 percent of the estrogen
replacement therapy market.
As we look ahead five years, the number of new drugs that will come to market
will increase dramatically. The potential explosion of new drug products is even
more dramatic when the current drug pipeline activity is examined. According to
SG Cowen, there are 1,051 pipeline products. Of these products, 181 are in
preclinical trials, 653 are in phase I, II or III clinical trials, and
applications for licenses for an additional 217 products have been filed with
the FDA(11). However, based on our analysis of existing pipeline products, we
think very few blockbuster drugs will come to market over the next five years.
In contrast, after 2004 the size of the new drug pipeline is likely to grow more
as new technologies enhance the discovery process. This pipeline will consist of
traditional drugs as well as biologics, which are drugs made from living
material -- human, plant or animal. Historically, biologics have consisted
primarily of vaccines used to treat relatively rare conditions. However, as
advances are made in genetic engineering, new biologics are likely to be
developed to treat more common diseases, such as HIV and cancer. In fact, the
biologic Enbrel(R), a genetically engineered protein used to treat rheumatoid
arthritis, was introduced in 1998 and has seen widespread use. When the
identification and sequencing of the DNA structure is completed in 2003, a
myriad of new DNA and protein targets will be discovered. This will allow for
the tailoring of medications to different genetic profiles. While such products
will not be seen for a number of years, the number and therapeutic promise of
such innovations are exciting. However, the cost of these technological advances
will likely be high.
(11) SG Cowen, Pipeline Pulse, March 2000.
23
<PAGE> 27
FIGURE 8: IMPACT OF NEW DRUGS INTRODUCED SINCE 1992
ON 1999 UTILIZATION AND COST
[BAR CHART]
FIGURE 9: PERCENT OF AWP ACCOUNTED FOR BY NEW DRUGS
[LINE CHART]
24
<PAGE> 28
TABLE 8: Top New Drugs in 1999
<TABLE>
<CAPTION>
FDA PRIMARY PMPY
DRUG NAME ROUTE APPROVAL DATE INDICATION % AWP COST COST
<S> <C> <C> <C> <C> <C>
CELEBREX(R) PO Dec-98 Osteoarthritis 1.0% $3.84
VIOXX(R) PO May-99 Osteoarthritis 0.2% $0.93
AVANDIA(R) PO May-99 Type 2 Diabetes 0.1% $0.33
XENICAL(R) PO Apr-99 Obesity 0.1% $0.23
ACTOS(R) PO Jul-99 Type 2 Diabetes 0.0% $0.12
ZIAGEN(R) PO Dec-98 HIV Infection 0.0% $0.11
PROVIGIL(R) PO Dec-98 Narcolepsy 0.0% $0.09
ACIPHEX(R) PO Aug-99 Erosive GERD 0.0% $0.08
AGENERASE(R) PO Apr-99 HIV Infection 0.0% $0.06
SANDOSTATIN LAR(R) IM Nov-98 Severe Diarrhea 0.0% $0.05
RELENZA(R) IH Jul-99 Influenza A & B 0.0% $0.03
SONATA(R) PO Aug-99 Insomnia 0.0% $0.03
XOPENEX(R) IH Mar-99 Asthma/COPD 0.0% $0.03
TAMIFLU(R) PO Oct-99 Influenza A & B 0.0% $0.03
TEMODAR(R) PO Aug-99 Brain Tumors 0.0% $0.03
MICARDIS(R) PO Nov-98 Hypertension 0.0% $0.02
PLETAL(R) PO Jan-99 Claudication 0.0% $0.02
MERREM(R) IV Jun-96 Bacterial Infection 0.0% $0.02
MIRALAX(R) PO Feb-99 Constipation 0.0% $0.01
CENESTIN(R) PO Mar-99 Estrogen Replacement 0.0% $0.01
TOP 20 NEW DRUGS 1.6% $6.08
ALL NEW DRUGS 1.6% $6.13
ALL OTHER DRUGS 98.4% $380.85
ALL DRUGS 100.0% $387.09
</TABLE>
PO-- ORAL
IM-- INJECTED INTO MUSCLE
IH-- INHALED
IV-- INJECTED INTO VEIN
25
<PAGE> 29
TABLE 9: Percent of 1999 Cost and AWP Cost/Rx for Top 50 New Drugs
<TABLE>
<CAPTION>
BRAND NAME YEAR OF INTRODUCTION % OF 1999 COST 1999 AWP/RX
<S> <C> <C> <C>
LIPITOR(R) 1997 2.83% $ 78.60
PREVACID(R) 1995 2.16% $ 125.60
CLARITIN(R) 1993 2.15% $ 66.41
ZOCOR(R) 1992 1.89% $ 106.18
ZOLOFT(R) 1992 1.69% $ 81.44
PAXIL(R) 1993 1.30% $ 77.19
ZITHROMAX(R) 1992 1.13% $ 38.16
GLUCOPHAGE(R) 1995 1.09% $ 57.43
NORVASC(R) 1992 1.04% $ 56.08
CELEBREX(R) 1999 0.99% $ 84.93
IMITREX(R) tablets 1995 0.86% $ 172.60
PREMPRO(R) 1995 0.73% $ 25.91
REZULIN(R) 1997 0.72% $ 153.00
ZYRTEC(R) 1996 0.69% $ 52.40
REBETRON(R) 600 1998 0.68% $1,467.60
EFFEXOR(R) 1994 0.67% $ 91.04
ALLEGRA(R) 1996 0.65% $ 51.68
FLONASE(R) 1994 0.59% $ 50.78
NEURONTIN(R) 1994 0.54% $ 114.17
AMBIEN(R) 1993 0.43% $ 55.41
LAMISIL(R) 1996 0.42% $ 210.22
AVONEX(R) ADMINISTRATION PACK 1996 0.42% $ 823.52
CEFZIL(R) 1992 0.41% $ 64.21
SEREVENT(R) 1994 0.41% $ 67.05
RELAFEN(R) 1992 0.39% $ 72.14
FLOVENT(R) 1996 0.39% $ 72.63
CELEXA(R) 1998 0.39% $ 68.13
ROXICODONE(R) 1992 0.39% $ 162.48
LEVAQUIN(R) 1997 0.38% $ 82.94
PROPULSID(R) 1993 0.38% $ 82.80
SINGULAIR(R) 1998 0.36% $ 73.86
FOSAMAX(R) 1995 0.35% $ 66.44
ULTRAM(R) 1995 0.34% $ 49.65
ZYPREXA(R) 1996 0.33% $ 243.91
DAYPRO(R) 1993 0.32% $ 79.34
ACCUTANE(R) 1992 0.31% $ 150.07
ENBREL(R) 1998 0.30% $1,029.49
ASACOL(R) 1992 0.29% $ 133.43
SPORANOX(R) 1992 0.28% $ 220.47
SERZONE(R) 1995 0.27% $ 73.23
COZAAR(R) 1995 0.26% $ 50.00
HYZAAR(R) 1995 0.26% $ 46.65
VALTREX(R) 1995 0.25% $ 84.64
NASONEX(R) 1997 0.25% $ 50.33
VIOXX(R) 1999 0.24% $ 75.97
RISPERDAL(R) 1994 0.24% $ 133.02
LOTREL(R) 1995 0.23% $ 57.29
IMITREX(R) injection 1993 0.23% $ 221.39
EVISTA(R) 1998 0.22% $ 66.63
ISMO(R) 1992 0.21% $ 44.76
Other 9.29% $ 82.68
TOTAL 41.66% $ 77.22
</TABLE>
26
<PAGE> 30
2000-2004 DRUG COST TREND FORECAST
Following a pattern seen since 1995, PMPY AWP prescription drug costs continued
to rise at an increasing rate in 1999. The 17.4-percent rise in PMPY drug costs
between 1998 and 1999 was the highest seen in the seven-year period that we have
been monitoring drug costs. In past Drug Trend Reports, specific cost
projections were given only for the following year and a range was given for the
succeeding four years. In this year's Report, specific annual projections for
the next five years are presented in the aggregate and for major therapy class
groupings. These projections suggest that costs will grow by an even higher rate
in 2000, before abating somewhat from 2001 through 2004. More specifically,
Express Scripts projects that drug costs will grow by:
- 17.6 percent in 2000
- 16.5 percent in 2001
- 13.4 percent in 2002
- 12.5 percent in 2003
- 12.1 percent in 2004
FIGURE 10: PER MEMBER PER YEAR AWP COSTS
1995-2004
[PER MEMBER PER YEAR AWP COSTS 1995-2040 BAR CHART]
<TABLE>
<CAPTION>
YEAR PMPY AWP Cost
<S> <C>
1995 $216
1996 $243
1997 $282
1998 $330
1999 $387
2000 $455
2001 $530
2002 $601
2003 $677
2004 $759
</TABLE>
These projections translate into a near-doubling of PMPY costs over the next
five years from $387.10 in 1999 to $758.81 in 2004 (see Figure 10). The
assumption regarding the inflation rate that will occur in this period is a key
factor influencing the magnitude of the projected rates of cost increase. As was
discussed in the inflation portion of this Report, inflation for prescription
drugs was 5.1 percent in 1998 and 5.4 percent in 1999. The CPI for prescription
drugs for the first quarter of 2000 relative to the first quarter of 1999 was
5.5 percent, indicating that inflation for 2000 likely will be about 6 percent.
However, we do not expect inflation rates to continue at such high levels for
the succeeding four years largely because the political environment is becoming
somewhat hostile toward the pharmaceutical industry. The industry probably will
react to this pressure by reducing the level of price increases in much the same
way that it did during the healthcare reform debate.
27
<PAGE> 31
The presidential campaign and parallel congressional elections have placed a
greater emphasis on establishing a Medicare prescription benefit. Both political
parties have developed plans to accomplish this goal, acknowledging the
political clout of the elderly, particularly in an election year. As this debate
has proceeded, greater attention has been paid to the cost of prescription
prices in general, as well as to the magnitude of recent price increases. The
number and frequency of media stories about the pharmaceutical industry have
risen dramatically. Some stories focus on the important role drugs play in
treating illnesses and the promise of more drugs to treat previously untreated
or under-treated diseases. Other stories are not so favorable toward the
industry. These stories have focused on the:
- Inability of the elderly to pay for much-needed high-cost prescription drugs
- Substantial differences in drug costs in the United States relative to other
countries
- Size of drug manufacturers' profits
- Various direct and indirect tax subsidies the United States provides to the
pharmaceutical industry
- FTC investigations of some pharmaceutical manufacturers regarding their
alleged engagement in unfair practices, including unfair competition in
generic pricing and "making deals with potential competitors ... that would
keep generic products and companies out of the market."(12)
One manifestation of this growing public concern was the recent action taken by
the state of Maine. Legislation was enacted creating a council that has the
power to set maximum drug prices beginning July 1, 2003, if drug prices exceed
council-determined levels.
Against this backdrop, we project that these political pressures will result in
pharmaceutical manufacturers reducing price increases as the debate over a
Medicare prescription drug benefit heightens this fall and next year. This
reaction has been translated into the following inflation assumptions:
- 6 percent in 2000
- 4 percent in 2001
- 2 percent in 2002
- 2 percent in 2003
- 2 percent in 2004
The relationship between our overall PMPY cost projections and our inflation
assumptions is graphically depicted in Figure 11.
(12) Mehl, Bernard and Santell, John P. "Projecting Future Drug Expenditures;"
American Journal of Health Systems Pharmacy; Vol 57, Jan. 15, 2000; p. 136.
28
<PAGE> 32
FIGURE 11: PERCENT CHANGE IN PMPY AWP COST 1993-2004
[PERCENT CHANGE IN PMPY AWP COST 1993-2004 BAR CHART]
<TABLE>
<CAPTION>
% Change in PMPY AWP Cost
-----------------------------------------------
Inflation rate Change in PMPY AWP Cost
<S> <C> <C>
93/94 1.8% 9.8%
94/95 1.0% 8.9%
95/96 3.3% 12.8%
96/97 2.4% 16.1%
97/98 5.1% 16.8%
98/99 5.4% 17.4%
99/00 6.0% 17.6%
00/01 4.0% 16.5%
01/02 2.0% 13.4%
02/03 2.0% 12.5%
03/04 2.0% 12.1%
</TABLE>
Although these assumed inflation rates were applied to all classes, the
utilization, mix, products losing patent status and role that new drugs will
play in projected costs vary by therapy class. For ease of discussion, we have
taken the major therapy classes and arranged them into 11 major groupings. To
get a better flavor of the degree to which these therapeutic groupings will
contribute to the overall change in PMPY costs between 1999 and 2004, the dollar
and percentage changes of each grouping were examined (see Table 10). The PMPY
costs for the central nervous system (CNS) grouping is projected to grow by 411
percent, representing the largest dollar growth, $99.99, of any grouping and
propelling this class to the most expensive therapeutic
TABLE 10: Forecasting by Grouping
<TABLE>
<CAPTION>
-------------------------------------------------------------------------------------------
$ CHANGE % CHANGE
CLASS GROUPING 1995 PMPY COSTS 2004 PMPY COSTS 1995-2004 1995-2004
-------------------------------------------------------------------------------------------
<S> <C> <C> <C> <C>
CNS $ 24.30 $124.29 $ 99.99 411%
Respiratory $ 22.85 $ 79.43 $ 56.58 248%
Antihyperlipidemics $ 11.48 $ 63.40 $ 51.92 452%
Pain/Inflammation $ 17.90 $ 68.27 $ 50.38 281%
Gastrointestinals $ 20.35 $ 61.71 $ 41.36 203%
Women's Health $ 12.64 $ 49.98 $ 37.35 295%
Antivirals $ 2.58 $ 36.05 $ 33.47 1297%
Cardiovasculars $ 33.57 $ 61.15 $ 27.58 82%
Anti-infectives $ 20.29 $ 44.57 $ 24.27 120%
Antidiabetics $ 5.40 $ 25.80 $ 20.40 378%
Dermatologicals $ 7.46 $ 18.99 $ 11.53 154%
Other $ 36.81 $125.16 $ 88.35 240%
TOTAL $215.64 $758.81 $543.17 252%
</TABLE>
29
<PAGE> 33
TABLE 11: DRUG TRENDS: ALL DRUGS 1998-1999 SUMMARY AND 2000 FORECAST
<TABLE>
<CAPTION>
1998 PREVIOUS 1999 SELECTED 2000 SELECTED 2001 ESTIMATED
THERAPY CLASS YEAR $PMPY % CHANGE YEAR $PMPY % CHANGE YEAR $PMPY % CHANGE YEAR $PMPY % CHANGE
<S> <C> <C> <C> <C> <C> <C> <C> <C>
GASTROINTESTINAL $28.53 20.0% $34.23 23.3% $42.22 19.6% $50.48 10.1%
PPIs $17.35 38.3% $23.99 32.0% $31.67 25.0% $39.58 12.0%
H2RAs $ 9.97 -10.6% $ 8.91 -1.0% $ 8.82 -1.0% $ 8.73 -1.0%
Other $ 1.21 9.9% $ 1.33 30.0% $ 1.73 25.0% $ 2.16 20.0%
CENTRAL NERVOUS $44.28 19.6% $52.95 20.2% $63.65 19.2% $75.86 18.2%
SYSTEM (CNS)
Antidepressants $28.31 19.0% $33.68 20.0% $40.42 19.0% $48.10 17.0%
Anticonvulsants $ 5.52 29.0% $ 7.13 25.0% $ 8.91 23.0% $10.96 25.0%
Antianxiety Agents $ 6.22 11.9% $ 6.96 9.0% $ 7.58 6.0% $ 8.04 3.0%
Antipsychotics $ 2.58 20.2% $ 3.10 40.0% $ 4.34 40.0% $ 6.08 40.0%
Hypnotics $ 1.64 26.8% $ 2.08 15.0% $ 2.39 12.0% $ 2.68 9.0%
ANTIHYPERLIPIDEMICS $21.64 20.9% $26.17 24.0% $32.45 22.0% $39.58 17.0%
CARDIOVASCULARS $41.08 8.9% $44.72 11.1% $49.69 8.5% $53.91 3.6%
Antihypertensives $18.13 12.3% $20.37 14.0% $23.22 11.0% $25.77 3.0%
Calcium Blockers $13.41 2.7% $13.77 5.0% $14.46 2.0% $14.74 0.0%
Beta Blockers $ 6.92 11.2% $ 7.70 14.0% $ 8.78 12.0% $ 9.83 9.0%
Diuretics $ 2.62 10.3% $ 2.89 12.0% $ 3.24 10.0% $ 3.56 8.0%
PAIN/INFLAMMATION $25.43 32.0% $33.57 14.5% $38.45 19.3% $45.87 17.5%
Anti-Rheum (NSAIDS) $12.88 2.2% $13.16 -2.0% $12.90 -2.0% $12.64 -3.0%
Cox-2s $ 4.77 62.0% $ 7.73 73.0% $13.37 50.0% $20.05 28.0%
Narcotic Analgesics $ 7.05 31.1% $ 9.24 14.0% $10.54 11.0% $11.70 9.0%
Migraine Products $ 5.50 16.3% $ 6.40 14.0% $ 7.29 12.0% $ 8.17 8.0%
ANTIDIABETICS $12.12 22.3% $14.82 15.6% $17.13 12.8% $19.33 10.4%
Oral $ 9.67 21.9% $11.79 17.0% $13.79 14.0% $15.73 11.0%
Insulin $ 2.45 23.7% $ 3.03 10.0% $ 3.33 8.0% $ 3.60 8.0%
RESPIRATORY $36.23 18.8% $43.04 16.7% $50.23 14.7% $57.63 11.9%
Antiasthmatics $12.25 11.6% $13.67 16.0% $15.86 14.0% $18.08 12.0%
Antihistamines $11.10 25.8% $13.96 23.0% $17.17 20.0% $20.61 16.0%
Cough/Cold $ 7.46 21.1% $ 9.03 10.0% $ 9.94 8.0% $10.73 6.0%
Decongestants/ $ 5.43 17.5% $ 6.38 14.0% $ 7.27 13.0% $ 8.21 9.0%
Nasal Steroids
DERMATOLOGICALS $10.29 14.6% $11.79 10.0% $12.97 10.0% $14.27 10.0%
ANTIVIRALS $ 7.35 40.1% $10.30 32.9% $13.69 33.3% $18.25 30.5%
HIV $ 3.77 10.3% $ 4.16 8.0% $ 4.49 4.0% $ 4.67 3.0%
Herpes $ 2.58 15.5% $ 2.98 13.0% $ 3.37 10.0% $ 3.70 8.0%
Hepatitis $ 0.12 58.3% $ 0.19 62.0% $ 0.31 57.0% $ 0.48 50.0%
Other/Flu $ 0.88 237.5% $ 2.97 86.0% $ 5.52 70.0% $ 9.39 52.0%
WOMEN'S HEALTH $20.22 19.1% $24.07 17.2% $28.22 16.4% $32.85 14.8%
Estrogens $ 8.29 15.7% $ 9.59 10.0% $10.55 9.0% $11.50 7.0%
Oral Contraceptives $ 8.07 13.7% $ 9.18 11.0% $10.18 9.0% $11.10 7.0%
Misc. Endocrine $ 3.86 37.4% $ 5.31 41.0% $ 7.48 37.0% $10.25 32.0%
ANTI-INFECTIVES $23.91 15.4% $27.58 13.7% $31.37 11.0% $34.81 8.9%
Macrolides $ 6.88 19.0% $ 8.18 15.0% $ 9.41 13.0% $10.63 13.0%
Cephalosporins $ 7.38 3.8% $ 7.65 5.0% $ 8.04 3.0% $ 8.28 1.0%
Penicillins $ 5.69 19.2% $ 6.78 16.0% $ 7.87 12.0% $ 8.81 8.0%
Quinolones $ 3.97 25.2% $ 4.97 22.0% $ 6.06 17.0% $ 7.09 13.0%
</TABLE>
30
<PAGE> 34
<TABLE>
<CAPTION>
2002 ESTIMATED 2003 ESTIMATED 2004 ESTIMATED ESTIMATED 2004- 2005
THERAPY CLASS YEAR $PMPY % CHANGE YEAR $PMPY % CHANGE YEAR $PMPY 2005 % CHANGE PMPY AWP
<S> <C> <C> <C> <C> <C> <C> <C>
GASTROINTESTINAL $ 55.57 4.6% $ 58.13 6.2% $ 61.71 6.6% $ 65.79
PPIs $ 44.33 5.0% $ 46.55 7.0% $ 49.81 7.0% $ 53.30
H2RAs $ 8.65 1.0% $ 8.73 2.0% $ 8.91 5.0% $ 9.35
Other $ 2.59 10.0% $ 2.85 5.0% $ 3.00 5.0% $ 3.15
CENTRAL NERVOUS $ 89.69 17.9% $105.72 17.6% $124.29 19.5% $148.48
SYSTEM (CNS)
Antidepressants $ 56.28 16.0% $ 65.28 15.0% $ 75.08 20.0% $ 90.09
Anticonvulsants $ 13.70 26.0% $ 17.26 28.0% $ 22.10 32.0% $ 29.17
Antianxiety Agents $ 8.28 3.0% $ 8.53 3.0% $ 8.79 6.0% $ 9.31
Antipsychotics $ 8.51 35.0% $ 11.48 30.0% $ 14.93 8.0% $ 16.12
Hypnotics $ 2.92 8.0% $ 3.15 8.0% $ 3.41 11.0% $ 3.78
ANTIHYPERLIPIDEMICS $ 46.31 17.0% $ 54.19 17.0% $ 63.40 20.0% $ 76.08
CARDIOVASCULARS $ 55.85 4.7% $ 58.45 4.6% $ 61.15 -0.6% $ 60.79
Antihypertensives $ 26.54 5.0% $ 27.87 5.0% $ 29.27 8.0% $ 31.61
Calcium Blockers $ 14.74 0.0% $ 14.74 0.0% $ 14.74 3.0% $ 15.19
Beta Blockers $ 10.71 9.0% $ 11.68 8.0% $ 12.61 11.0% $ 14.00
Diuretics $ 3.85 8.0% $ 4.15 9.0% $ 4.53
PAIN/INFLAMMATION $ 53.88 13.2% $ 60.98 12.0% $ 68.27 10.0% $ 75.13
Anti-Rheum (NSAIDS) $ 12.26 -2.0% $ 12.01 -1.0% $ 11.89 5.0% $ 12.49
Cox-2s $ 25.67 22.0% $ 31.31 12.0% $ 35.07
Narcotic Analgesics $ 12.75 8.0% $ 13.77 8.0% $ 14.87 10.0% $ 16.36
Migraine Products $ 8.82 8.0% $ 9.52 7.0% $ 10.19 10.0% $ 11.21
ANTIDIABETICS $ 21.34 10.6% $ 23.61 9.3% $ 25.80 12.1% $ 28.93
Oral $ 17.46 11.0% $ 19.38 10.0% $ 21.31 13.0% $ 24.08
Insulin $ 3.89 9.0% $ 4.24 6.0% $ 4.49 8.0% $ 4.85
RESPIRATORY $ 64.48 11.4% $ 71.83 10.6% $ 79.43 13.0% $ 89.76
Antiasthmatics $ 20.25 12.0% $ 22.67 12.0% $ 25.40 15.0% $ 29.21
Antihistamines $ 23.91 14.0% $ 27.25 12.0% $ 30.52 13.0% $ 34.49
Cough/Cold $ 11.38 6.0% $ 12.06 6.0% $ 12.78 9.0% $ 13.93
Decongestants/ $ 8.95 10.0% $ 9.85 9.0% $ 10.73 13.0% $ 12.13
Nasal Steroids
DERMATOLOGICALS $ 15.69 10.0% $ 17.26 10.0% $ 18.99 10.0% $ 20.89
ANTIVIRALS $ 23.81 28.6% $ 30.62 17.7% $ 36.05 21.6% $ 43.82
HIV $ 4.81 3.0% $ 4.96 3.0% $ 5.11 6.0% $ 5.41
Herpes $ 4.00 8.0% $ 4.32 8.0% $ 4.67 11.0% $ 5.18
Hepatitis $ 0.72 48.0% $ 1.07 44.0% $ 1.54 50.0% $ 2.32
Other/Flu $ 14.27 42.0% $ 20.27 22.0% $ 24.73 25.0% $ 30.91
WOMEN'S HEALTH $ 37.71 14.9% $ 43.33 15.4% $ 49.98 18.3% $ 59.11
Estrogens $ 12.31 7.0% $ 13.17 8.0% $ 14.22 11.0% $ 15.79
Oral Contraceptives $ 11.88 7.0% $ 12.71 7.0% $ 13.60 10.0% $ 14.96
Misc. Endocrine $ 13.53 29.0% $ 17.45 27.0% $ 22.16 28.0% $ 28.37
ANTI-INFECTIVES $ 37.90 8.3% $ 41.04 8.6% $ 44.57 11.6% $ 49.74
Macrolides $ 12.01 14.0% $ 13.69 15.0% $ 15.75 18.0% $ 18.58
Cephalosporins $ 8.36 1.0% $ 8.44 1.0% $ 8.53 4.0% $ 8.87
Penicillins $ 9.52 6.0% $ 10.09 5.0% $ 10.59 7.0% $ 11.33
Quinolones $ 8.02 10.0% $ 8.82 10.0% $ 9.70 13.0% $ 10.96
</TABLE>
<TABLE>
<CAPTION>
THERAPY CLASS COMMENTS
<S> <C>
GASTROINTESTINAL
PPIs Growth rate will moderate as market reaches
saturation and Prilosec goes off patent
H2RAs Utilization will continue to shift to PPIs
Other Treatment of IBS will offset decreased use
of other drugs
CENTRAL NERVOUS
SYSTEM (CNS)
Antidepressants New indications for existing products will
drive up costs
Anticonvulsants Use of Neurontrin and its successor
Pregabalin for pain relief will drive up costs
Antianxiety Agents Little growth expected because of growing
preference for SSRIs for treatment of anxiety
Antipsychotics Increased use of atypicals will drive costs
Hypnotics Modest increase in use expected
ANTIHYPERLIPIDEMICS With aging of population and DTC, expect
high growth to continue
CARDIOVASCULARS
Antihypertensives Key products going generic will slow growth
Calcium Blockers Little additional use of class expected
Beta Blockers Continued important role of class in
treatment of hypertention and new use
for heart failure
JNC-6 guidelines for HTN advocate
Diuretics first-line use
PAIN/INFLAMMATION
Anti-Rheum (NSAIDS) Cox-2s eroding market share of brand NSAIDs
Cox-2s Will continue to bring in new users
Narcotic Analgesics Use will continue to increase as terminal
patients live longer and rely on outpatient
procedures
Migraine Products Modest increases expected to continue
ANTIDIABETICS
Oral Move to more expensive products will fuel growth
Insulin New modes of administration will increase
utilization primarily for Type 2
RESPIRATORY
Antiasthmatics Utilization grows marginally but use of more
expensive products (Accolate, Singulair,
Flovent) will lead to double digit growth
Antihistamines Significant but declining utilization increases
Cough/Cold Modest increases anticipated because of
DTC advertising
Decongestants/ Growth to continue due to supported
Nasal Steroids effectiveness of these products
DERMATOLOGICALS Price increases will drive class costs
ANTIVIRALS
HIV Cost growth will be minimal due to shifts
toward less intensive treatment
Herpes Modest growth will continue
Hepatitis Will grow significantly but impact will
partially be reflected in cancer class
(Intron A)
Other/Flu Flu product growth expected due to consumer
awareness and possible indication for
prevention
WOMEN'S HEALTH
Estrogens Continued modest growth due to
aging population
Oral Contraceptives Expect somewhat more coverage
of OCs by plan sponsors
Misc. Endocrine The availability of new products, coupled with
the aging of the population and massive
undertreatment of osteoporosis, will lead to
substantial utilization growth
ANTI-INFECTIVES
Macrolides Physician preference for use in respiratory
infections will continue
Cephalosporins Market for these products supplanted by
quinolones
Penicillins Utilization declines as preference for other
antibiotic classes expands, but use of
Augmentin will grow
Quinolones Growth in class costs will decline when
Cipro goes generic in 2003
</TABLE>
31
<PAGE> 35
class. 1999-2004 PMPY cost increases for respiratory, antihyperlipidemics and
pain/inflammation are projected to grow by $56.58, $51.92 and $50.38,
respectively. The dollar rise for antihyperlipi-demics represents a projected
452-percent increase, explaining its ascension from the eighth-ranked to the
fourth-ranked class.
Express Scripts' annual PMPY cost estimates from 2000 through 2004 are presented
in the aggregate and for major therapeutic classes, along with a brief rationale
for these projections in Table 11. Key new drugs and patent expirations that
were considered in developing our cost projections for each therapy class are
highlighted.
GASTROINTESTINAL
There are two major developments in the gastrointestinal class. First is the
expiration of the Prilosec(R) patent in 2001. This will create new competition
in the proton pump inhibitor (PPI) class of drugs. The second development is in
new treatments for irritable bowel syndrome (IBS). The first drug in this class,
Lotronex(R) (alosetron), was approved in early 2000, and the second drug,
Zelmac(R) (tegaserod), is expected to be approved near the end of 2000. IBS
affects 10 percent-20 percent of the adult population and is currently an
under-treated condition.
TABLE 12: New Gastrointestinal Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ -------------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Protonix(R) Pantoprazole GERD, PUD X
---- ---- ---- ---- ----
Nexium(R) Esomeprazole GERD, PUD X
---- ---- ---- ---- ----
Zelmac(R) Tegaserod IBS X
---- ---- ---- ---- ----
MK-869 Chemotherapy- X
induced vomiting
---- ---- ---- ---- ----
Prucalopride GERD X
---- ---- ---- ---- ----
Mosapride GERD X
---- ---- ---- ---- ----
Norcisapride GERD X
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS:
PEPCID(R) - 2001
PRILOSEC(R) - 2001
AXID(R) - 2002
32
<PAGE> 36
CENTRAL NERVOUS SYSTEM (CNS)
Developments in the central nervous system pipeline are focused on both new drug
discovery and new uses for existing drugs. There are several new compounds in
development for depression and psychosis, but most are not significantly
different than existing products. The pipeline for anti-anxiety and hypnotic
drugs is relatively quiet. Some new uses for existing drugs include the use of
Prozac(R) for premenstrual dysphoric disorder and Prozac(R) in combination with
Zyprexa(R) for refractory depression. Zyprexa(R), which recently received an
indication for the short-term treatment of acute mania, is being studied for
additional uses, including dementia associated with Alzheimer's disease. A
pipeline product that may have a broad range of uses is the anticonvulsant
pregabalin, which is expected on the market in 2001. Pregabalin is similar to
Neurontin(R) (gabapentin) and may have indications for both epilepsy and pain
when it is approved. A significant upcoming patent expiration is that of
Prozac(R), which may occur any time between 2001 and 2003.
TABLE 13: New CNS Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ --------------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Zeldox(R) Ziprasidone Psychosis X
---- ---- ---- ---- ----
Zomaril(R) Iloperidone Psychosis X
---- ---- ---- ---- ----
Aripiprazole Psychosis X
---- ---- ---- ---- ----
Duloxetine Depression X
---- ---- ---- ---- ----
Vestra(R) Reboxetine Depression X
---- ---- ---- ---- ----
r-fluoxetine Depression X
---- ---- ---- ---- ----
Pregabalin Epilepsy, pain X
---- ---- ---- ---- ----
Tomoxetine Attention-deficit
hyperactivity X
disorder
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS:
BUSPAR(R) - 2000
NEURONTIN(R) - 2000
PROZAC(R) - 2001/2003
33
<PAGE> 37
RESPIRATORY
A number of new products are in the pipeline for the treatment of respiratory
disease, but most are similar to existing products. New antihistamines include
desloratadine, which is a derivative of Claritin(R), and norastemizole, which is
a derivative of Hismanal(R). Developments in the asthma pipeline include new
inhaled steroids and a number of early-stage compounds that target the
underlying causes of the disease. One unique product in the final stages of
development is Xolair(R) (olizumab), which is being studied in both asthma and
allergic rhinitis. Xolair(R) works by antagonizing the effects of IgE, which is
an inflammatory protein found in the lungs.
TABLE 14: New Respiratory Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ ----------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Advair(R) Salmeterol/ Asthma X
fluticasone
---- ---- ---- ---- ----
Asmanex(R) Mometasone Asthma X
---- ---- ---- ---- ----
Qvar(R) Beclomethasone Asthma X
(CFC-free)
---- ---- ---- ---- ----
Foradil(R) Formoterol Asthma X
---- ---- ---- ---- ----
Desloratadine Allergic Rhinitis X
---- ---- ---- ---- ----
Norastemizole Allergic Rhinitis X
---- ---- ---- ---- ----
Zyrtec-D(R) Cetirizine/ Allergic Rhinitis/
pseudoephedrine congestion X
---- ---- ---- ---- ----
Xolair(R) Olizumab* Asthma, X
Allergic Rhinitis
---- ---- ---- ---- ----
Anti-Inter- Asthma X
leukin-5*
---- ---- ---- ---- ----
Interleukin-4* Asthma X
---- ---- ---- ---- ----
Neurokinin-1 Asthma
antagonist* X
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS: *INJECTABLE PRODUCT
FLOVENT(R) - 2003
CLARITIN(R) - 2004, PENDING OUTCOME OF LIGITATION
34
<PAGE> 38
PAIN/INFLAMMATION
This therapeutic category contains drugs for general pain, osteoarthritis,
rheumatoid arthritis and migraine headaches. There have been a number of
significant drugs approved in this area during the past couple of years, and new
products appear similar to those on the market. New COX-2 inhibitors and
triptans for migraine headache are among the more notable products in the
pipeline. The use of Enbrel(R) as first-line therapy for the treatment of
rheumatoid arthritis is likelY to be approved by the FDA in 2000, and studies in
congestive heart failure patients are ongoing.
TABLE 15: New Pain/Inflammation Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ ----------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Valdecoxib Arthritis, pain X
---- ---- ---- ---- ----
Parecoxib* Acute pain X
---- ---- ---- ---- ----
MK-663 Arthritis, pain X
---- ---- ---- ---- ----
Kineret(R) Anakinra* Rheumatoid X
arthritis
---- ---- ---- ---- ----
Dirame(R) Propiram Pain X
---- ---- ---- ---- ----
Relpax(R) Eletriptan Migraine headache X
---- ---- ---- ---- ----
Miguard(R) Frovatriptan Migraine headache X
---- ---- ---- ---- ----
Axert(R) Almotriptan Migraine headache X
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS: *INJECTABLE PRODUCT
RELAFEN(R) - 2002
DAYPRO(R) - 2000
35
<PAGE> 39
CARDIOVASCULAR
Patent expirations will likely play a larger role than new drug introductions in
this class for the next few years. Mevacor(R) will be the first statin to lose
patent protection in 2001, and several ACE inhibitors will also lose patent
protection soon, starting with Vasotec(R)in 2000. The most significant product
in the short-term cardiovascular pipeline was thought to be
Vanlev(R)(omapatrilat), a vasopeptidase inhibitor that works on multiple sites
in the kidney to lower blood pressure. However, FDA concerns over side effects
will require new clinical trials and delay the approval of the drug until late
2001 or early 2002. There are several compounds similar to Vanlev(R) in clinical
trials, although none is close to approval.
TABLE 16: New Cardiovascular Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ ----------------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
ZD-4522 Hyperlipidemia X
---- ---- ---- ---- ----
Vanlev(R) Omapatrilat Hypertension X
---- ---- ---- ---- ----
Eplerenone Hypertension,
heart failure X
---- ---- ---- ---- ----
Olmesartan Hypertension X
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS:
PROCARDIA(R) XL - 2000
VASOTEC(R) - 2000
MEVACOR(R) - 2001
ZESTRIL(R)/PRINIVIL(R) - 2002
ACCUPRIL(R) - 2002
LOTENSIN(R) - 2003
36
<PAGE> 40
WOMEN'S HEALTH
New compounds for osteoporosis dominate the pipeline for women's health
products. Actonel(R) (residronate) was approved in 2000 and will compete with
Fosamax(R) in the bisphosphonate class. Another bisphosphonate, Bonviva(R)
(ibandronate), is in the late stages of development. A second class of drugs
receiving attention is the selective estrogen receptor modulators (SERMs). The
SERM, Evista(R), was approved in 1998, and several more are in development.
These drugs are being investigated for osteoporosis and for breast-cancer
prevention. The use of parathyroid hormone as a treatment for osteoporosis is
also being studied in large-scale trials. Another area of women's health that
may receive greater attention in the coming years is sexual dysfunction.
Viagra(R) is currently being studied in women, as are other drugs in earlier
stages of development.
TABLE 17: New Women's Health Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ ----------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Actonel(R) Risedronate Osteoporosis X
---- ---- ---- ---- ----
Bonviva(R) Ibandronate Osteoporosis X
---- ---- ---- ---- ----
Fosamax(R) Alendronate Osteoporosis X
once-weekly
---- ---- ---- ---- ----
Arzoxifene Cancer X
---- ---- ---- ---- ----
Lasofoxifene Osteoporosis,
breast cancer X
---- ---- ---- ---- ----
Parathyroid Osteoporosis
hormone* X
---- ---- ---- ---- ----
Viagra(R) Sildenafil Female sexual
dysfunction X
---- ---- ---- ---- ----
Tibolone Osteoporosis X
---- ---- ---- ---- ----
Lunelle(R) Medroxyproges- Contraception, X X
---- ---- ---- ---- ----
terone/estradiol* monthly injection (IM) (SQ)
---- ---- ---- ---- ----
</TABLE>
*INJECTABLE PRODUCT
37
<PAGE> 41
ANTI-INFECTIVES
A few new classes of drugs are in the anti-infective pipeline, along with many
compounds similar to existing products. The first antibacterial drug in the
oxazolidinone class, Zyvox(R), was approved in 2000. Zyvox(R) will mainly be
used in the hospital, but its availability in an oral formulation may
TABLE 18: New Anti-Infective Products
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ ----------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Zyvox(R) Linezolid Pneumonia, X
skin infections
---- ---- ---- ---- ----
Spectracef(R) Cefditoren Respiratory tract X
infection
---- ---- ---- ---- ----
Ketek(R) Telithromycin Respiratory tract X
infection
---- ---- ---- ---- ----
Factive(R) Gemifloxacin Respiratory tract
infection, urinary X
tract infection
---- ---- ---- ---- ----
Faropenem Multiple infections X
---- ---- ---- ---- ----
Vfend(R) Voriconazole Fungal infections X
---- ---- ---- ---- ----
Trizivir(R) Lamivudine/ HIV
zidovudine/ X
abacavir
---- ---- ---- ---- ----
Coactinon(R) Emivirine HIV X
---- ---- ---- ---- ----
Tenofovir HIV X
---- ---- ---- ---- ----
Capravirine HIV X
---- ---- ---- ---- ----
Tipranavir HIV X
---- ---- ---- ---- ----
BMS-232632 HIV X
---- ---- ---- ---- ----
GW-433908 HIV X
---- ---- ---- ---- ----
MK-944A HIV X
---- ---- ---- ---- ----
Pegasys(R) Pegylated Hepatitis C
interferon
alfa-2b* X
---- ---- ---- ---- ----
Peg-Intron(R) Pegylated Hepatitis C
interferon X
alfa-2a*
---- ---- ---- ---- ----
Pleconaril Common Cold X
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS: *INJECTABLE PRODUCT
AUGMENTIN(R) - 2002
CEFTIN(R) - 2003
CIPRO(R) - 2003
38
<PAGE> 42
allow for earlier hospital discharges. Another new class of antibacterials is
the ketolides. Ketolides are similar to macrolides (i.e., erythromycin) in
chemical structure and activity, so they will be used mainly in respiratory
tract infections. The first product in this class, Ketek(R), was recently filed
with the FDA and is expected on the market in 2001. Faropenem(R) is a new drug
in the penem class of antibacterials and is the first that can be taken orally.
Pipeline products in the HIV category of antivirals are similar to those
currently available. New products for hepatitis include pegylated interferons,
which can be given once weekly, instead of three times a week with current
interferon products. The antiviral drugs Relenza(R) and Tamiflu(R) are pursuing
an indication for the prevention of influenza, which could increase utilization
of these products.
DIABETES
The diabetes pipeline centers on the insulin product Exubera(R). This product
administers dry powder human insulin by use of an inhaler rather than the
traditional method of injection. Exubera(R) is in Phase III trials and may be
available in 2001 or 2002. Other oral insulin products are in earlier stages of
development. Oral agents for type 2 diabetes are similar to existing products.
The patent for Glucophage(R) expires in 2000, but an extended-release product,
Glucophage(R) XR, is expected to be approved this year. The removal of
Rezulin(R) from the market has not discouraged the development of similar drugs
in that class.
TABLE 19: Diabetes
<TABLE>
<CAPTION>
Brand name Generic name Proposed use Estimated Release Date
---------- ------------ ------------ ----------------------------
2000 2001 2002 2003 2004
---- ---- ---- ---- ----
<S> <C> <C> <C> <C> <C> <C> <C>
Lantus(R) Insulin glargine Diabetes X
(injection) type 1 and 2
---- ---- ---- ---- ----
Exubera(R) Insulin, inhaled Diabetes
type 1 and 2 X X
---- ---- ---- ---- ----
Starlix(R) Nateglinide Diabetes type 2 X
---- ---- ---- ---- ----
Glucophage(R)XR Metformin Diabetes type 2 X
---- ---- ---- ---- ----
Glucovance(R) Metformin/ Diabetes type 2
glyburide X
---- ---- ---- ---- ----
Voglibose Diabetes type 2 X
---- ---- ---- ---- ----
GI-262570 Diabetes type 2 X
---- ---- ---- ---- ----
PNU-182716 Diabetes type 2 X
---- ---- ---- ---- ----
Symlin(R) Pramlintide Diabetes
(injection) type 1 and 2 X
---- ---- ---- ---- ----
Oralgen(R) Insulin, oral Diabetes
liquid type 1 and 2 X
---- ---- ---- ---- ----
</TABLE>
PATENT EXPIRATIONS:
GLUCOPHAGE(R): 2000
39
<PAGE> 43
[BLANK PAGE]
40
<PAGE> 44
ACTIONS TO MITIGATE IMPACT OF THESE TRENDS
DISCUSSION
The fourth edition of the Express ScriptsDrug Trend Report documents a continued
escalation of prescription drug expenditures in 1999. Indeed, the rate of
increase between 1998 and 1999 was the highest seen since Express Scripts began
monitoring drug costs in 1993. Between 1998 and 1999, PMPY AWP costs increased
by 17.4 percent, compared with the 16.8-percent rise seen in the 1997-1998
period. About half of this growth is attributable to per-prescription increases,
stemming primarily from the rise in price and, secondarily, to therapeutic and
strength mix. In addition, growth in common drug utilization, 6.3 percent, was
the highest increase in this factor seen since 1993. Despite the promise of
significant products going generic over the next several years, it is
anticipated that prescription drug costs will continue to grow at a rapid but
declining rate of growth over the next five years.
It must be emphasized that the trend figures cited above reflect past experience
and future expectations about the magnitude of drug cost increases if plan
sponsors take no aggressive action to curb costs. Plan sponsors that did take
aggressive steps saw their drug cost trend increase by only about half the 1999
PMPY AWP trend.
The dynamics underlying these substantial cost increases are the same as those
discussed in previous editions of this Report. The key cost drivers are:
- The continued supply of new drugs coming to market: The pharmaceutical
industry has continued to pour billions of dollars into research and
development. According to the Pharmaceutical Research and Manufacturers of
America, an estimated $26.4 billion will be spent in 2000 alone. Some new
products will be innovative agents designed to treat previously untreated or
under-treated diseases. Others may be more efficacious therapies than
products now on the market. In the short run, most probably will not be more
efficacious than current products but will likely have better side-effect
profiles -- witness the COX-2 inhibitors Celexa(R) and Vioxx(R) and
anticipated isomers of existing products such as Prozac(R). In addition,
during the past several years, a spate of mergers has occurred between
pharmaceutical manufacturers, as well as acquisitions and strategic alliances
between large pharmaceutical companies and biotechnology companies. The goals
of these activities are to enrich drug pipelines and achieve economies of
scale in all phases of business operations, including research and
development.
- The demand for prescription drugs continues unabated, fueled by a society
that looks to drugs as a primary curative for all sorts of maladies: This
phenomenon has occurred with an apparent disregard for the possible known and
unknown long-term effects of some prescription drugs. Some drugs are used by
consumers in lieu of changing their behavior or lifestyle. Why should a
person with high blood pressure or elevated cholesterol levels exercise or
modify diet when it is easier to take a pill? Other products are
life-enhancing. Antihistamines and decongestants alleviate symptoms from
allergies. Fertility and anti-impotence agents clearly promote better quality
of life. At the extreme are products that treat cosmetic conditions such as
wrinkles and baldness. The view of Americans that drugs are the panacea of
all ills is not restricted to prescription drugs.
41
<PAGE> 45
A survey conducted by the Hartman Group found that alternative therapies are
being used by 85 percent of American households. About 40 percent of households
would use alternative medicines even more if they were covered by health
insurance.(13)
To obtain an idea of the proportion of 1999 spending attributable to drugs that
may be considered more closely akin to life-enhancing, drugs in therapy classes
representing more than 95 percent of the drug spend were arrayed along a
continuum ranging from life-sustaining to life-enhancing. This grouping of drug
classes along the continuum does not imply that a given drug class that falls
more toward the life-enhancing end of the continuum would not fall more toward
the life-sustaining end of the continuum for an individual patient. Neither does
the placement of the various drug classes on the continuum imply that drugs on
the life-enhancing end of the continuum should be placed on a third copay tier
or not be covered by a plan sponsor. Rather, the arrangement of drug classes
along the continuum is only meant as a tool to gain better insights into the
dynamics of drug cost increases. As shown in Table 20, only a small percentage
of costs are attributable to life-sustaining drugs, such as anticancer agents
and antiviral products that are used to treat AIDS and hepatitis (4.5 percent).
Another one-third of the 1999 spend is for drugs that most would view as
essential to a pharmacy benefit -- antibiotics, antidepressants, antiasthmatics,
etc. In contrast, 6.3 percent of 1999 costs are accounted for by clearly
life-enhancing drugs, such as antifungals and treatments for erectile
dysfunction. The remaining half of 1999 costs are for drugs in the middle of the
continuum. Drugs in these middle categories range from products treating high
blood pressure and hyperlipidemia to those treating allergies.
TABLE 20: Distribution of AWP Cost by Groupings of Therapy Classes 1995-1999
<TABLE>
<CAPTION>
--------------------------------------------------------------------------------------------------------
THERAPY CLASSES INCLUDED % OF 1999 AWP COST
--------------------------------------------------------------------------------------------------------
<S> <C> <C>
Life-Sustaining Antineoplastics, Antivirals 4.5%
Anticonvulsants, Thyroid, Cephalosporins, Antidiabetics,
Hematopoietic Agents, Opthalmic Products, Macrolides,
Quinolones, Antiasthmatics, Penicillins, Antipsychotics,
Misc. Anti-infectives, Tetracyclines, Antianxiety Agents,
Anticoagulants, Misc. Hematologicals, Antidepressants 31.5%
[UP-AND-DOWN Antiarrhythmics, Antiparkinsonians, Beta Blockers, Misc. GI
ARROW GRAPHIC] Agents, Antianginal Agents, Antihyperlipidemics, Diuretics,
Antihypertensives, Calcium Blockers, Ulcer Drugs, Unclassified 29.9%
Vaginal Products, Migraine Products, Anti-Rheum (NSAIDS),
Narcotic Analgesics, Hypnotics, Skel. Musc. Relaxants,
Dermatologicals, Cough/Cold, Decongestants, Antihistamines,
Estrogens 23.4%
Oral Contraceptives, Stimulants/Weight Loss, Misc. Endocrine
(includes Fertility Agents), Misc. Cardiovascular (includes
Life-Enhancing agents to treat Erectile Dysfunction), Antifungals, Misc. Psych. 6.3%
Other 4.4%
TOTAL 100.0%
</TABLE>
(13) Drug Topics, November 1, 1999.
42
<PAGE> 46
Some of these illnesses are controllable through exercise and diet, while
others can be treated with over-the-counter products.
- Consumers expect all prescription drugs should be available and accessible
and that employers or health plans should subsidize the cost of these drugs:
Most Americans look at the drug benefit as an entitlement. That is, many
Americans think they are guaranteed the right to receive any prescription
drug from any provider of their choosing and to have their employer or
relevant government program subsidize the cost of those pharmaceuticals. Just
as consumers began to react against MCOs for limiting access to providers and
types of services, so too are consumers beginning to actively express
dissatisfaction about their inability to access certain drugs not covered on
formulary. This discontent has forced MCOs to heavily market PPO plans and to
break away from closed formularies. In addition, several state legislatures
are considering measures to control what prescription drugs MCOs can exclude
from formulary coverage.
- Consumer demand is also stimulated by DTC advertising: IMS HEALTH and
Competitive Media Reporting estimate 1999 DTC spending for pharmaceuticals
was in excess of $1.85 billion, up from $969 million in 1997. Sixty-one
percent of these expenditures was for television ads, and 36 percent was for
magazine ads. The success of DTC advertising from the manufacturers point of
view is clear. According to a FDA-sponsored consumer survey, about 70 percent
of the respondents indicated they saw or heard an advertisement for a
prescription drug, and 86 percent thought the prescription drug ads "help
make me aware of new drugs."(14) Of those respondents who saw their
physicians in the previous three months, 23 percent either asked about
prescriptions or mentioned they had seen or heard prescription advertising.
Some even brought information about a drug to the physician's office. Half of
these people were given the prescription drug they asked about.
DTC ads can be a positive force in promoting health awareness. Of those
FDA-sponsored survey respondents who saw their physician in the past three
months, 51 percent thought that the DTC ads for prescription drugs "caused
(me) to look for more information for ... the drug or about (my) health," and
47 percent thought that these ads "help me make better decisions about my
health." Forty-one percent of respondents who had not seen their physicians
in the past three months responded in a similar fashion. On the other hand,
about 57 percent of all respondents thought DTC ads for prescription drugs
"make drugs seem better than they are," and about 58 percent thought these
ads "do not give enough information about the possible risks and negative
effects of using the drug."
DTC advertising is certainly not the only readily available source of medical
and pharmaceutical information. The proliferation of the Internet and the
multitude of Web sites that contain medical and drug information further
broaden access to data. With all this available information, more patients
are encouraged to take charge of their medical problems. This includes
becoming educated about one's illness, alternative ways of treating the
condition and the costs associated with these treatments, as well as feeling
free to ask physicians about the illnesses and how they plan to treat the
diseases. On the positive side, the more patients learn about their diseases,
the more likely patients will "own" the disease, including adhering to a
recommended regimen and altering lifestyle and behavior as needed.
(14) Attitudes and Behaviors Associated with Direct-to-Consumer(DTC) Promotion
of Prescription Drugs. Main Survey Results.
www/fda/gov/cder/ddmac/dtcindex.htm
43
<PAGE> 47
Empowering patients in this way presents great opportunities to enhance care
but has risks. How can a layperson sift through all of this information and
determine what articles or studies on a given topic are valid? How can one
guard against the purposeful or inadvertent inclusion of false or misleading
information on the Internet? How can the trailer advertisements promoting
various products be monitored to prevent misleading information from
appearing?
Faced with these underlying phenomena, plan sponsors or payers are faced with
the problem of how to finance ever-growing pharmacy costs. One strategy being
considered by employers is to get out of the business of providing healthcare
benefits altogether. This approach involves allowing each employee a fixed
amount of money to purchase his or her own healthcare coverage. Although this
tactic caps the employer's financial exposure, this tactic places the employee
in the difficult position of having to purchase health insurance without the
leverage of numbers enjoyed by an employer who is negotiating rates for many
lives. Without a government-mandated set of coverages, risk-pooling plans and
regulation of premiums, the employee may be unable to find affordable health
insurance with adequate coverage. Alternatively, if enough employers adopt this
tactic, the medical provider/insurance industry may fill this need. If so,
government likely would have to regulate these providers to ensure their
financial viability as well as the quality of care they deliver.
A second, more likely scenario has the employer moving toward a
defined-contribution approach. This strategy involves the employer offering its
workers multiple drug-coverage options but capping the employer contribution at
a set amount. This approach responds to consumer choice and at the same time
ties pharmacy use more directly to member financial responsibility. For example,
an employer could provide one coverage for all drugs, regardless of the type of
condition the drug treats, and another that excludes coverage of drugs for which
there are less expensive alternatives and for drugs used for cosmetic purposes.
In either case, the employer will contribute the same amount of money. The
employee selecting the richer benefit that includes all drugs or drugs that
treat cosmetic conditions pays the incremental costs attached to the coverage of
these drugs. This approach provides the employee open access to all drugs but
places part of the financial burden on the employee for his or her choices. One
important consideration that must be taken into account when adopting this
strategy is whether to maintain some element of insurance in the pricing
decision. A key assumption in insurance is that the price of the benefit should
be spread across both the healthy and sick or, put another way, between low and
high utilizers. This principle entails low utilizers subsidizing the costs of
high utilizers.
One approach to this insurance issue is to redefine how one looks at the drug
benefit. Instead of conceptualizing the drug benefit as an entitlement for all
employees and their dependents, the payer could design the benefit to address
primarily the needs of the sick. This strategy takes the point of view that a
drug benefit should focus primarily on subsidizing the financial burden of the
sick -- the high utilizers. In contrast, episodic, lower utilizers would be
expected to pay all or a significant portion of their drug costs. This approach
consists of abandoning the notion of first-dollar coverage and replacing it with
the medical indemnity practice of implementing a member deductible. After this
deductible is reached, the plan sponsor and member would share the financial
risk for an amount between the deductible and a predetermined amount
(stop-loss), after which the plan sponsor would pay the entire costs of drugs
used.
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<PAGE> 48
For instance, such a plan could take the following form. The plan sponsor offers
a drug benefit that covers a set list of drugs -- a drug formulary. In a given
plan year, each member is responsible for the first $100 of drug costs he or she
incurs, regardless of whether the drugs used were generics, preferred brands or
non-preferred brands. After this $100 deductible is met, the member is
responsible for paying, for example, $5 for each generic product, $15 for each
preferred product and $30 for each non-preferred product prescribed, up to an
out-of-pocket expense of $1,500. Once that member has paid $1,500 in the form of
the $100 deductible and copays, the plan sponsor will pay the entire cost of
drugs for the remainder of the plan year.
Under this scheme, for an average non-retiree population, roughly 35 percent of
the total plan population uses no prescription drugs and, therefore, would be
unaffected by any plan change (see Figure 12). An additional 30 percent has a
gross AWP spend of between $0.01 and $100, accounting for about 5 percent of
total plan population expenditures. This group would assume the entire financial
burden for its total prescription cost under a $100 deductible. The remaining
roughly 35 percent of the population would be subject to three-tier copayments
up to an out-of-pocket stop-loss of $1,500. Of this 35-percent segment, 15
percent spend between $100 and $250, representing about 10 percent of total plan
costs. The rest of the 20 percent of the population spends more than $250
annually and accounts for about 85 percent of total plan costs. Of this
population segment, 15 percent incurs between $250 and $1,000 in drug costs and
accounts for 30 percent of the total gross plan spend. The other 5 percent
spends more than $1,000 annually and represents 55 percent of total gross plan
costs. Under this scheme, approximately 1 percent of the plan population would
reach the out-of-pocket stop-loss level of $1,500.
FIGURE 12: PERCENT OF MEMBERS AND GROSS COST
[PERCENT OF MEMBERS AND GROSS COST BAR CHART]
In designing this type of catastrophic approach to the pharmacy benefit design,
the plan sponsor has to carefully consider the demographic and use pattern of
its members. The older the population, the higher their prescription drug use
and consequently their costs. Moreover, in setting deductible, copay and
out-of-pocket stop-loss amounts, the salary levels of their employees must be
considered. If these factors are set too high, those at the lower end of the
salary scale may
45
<PAGE> 49
be overly disadvantaged. This obstacle, at least to a degree, can be mitigated
by setting deductible and stop-loss amounts differentially for people in various
salary buckets. That is, people with lower salaries would have lower deductible
and stop-loss levels than those at the upper end of the pay scale. Given these
issues, employers may consider involving their employees in the design of such a
longer-term cost management strategy.
SHORT-TERM COST MANAGEMENT STRATEGIES
Payers can use a number of techniques in the short term to offset rising drug
costs. These techniques include actions aimed at controlling per-prescription
drug costs, reducing utilization of prescription drugs, and reducing both
prescription costs and utilization.
ACTIONS AIMED AT CONTROLLING PER-PRESCRIPTION COSTS
Although the payer community cannot directly influence manufacturer pricing,
individual payers can affect per-prescription costs by adopting particular
ground rules under which they will pay for drug products. Such strategies
include limiting the size of retail networks; and promoting the use of mail
service, mandatory generic programs, quantity limits, step therapy and
therapeutic switching.
Generally the deepest discounts payers can attain are through a mail service
pharmacy, which can capitalize on economies of scale to lower cost, with the
resulting savings being passed on to clients. Consequently, it would behoove the
payer to encourage members to have prescriptions that are used to treat chronic
disease filled through mail service. About 80 percent of Express Scripts members
have a choice of retail or mail order usage. On the retail side of the equation,
better discounts can be obtained in exchange for driving higher volume into
network stores. Consequently, a payer willing to limit the number of retail
pharmacies in its network can obtain deeper discounts from this limited network.
The plan sponsor can directly impact the per-prescription cost by controlling or
influencing the mix of products reimbursable under the drug plan benefit. In a
mandatory generic program, the member is required to pay the difference between
the price for a multi-source brand for which a generic is available and the
price for the generic equivalent. A mandatory generic program can be implemented
requiring the member to pay the difference only if the physician has indicated
that a generic can be substituted or regardless of whether the physician had
indicated that a generic can be substituted. The percentage of Express Scripts'
sample clients that adopted one of these mandatory generic programs grew from 40
percent in 1996 to about 47 percent in 1997 and 1998, and to 55 percent in 1999.
In both 1998 and 1999, 69 percent of HMO clients had a mandatory generic
program. In contrast, only 32 percent of non-managed care commercial clients had
such a program in 1998. This figure grew to 50 percent in 1999.
Excessive quantities per prescription can be controlled by implementing quantity
limits per copay. This strategy involves targeting products for which
prescriptions are prone to include quantities beyond what is suggested for
typical use. Depending on how aggressive the client is willing to be, limiting
the quantity per prescription can save between $0.10 and $0.20 per member per
month.
Additionally, managing drug choices within a therapeutic class has become a
viable alternative for reducing costs. Compared with the more indirect approach
of physician intervention and behavior changes, plans are opting to manage
utilization choices at the point of service. Requiring the
46
<PAGE> 50
participant/member to attempt a trial of a less expensive drug, such as a
generic, for a specified period of time before the plan will pay for the
originally prescribed medication, often referred to as "step-therapy,"
successfully reduces the cost of treatment, especially in short-term drug
therapies.
Therapeutic switching is another vehicle that can be used to reduce
per-prescription costs. Most formulary lists designate specified products as
preferred -- products that are at least as efficacious as non-preferred drugs
but that have the potential to provide the greatest level of net savings for the
plan. Increased use of these less expensive preferred drugs may be obtained if a
plan sponsor chooses to implement initiatives like those recommended in Express
Scripts' Drug Choice Management(SM) program. Such programs encourage physicians
and members to switch from more expensive products to less costly
therapeutically equivalent products. As connectivity between the PBM and the
physician's office becomes more widespread, real-time implementation regarding
formulary compliance and concurrent plan design edits will become a more
effective and less cumbersome method of implementing plan sponsor programs.
REDUCING UTILIZATION OF PRESCRIPTION DRUGS
A number of strategies can be employed to reduce utilization in a responsible
manner. One approach is simply to exclude cosmetics and other lifestyle drugs.
Most plans do exclude a variety of such products, but given the number of
lifestyle products that continually come to market, the list of excluded
products must be continually re-evaluated. Concurrent DUR programs include
online edits for duplicate therapies, drug interactions, too-early refills and
the like. Another concurrent program aimed at reducing unnecessary utilization
is prior authorization. Prior authorization programs require a patient be a
given age or have a documented diagnosis to receive a prescription for a
specific drug. Retrospective DUR programs also can be implemented. Such programs
are designed to identify issues pertaining to poly-pharmacy, drugs of concern
for specific age groups and questionable use of controlled substances.
Other types of initiatives can be adopted to assist payers that have a closed
panel of physicians. One such technique is to place the physician at some form
of risk for prescription drug costs. The 1999 Hoechst Marion Roussel Managed
Care Digest Series reports that the percentage of HMOs using capitation
reimbursement for primary care physicians (PCPs) dropped from 79.5 percent to
73.4 percent in 1998. The percentage of contracts associated with
fee-for-service payments has increased during the same time period. Some plans
have incorporated incentives for management of prescription drug costs into
risk-sharing contracts. Some of the larger at-risk physician groups have hired
pharmacists to help them manage the prescription drug risk. Challenges to
capitation and risk pools have emerged in some states through litigation and
proposed legislation to prohibit or modify these reimbursement techniques.
A strategy for promoting the appropriate use of drugs is to look at prescription
drugs within the context of overall health resources expended to treat a
specific disease. This requires integrated medical and drug data that can be
organized around disease states and that embed severity-of-illness measures in
the definition of disease state. This allows for physicians' practice patterns
to be analyzed in the context of their respective treatment/resource expenditure
patterns relative to their peers or to some agreed treatment protocols.
Physicians whose resource consumption, including prescription cost, is
significantly beyond the norm can be identified and counseled. Such tools, like
those developed by Express Scripts' Practice Patterns Science, are now available
in the marketplace.
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<PAGE> 51
Another strategy to encourage appropriate prescription drug use is disease
management, an approach that encompasses the comprehensive management of a
patient with a specific disease. Programs range from identifying patients who
have a given disease and sending them objective educational materials to active
intervention/contact and monitoring/evaluation of these patients on a regular
basis. The latter strategy necessitates not only the availability of data to
identify patients with those diseases but also the mechanisms to intervene.
A variety of companies, including Express Scripts, offer disease management
services and retrospective DUR programs. While ensuring that key disease states
are appropriately managed with medications is purported to promote better
outcomes, the drug costs within these diseases usually increase as they promote
appropriate utilization of medication. Retrospective DUR programs provided by
Express Scripts include those promoting compliance with and use of inhaled
steriods for asthmatics. Communications with physicians and members for disease
management and retrospective DUR programs will be greatly enhanced by the
availability of the Internet.
REDUCING PER PRESCRIPTION COSTS AND UTILIZATION
Persons who view prescription drugs as a virtually free good to which they are
entitled have little or no incentive to worry about the cost of that drug.
Consequently, one critical challenge facing the payer is to sensitize
participants/members to drug costs. The most direct way of accomplishing this
goal is to make the member financially responsible for part of the cost of the
medications consumed. Members who are not cost-sensitive have no reason to think
about whether they really need the prescription. Neither do they consider the
number of units of the drug needed vs. how many might be used or whether a less
expensive drug will yield the same clinical outcome as a more costly agent.
Member cost share directly affects the cost of every prescription covered by
plan sponsors. Every dollar the member pays for a drug is a dollar the payer
does not have to pay. Despite this fact, many plan sponsors do not regularly
adjust their member cost-share structure. The effects of holding member cost
share static can be dramatic. The average AWP cost per prescription grew by 49.3
percent between 1995 and 1999. As is shown in Figure 13, average
per-prescription costs rose for all but one of the top 25 therapy classes. These
increases appeared from commonly utilized gastrointestinal drugs to less-used
but very expensive antivirals. Payers that had constant member cost share levels
during this period had to bear the entire burden of these increases. Continuing
a trend seen since 1995, member share of cost for clients in this report
actually declined from 21.8 percent in 1995 to 20.8 percent in 1999. Member
share of cost decreased for both HMO and commercial clients -- from 24.2 percent
to 23.3 percent for HMOs and from 19.2 percent to 18.7 percent for commercial
clients. However, 1999 levels for both HMOs and commercial clients increased
slightly, 1 percent and 0.5 percent respectively, over 1998 levels.
The member share of cost generally takes the form of a front-end deductible, a
copay for every prescription dispensed or a limitation on the total amount of
drug costs for which the plan sponsor will pay over a year. The use of a
front-end deductible has declined somewhat in both the commercial and MCO
markets. About 5 percent of Express Scripts' clients have a front-end
deductible. For those with such plan designs, the average deductible for an
individual was about $60 and for a family $195.
48
<PAGE> 52
FIGURE 13: INCREASES IN AVERAGE PRESCRIPTION COST FROM
1995 TO 1999 BY THERAPY CLASS
[INCREASES IN AVERAGE PRESCRIPTION COST FROM
1995 TO 1999 BY THERAPY CLASS BAR CHART]
<TABLE>
<CAPTION>
1995 1999
<S> <C> <C>
Gastrointestinals $ 78.72 $ 106.60
Antidepressants $ 53.45 $ 72.55
Antihyperlipidemics $ 71.31 $ 82.37
Antihypertensives $ 35.16 $ 39.96
Anti-Rheum (NSAIDS) $ 39.62 $ 58.90
Antidiabetics $ 29.50 $ 51.57
Antihistamines $ 40.26 $ 54.48
Calcium Blockers $ 48.44 $ 54.79
Antiasthmatics $ 32.50 $ 46.96
Dermatologicals $ 28.87 $ 42.94
Antivirals $ 84.45 $ 194.25
Estrogens $ 15.36 $ 22.59
Narcotic Analgesics $ 14.09 $ 24.48
Oral Contraceptives $ 24.60 $ 31.17
Cough/Cold $ 16.20 $ 24.64
Macrolides $ 31.53 $ 40.90
Beta Blockers $ 28.16 $ 31.68
Cephalosporins $ 44.40 $ 49.64
Anticonvulsants $ 39.85 $ 66.73
Antianxiety Agents $ 24.21 $ 39.18
Penicillins $ 13.24 $ 22.26
Migraine Products $ 61.15 $ 124.28
Decongestants $ 33.94 $ 47.03
Misc. Endocrine $ 174.29 $ 110.71
Quinolones $ 61.03 $ 76.23
Other $ 21.34 $ 34.38
Total $ 31.32 $ 46.77
</TABLE>
* Antihypertensives include ACE Inhibitors, Angiotensin Receptor Blockers and
other antihypertensives.
** Dermatologicals include topical antifungal agents.
*** Decongestants include nasal corticosteroids.
Express Scripts clients, like other payers nationwide, have raised 1999 copay
levels more aggressively than in the past, particularly for branded products. In
the aggregate, between 1997 and 1998, MCO and commercial clients raised network
generic copays from $5.57 to $5.84 to $6.40 and copays for brands from $10.91 to
$11.60 to $12.61. MCO clients raised copays more than their commercial
counterparts. Generic copays went from $5.79 to $6.05 to $7.06 and copays for
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<PAGE> 53
brands from $11.22 to $11.91 to $14.84. Commercial clients raised their generic
copays from $5.07 to $5.40 to $6.73, and branded copays from $10.04 to $10.39 to
$12.20.
As pointed out earlier, despite these increases, payers lost some ground because
member share of cost did not keep pace with increases in the average cost per
prescription. Clients that have percentage member copays do not have to worry
about this inflation creep because the member automatically assumes a constant
percentage of that per-prescription cost increase.
Another opportunity to reduce cost and utilization is by augmenting a mandatory
generic program with a closed formulary, which limits the single-source drugs
for which the plan sponsor will pay. A payer can choose to exclude from coverage
more expensive branded products for which less costly therapeutic alternatives
are available. An even more aggressive strategy is to deny coverage for entire
classes of drugs, such as those to treat baldness or obesity. A payer adopting a
closed formulary must have medical override protocols to deal with instances in
which the physician determines that a patient must have the non-covered drug.
The amount of saving from this strategy is directly related to the degree of
restrictiveness of the formulary.
In the recent past, few payers adopted closed formularies that exclude
significant numbers of branded drugs from coverage. As consumers have
increasingly demanded access to all drugs, even fewer payers have chosen this
approach. To the contrary, more plans that had closed formularies are moving to
less restrictive approaches. One such approach is a three-tier copay plan. Under
this scenario, a member's copay is lowest for generics (tier one), somewhat
higher for preferred or neutral brands (tier two), and highest for expensive and
non-preferred branded products (tier three). Members desiring tier-three
products are not denied access to them as part of the covered benefit but
instead are charged a premium, in the form of a higher copay, for using those
products. This type of plan helps the payer either by inducing the member to use
less expensive brands (tier-two drugs) or generics (tier-one drugs) or by
allowing the payer to reduce costs for tier-three drugs through higher member
copays.
A three-tier copay plan has become more attractive to payers because the plan
sponsor still pays for the drug, albeit a lesser amount, making it perhaps more
marketable than a closed formulary. A plan moving from a $5/$10 copay structure
to a three-tier plan at $5/$10/$25 structure can save between 7 percent and 8
percent of its overall drug cost. According to the Scott-Levin 1999 Managed Care
Formulary Drug Audit, the percentage of MCOs offering a three-tier copay
structure rose from 36 percent in the spring of 1998 to 52 percent by the fall
of 1998 to 67 percent in the fall of 1999. According to the Scott-Levin
findings, the average three-tier copayment system is $6.63 for generics, $13.94
for formulary branded drugs and $28.32 for non-formulary drugs. For clients
choosing a three-tier copay approach, care should be taken to not set the
third-tier copay level so high as to dissuade members from having essential
prescriptions filled or refilled, a situation that could result in emergency
room or inpatient admissions.(15) Thus, the levels at which copays are set must
take into account the family income of the covered membership and the types of
drugs placed on the third tier.(16)
(15) Roe, C.M. "Have You Been Taking Your Medications?" Proceedings of the
1999 Express Scripts, Inc. Outcomes Conference.
(16) Fairman, K. A., Motheral, B.R. and Teitelbaum, F. "One Size Fits Most:
Commercially Insured Enrollees Respond to a Three-Tier Drug Copayment,"
Presented at Managing the Pharmacy Benefit, Tucson Arizona, January 27,
1999.
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<PAGE> 54
Some clients have initiated or are contemplating a four-tier copay system. This
approach essentially is a variant of a closed formulary in that the member must
pay 100 percent of the costs for some drugs. As in a three-tier system, there
are three escalating copay amounts for generics, preferred brands and
non-preferred brands. However, there is a group of drugs that are placed on a
fourth tier. The member is responsible for paying the total cost of all of these
fourth-tier products. The marketing spin on this strategy is that all drugs are
accessible but the member copay varies according to which drugs the member
chooses. The advantage to members is that they benefit from the negotiated
discounts for the tier-four products. Another variation of a four-tier copay
system is to cover these fourth-tier drugs but charge the member a substantial
copay, 50 percent-75 percent, of the cost of these products.
Regardless of the method employed, payers have been and will continue to pass
along to patients an ever-growing financial contribution for the prescription
drugs consumers take for granted as being readily accessible and inexpensive.
Depending on how the financial shift is accomplished, those who can least
financially afford to pay this extra amount might be forced to do without
much-needed medications. Consequently, payers must carefully consider the
demographic makeup of their employees and their dependents, as well as the types
of drugs that may be placed on a third tier.
SUMMARY
This report is the fourth edition of the Drug Trend Report published by Express
Scripts. The purposes of this series are to:
- Describe the drug cost trends payers have confronted over the past five
years
- Delineate primary factors underlying these trends
- Project future levels of drug increase that payers can expect
- Discuss the various tools payers can adopt to mitigate anticipated cost
escalation
The fourth edition of this Report generally reaffirms many of the conclusions
reached in earlier editions. Over the next five years, Express Scripts expects
drug costs to rise. However, after 2000, Express Scripts projects the rate of
increase in costs to decline to about 12 percent. This decline in the rate of
growth largely is a function of reduced inflation rates as pharmaceutical
manufacturing adapts to the political environment over the next several years.
In general, however, PMPY drug costs will continue to rise because of:
- The availability of newer, clinically superior, more expensive medications
- Growing numbers of consumers who:
- Look to drug therapy as a substitute for lifestyle changes, as a way of
enhancing quality of life and as a "fix" for cosmetic blemishes
- Expect drugs to be readily accessible and subsidized by their employers
or health plans
- The superior marketing prowess of pharmaceutical manufacturers
In turn, payers are facing the difficult challenge of financing these growing
bills. As a result, plan sponsors are being forced to ask their employees and
dependents to be part of the solution by paying for a larger share of drug
costs. While in the short-run, most payers will simply raise co-pays or
implement three-tier copay plans, in the longer term, many plan sponsors will be
forced to
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re-evaluate the nature of the pharmacy benefit. The next generation of pharmacy
benefit plans may well be based on a new philosophy that the drug benefit should
be focused more on subsidizing the costs of the sicker people. The approach is a
throwback to the fee-for-service indemnity plans that had a deductible instead
of first-dollar coverage. Alternatively, plan sponsors may opt to address the
member choice preference and adopt a defined-contribution strategy with the
member given a choice between the drug plans. Payers adopting this approach must
carefully consider how to price such options given the measurable principle that
healthier people should subsidize the costs of sicker people.
In considering what cost management approach to take, employers must balance the
goal of cost trend reduction against employee retention issues in today's labor
market. In this environment, the pharmacy benefit is viewed as an important part
of the employee compensation package. Thus, employers may have to adopt less
aggressive short-term cost management techniques such as those described above.
However, as pharmacy cost pressures mount or the economy dips, employers must
begin to think through the longer-term strategies they may need to adopt.
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Drug Therapy
Class Review
APPENDIX A
53
<PAGE> 57
DRUG THERAPY CLASS REVIEW
The top 25 therapy classes ranked by cost account for about 80 percent of total
AWP prescription expenditures. The data in Appendix A describe the cost and
utilization trends for these classes since 1995. The discussion of these therapy
classes focuses primarily on changes that took place between 1998 and 1999 and
highlights drugs in the pipeline that are likely to have a significant impact on
these classes over the next several years. The data included in this Appendix
include all drugs, both common and new.
TABLE A1: COST PER PRESCRIPTION AND PMPY COST
FOR MAJOR THERAPY CLASSES 1998-1999
<TABLE>
<CAPTION>
1998 1999 % 1998 1999 %
THERAPY CLASS AWP/RX AWP/RX CHANGE $ PMPY $ PMPY CHANGE
<S> <C> <C> <C> <C> <C> <C>
Gastrointestinals $ 97.68 $106.60 9.1% $ 28.53 $ 34.23 20.0%
Antidepressants $ 67.87 $ 72.55 6.9% $ 28.31 $ 33.68 19.0%
Antihyperlipidemics $ 80.49 $ 82.37 2.3% $ 21.64 $ 26.17 20.9%
Antihypertensives $ 38.63 $ 39.96 3.4% $ 18.13 $ 20.37 12.3%
Anti-Rheum (NSAIDS) $ 47.62 $ 58.90 23.7% $ 12.88 $ 17.93 39.2%
Antidiabetics $ 46.36 $ 51.57 11.2% $ 12.12 $ 14.82 22.2%
Antihistamines $ 51.24 $ 54.48 6.3% $ 11.10 $ 13.96 25.8%
Calcium Blockers $ 52.98 $ 54.79 3.4% $ 13.41 $ 13.77 2.7%
Antiasthmatics $ 43.89 $ 46.96 7.0% $ 12.25 $ 13.67 11.6%
Dermatologicals $ 37.48 $ 42.94 14.6% $ 10.29 $ 11.79 14.6%
Antivirals $159.06 $194.25 22.1% $ 7.36 $ 10.29 39.9%
Estrogens $ 20.44 $ 22.59 10.5% $ 8.29 $ 9.59 15.7%
Narcotic Analgesics $ 20.23 $ 24.48 21.0% $ 7.05 $ 9.24 31.1%
Oral Contraceptives $ 29.28 $ 31.17 6.4% $ 8.07 $ 9.18 13.7%
Cough/Cold $ 22.96 $ 24.64 7.3% $ 7.46 $ 9.03 21.1%
Macrolides $ 38.93 $ 40.90 5.0% $ 6.88 $ 8.18 19.0%
Beta Blockers $ 30.52 $ 31.68 3.8% $ 6.92 $ 7.70 11.2%
Cephalosporins $ 47.17 $ 49.64 5.2% $ 7.38 $ 7.65 3.8%
Anticonvulsants $ 58.71 $ 66.73 13.7% $ 5.52 $ 7.13 29.0%
Antianxiety Agents $ 36.40 $ 39.18 7.6% $ 6.22 $ 6.96 11.9%
Penicillins $ 19.14 $ 22.26 16.4% $ 5.69 $ 6.78 19.2%
Migraine Products $112.68 $124.28 10.3% $ 5.50 $ 6.40 16.3%
Decongestants $ 43.27 $ 47.03 8.7% $ 5.43 $ 6.38 17.5%
Misc. Endocrine $112.17 $110.71 -1.3% $ 3.86 $ 5.31 37.4%
Quinolones $ 69.55 $ 76.23 9.6% $ 3.97 $ 4.97 25.2%
Other $ 30.74 $ 34.38 11.9% $ 65.29 $ 71.92 10.2%
TOTAL $ 42.68 $ 46.77 9.6% $329.83 $387.09 17.4%
</TABLE>
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<PAGE> 58
GASTROINTESTINALS
For decades, research on conditions affecting the gastrointestinal (GI) tract
has centered on the treatment of Peptic Ulcer Disease (PUD) and Gastroesophageal
Reflux Disease (GERD). PUD occurs when breaks in the mucous lining of the
stomach -- gastric ulcers -- or upper intestines (duodenum) create places that
are damaged by stomach acids. Typically, ulcers cause burning pain in the
abdomen. The discovery that a bacteria known as Helicobacter pylori causes
ulcers completely revolutionized ulcer treatment and dramatically reduced the
need for continuing maintenance therapy. The most typical sign of GERD is
heartburn, the irritation caused when stomach contents flow backward into the
esophagus. Untreated, chronic inflammation of the esophagus can cause more
serious conditions including cancer. Treatment for GERD may last months or even
years.
Although the same drug classes are used to treat ulcers and GERD, dosing and
length of therapy can differ greatly. Proton Pump Inhibitors (PPIs) are rapidly
replacing histamine-2 blockers (H2RAs) as the most used prescription GI
medications. Another class used much less often for GI conditions is called
promotility agents or GI stimulants. These drugs speed up gastric emptying time
so stomach acid has less chance to damage exposed tissue. Because of severe side
effects, Propulsid(R), the most widely used promotility product, was recently
taken off the market.
In 1999, guidelines for the treatment of GERD were updated by a committee of the
American College of Gastroenterology. Taking into account the OTC status of
low-dose versions of the H2RAs, which were available only by prescription when
the original guidelines were issued in 1995, the recommendations now include
more information on patient-directed therapies in addition to the use of
prescription drugs.
FIGURE A1: THERAPY CLASS DRUG MARKET SHARE TREND
GASTROINTESTINALS
[THERAPY CLASS DRUG MARKET SHARE TREND
GASTROINTESTINALS LINE CHART]
Drugs used to treat GI diseases are the most costly, as well as some of the most
widely used. In 1999, the PMPY costs for GI products grew to $34.23, 20 percent
over 1998 levels, despite utilization increases of only 10 percent. The
substantial rise in costs for this class owes to the dramatic shift away from
less expensive H2RAs to PPIs.
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<PAGE> 59
- Until recently, Zantac(R) (ranitidine) dominated this class with a 39
percent market share in 1994. Consequently, when Zantac(R) went generic a
couple of years ago, many thought that the cost of this class would at least
remain somewhat stable. This hypothesis proved untrue as the more expensive
PPIs, Prilosec(R) (omeprazole) and the newer product, Prevacid(R)
(lansoprazole), came to dominate the GI market. Between 1998 and 1999, these
products together grew in share from 46.4 percent to 55.5 percent primarily
at the expense of generic ranitidine and branded H2RA products Pepcid(R)
(famotidine) and Axid(R) (nizatidine).
- This shift to more expensive PPIs has resulted in higher PMPY costs for this
class. The 1999 average AWP per prescription costs for Prilosec(R) and
Prevacid(R) increased by 6.2 percent and 5.5 percent, respectively, to
$139.57 and $125.56. In contrast the average 1999 AWP cost for ranitidine
was $84.94.
- The third PPI to become available in the United States, Aciphex(R)
(rabeprazole), was approved in August and marketed in fourth quarter 1999.
Aciphex(R) is indicated for the treatment of gastric ulcers, duodenal
ulcers, gastroesophageal reflux disease and hypersecretory conditions.
FUTURE TRENDS
- On Dec. 6, 1999, a new drug application (NDA) was filed for Nexium(R)
(esomeprazole -- previously called perprazole). One of omeprazole's isomers,
Nexium(R) is a second-generation PPI expected to have more predictable
activity against GERD, reflux esophagitis and duodenal ulcers.
- Approved on Feb. 3, 2000, to treat erosive esophagitis, Protonix(R)
(pantoprazole) was expected to be launched in second quarter 2000. Other
indications are still under FDA consideration. Protonix(R) is presently the
only PPI to come in both oral and IV forms.
- Despite an extension, the U.S. patents for some Prilosec(R) indications will
begin to expire in 2001.
- Generic forms of Pepcid(R) are due in 2000 and of Axid(R) in 2002. Both of
these H2RAs are already available in reduced-strength OTC versions.
- The number of drugs available for Irritable Bowel Syndrome (IBS) and for
Inflammatory Bowel Diseases (IBDs), such as Crohn's Disease and ulcerative
colitis, is growing since the 1998 approval of Remicade(R) (infliximab), a
monoclonal antibody for Crohn's Disease. Lotronex(R) (alosetron), was
approved in February 2000 for treating IBS in women whose primary symptom is
diarrhea. The following week an NDA was filed for Zelmac(R) (tegaserod),
representing a new class of agents that affects 5HT-4 receptors in the GI
tract. Zelmac(R) improves GI motility to relieve constipation and may
diminish the perception of pain as well. A number of other products are
currently in development.
CENTRAL NERVOUS SYSTEM
Designated the "Decade of the Brain" by the National Institute of Mental Health
(NIMH) and the Library of Congress, the 1990s produced significant research
results that increased understanding of both the structure and the functions of
the central nervous system (CNS). Conditions affecting the brain and spinal
column include pain, depression and anxiety, as well as epilepsy. The number of
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<PAGE> 60
medications available for these conditions has increased significantly in the
past several years. Additionally, new classes of drugs are being developed for
previously untreatable conditions like Alzheimer's Disease, Multiple Sclerosis
(MS) and Amyotrophic Lateral Sclerosis (ALS). As scientists understand more
about the substances and processes involved in normal nerve function, the
scientists are beginning to discover new techniques that will potentially
restore function to damaged nerves.
ANTIDEPRESSANTS
Prescription medications used to treat depression enhance the activity of one or
more neurotransmitters -- chemicals that facilitate electrical signals along
nerve cells. The three principal neurotransmitters involved in depression are
dopamine, norepinephrine and serotonin. Newer antidepressants called selective
serotonin reuptake inhibitors (SSRIs) have fewer side effects than tricyclics
(TCAs) and monoamine oxidase inhibitors (MAOIs).
Expenditures for antidepressants have grown at a substantial rate as the use of
more costly SSRIs -- Prozac(R) (fluoxetine), Paxil(R) (paroxetine), Zoloft(R)
(sertraline) and Celexa(R) (citalopram) -- has increased dramatically. To a
lesser extent, use of equally expensive SNRIs -- Serzone(R) (nefazodone) and
Effexor(R) (venlafaxine) -- has increased, as well.
FIGURE A2: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIDEPRESSANTS
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIDEPRESSANTS LINE CHART]
- PMPY costs for antidepressants continued to grow, rising by 19 percent to
$33.68 in 1999. Most of this growth is attributable to the 11.3 percent
increase in the use of drugs in this class. Utilization of Prozac(R), which
peaked at 27.4 percent market share in 1994, continued its decline to 19.9
percent in 1999. Market shares of the other older SSRIs -- Zoloft(R) and
Paxil(R) -- remained stable at a combined 1998 market share of 31.4 percent,
while the use of the newer agent, Celexa(R), grew to 4.8 percent; the
combined market share of Effexor(R) and Effexor(R) XR rose to 6.1 percent.
The product whose market share has grown the most -- from 2.5 percent in
1997 to 7.0 percent in 1999 -- is Wellbutrin(R) SR (bupropion, extended
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<PAGE> 61
release). The primary reason for the growth is its off-label use as a
smoking cessation tool, despite the availability of OTC products and of
Zyban(R) (bupropion, extended release), which is not covered by many health
plans.
FUTURE TRENDS
- Although no new SSRIs have been approved for several years, most activity in
the antidepressant area centers on new indications or dosages for SSRIs.
Zoloft(R) has been given a new indication for post-traumatic stress
disorder. Paxil(R) is now indicated for social phobia, and an additional NDA
has been filed for its use in generalized anxiety disorder. The makers of
Luvox(R) received a six-month extension of the original December 1999
expiration date because they are conducting studies in a pediatric
population. Prozac(R) has been granted a new indication for the treatment of
depression in geriatric patients. It is also under FDA review for
premenstrual dysphoric disorder and for pediatric depression. A separate
application for approval of a once-weekly 60mg dosage of Prozac(R) was filed
with the FDA in March 2000. The FDA has already given tentative approval for
generic fluoxetine in 10mg and 20mg strengths, but ongoing lawsuits are
delaying introduction of the generic -- perhaps by as much as two years.
- The patent for immediate-release Wellbutrin(R) (bupropion) in the treatment
of anxiety expired in 1999. Generic 75mg and 100mg bupropion tablets are
being marketed in the United States. Extended-release bupropion, already
reformulated to Zyban(R) for smoking cessation, is also under investigation
for effectiveness in bipolar disorder. To further extend the brand-name
line, an application for a transdermal bupropion patch has been submitted
for approval in the treatment of anxiety and attention deficit disorder
(ADD).
- A selective norepinephrine reuptake blocker, Vestra(R) (reboxetine mesylate)
has been under FDA review since 1998. On Feb. 23, 2000, the FDA issued a
second approvable letter for Vestra(R) but also requested that an additional
clinical trial be conducted to clarify inconsistent results from earlier
studies.
- Patents for Serzone(R) expire early in 2003.
- R-fluoxetine, the active isomer of Prozac(R) will continue clinical trials
for at least another year.
- A modification of the monoamine oxidase inhibitor (MAOI) class of
antidepressants resulted in a group called reversible inhibitors of
monoamine oxidase type A (RIMAs). Approved in several countries around the
world, RIMAs produce enzyme modulation that is not permanent. In addition,
RIMAs are much more selective than MAOIs, and they do not cause the side
effects associated with either MAOIs or TCAs. RIMAs seem, however, to be as
effective as other drug classes in the treatment of depression. At least one
RIMA, Manerix(R) (moclobemide), is in U.S. clinical trials.
ANTIANXIETY AGENTS
Pharmacologic treatment for anxiety can be complex -- often because more than
one type of anxiety can be experienced at the same time. Patients with anxiety
may also suffer from depression. Both conditions
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<PAGE> 62
FIGURE A3: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIANXIETY A GENTS
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIANXIETY A GENTS LINE CHART]
can have psychological causes as well as physical ones. Benzodiazepines,
antidepressants, anticonvulsants and a unique agent, BuSpar(R) (buspirone), are
commonly used to treat various types of anxiety.
- Similar to the pattern seen between 1997 and 1998, PMPY cost rose by 11.9
percent in 1999, although PMPY utilization increased by only 3.9 percent.
- The generics market share continued to increase in 1999 to 82.6 percent.
- Effexor XR, was approved in March 1999 for the treatment of generalized
anxiety disorder.
FUTURE TRENDS
- BuSpar(R) will go off patent for its anxiety indication in 2000.
INFLAMMATION AND PAIN MANAGEMENT
New procedures allow researchers to track very precisely the ways that pain
signals progress through the body. Although chronic and acute pain follow
different specific routes, all pain signals travel along the same general
pathway. In response to neurotransmitters, which are chemicals released at the
site of injury or inflammation, pain impulses move through nerve cells -- also
called neurons -- to the spinal cord. After gathering momentarily at the dorsal
horn, a type of central switching facility in the spinal cord, pain travels up
the spinal cord and through the thalamic region of the brain until it finally
reaches the cerebral cortex where it is actually perceived. Blocking any of the
chemicals, channels or receptors involved in transmitting pain can potentially
interrupt the signals and, therefore, relieve pain.
FUTURE TRENDS
- An NDA for ziconotide, the first in a new class of pain relievers called
neuronal calcium channel blockers, was submitted in December 1999. The FDA
not only accepted this application in February 2000 but also promised to
make a decision regarding its approval by September.
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If approved, ziconotide will be administered directly into the area
surrounding the spinal cord to treat intense chronic pain that has been
unresponsive to other therapies.
- ABT-564, an experimental drug derived from the skin of poisonous frogs,
seems to produce analgesic effects without the addiction and withdrawal
problems associated with narcotics. This may be due to the fact that ABT-564
attaches to nicotine receptors instead of the opiod receptors that are
affected by narcotics.
- Still in early stages of development, Prosaptides(R) are a group of peptides
derived from natural proteins that affect damaged nerve tissues in a number
of positive ways. Prosaptide(R) TX14a, the most advanced drug in this new
therapy class, is in Phase II clinical trials for the treatment of
neuropathies and pain resulting from the complications of diabetes and other
conditions.
- Scientists are also studying the pain controlling aspects of drugs that have
already been approved for the treatment of other conditions. An example is
the use of Botox(R), a refined injectable form of the toxin that causes
botulism. Currently used in the treatment of strabismus and blepharospasm,
conditions that affect the eye, Botox(R) is now being studied for use in
migraine headaches, back pain, whiplash and temporomandibular joint (TMJ)
disorder. Remicade(R) (infliximab), a monoclonal antibody originally
approved to treat the intestinal disorder Crohn's Disease, has now been
approved for use in rheumatoid arthritis (RA). Duraclon(R) (clonidine
hydrochloride injection), a higher dose injectable form of an alpha blocker
that is used orally for hypertension and benign prostatic hyperplasia, has
orphan indications in the treatment of severe pain as well.
ANTI-RHEUM (NSAIDS AND COX-2S)
Non-steroidal anti-inflammatory drugs (NSAIDs) relieve pain by suppressing
production of prostaglandins. As a side effect, NSAIDs can cause GI problems
because they interfere with cyclo-oxygenase 1 (COX-1), an enzyme that helps to
preserve the lining of the stomach. Cyclo-oxygenase 2 enzyme blockers (COX-2s)
work by blocking a specific enzyme involved in pain but not affecting COX-1.
Celebrex(R) (celecoxib) and Vioxx(R) (rofecoxib) are the two COX-2s available in
the United States. Already used for several types of pain, COX-2s are also
likely to receive a flood of new indications. Celebrex(R) is already approved
for familial colonic polyps, a predisposing factor in the development of colon
cancer. Still under investigation are the apparent protective effect of NSAIDs
against Alzheimer's Disease and their possible use in irritable bowel syndrome,
urinary incontinence and the complications of diabetes.
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FIGURE A4: THERAPY CLASS DRUG MARKET SHARE TREND
ANTI-RHEUM (NSAIDS AND COX-2S)
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTI-RHEUM (NSAIDS AND COX-2S) LINE CHART]
- Anti-inflammatories represent the second fastest growing class in 1999,
increasing by 39.2 percent to $17.93.
- This dramatic cost increase was driven primarily by the use of newly
introduced more expensive COX-2 products Celebrex(R) and Vioxx(R). Costing
an average AWP per prescription of $84.93 and $75.97, respectively,
Celebrex(R) and Vioxx(R) captured a combined 18.9 percent market share. In
contrast, generic ibuprofen at an average cost of $14.05 and generic
naproxen at $49.83 saw their combined market share decline from 43.4 percent
in 1998 to 39.4 percent in 1999.
- The combined market share for Relafen(R)(nabumetone), Lodine(R)(etodolac),
Lodine(R)XL (etodolac extended-release) and Daypro(R) (oxaprozin), all
branded products, dropped from 20.4 percent to 14.3 percent between 1998 and
1999.
FUTURE TRENDS
- Mobic(R) (meloxicam), is a new NSAID that was approved for osteoarthritis
(OA) in April 2000.
- Patent protection is running out for Daypro(R) in 2000 and for Relafen(R) at
the end of 2002.
- COX-2s in late stages of development are parecoxib, an injectable product
for the management of acute pain; valdecoxib for pain and arthritis; and
MK-663 for OA.
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NARCOTIC ANALGESICS
In the past, the fear that people who take narcotics may develop addictions or
abuse the medications has kept many physicians from prescribing narcotics for
chronic non-terminal pain. Attitudes about the use of narcotics are changing,
however, and long-term narcotic prescriptions for patients outside of care
facilities are becoming more common.
FIGURE A5: THERAPY CLASS DRUG MARKET SHARE TREND
NARCOTIC ANALGESICS
[THERAPY CLASS DRUG MARKET SHARE TREND
NARCOTIC ANALGESICS LINE CHART]
- After growing 20.6 percent between 1997 and 1998, overall PMPY cost for
narcotic analgesics continued its rapid ascent, rising 31.1 percent in 1999
to $9.24.
- PMPY utilization for this class grew by 8.3 percent. In contrast the average
prescription cost rose by 21 percent. Per prescription cost increases of 25
percent were seen for generics, which accounted for 77.4 percent of the
total class market share. In 1999 Ultram(R) (tramadol) held its leading
position among branded products with a 7.1 percent share of the market.
- The nasal drug Stadol(R) NS (butorphanol nasal spray), reclassified as a
controlled substance in 1998, is expensive (averaging $123.46 per
prescription). At only 0.8 percent of the market share, though, it shows a
low level of use.
- Percocet(R) (acetaminophen and oxycodone) is now available in four strengths
-- making doses easier to adjust but also creating a greater potential for
mistakes in both prescribing and dispensing.
FUTURE TRENDS
- Dirame(R) (propiram) is an oral opiate that is close to NDA filing for
moderate to severe pain.
- A skin patch that would deliver steady and controlled doses of marijuana is
under research. Still in the preclinical stage of development, the marijuana
patch is many years from realization. It would potentially stimulate
appetite as well as relieve pain for people who suffer from chronic painful
conditions.
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MIGRAINE PRODUCTS
Approximately 12 percent of adults in the United States experience migraine
headaches. Caused when blood vessels in the brain expand and become inflamed,
migraine pain is often accompanied by nausea and sensory disturbances. In the
1990s, migraine treatment underwent a radical shift from older ergotamine-based
drugs to more effective and more potent 5-hydroxytriptamine receptor agonists --
commonly referred to as "triptans." Developed to affect specific serotonin
receptors in the brain, all triptan drugs reduce inflammation and swelling in
cranial arteries. In addition, triptan drugs reduce the excitability of certain
cells in the brainstem and constrict various blood vessels in and around the
brain. People with heart disease should use triptans only with a great deal of
caution because these drugs also constrict coronary arteries. All the triptans
produce milder side effects -- the so-called triptan sensation -- which involves
flushing, tingling, anxiety and feelings of tightness in the chest or throat.
FIGURE A6: THERAPY CLASS DRUG MARKET SHARE TREND
MIGRAINE PRODUCTS
[THERAPY CLASS DRUG MARKET SHARE TREND
MIGRAINE PRODUCTS LINE CHART]
- The PMPY cost of migraine products rose 16.3 percent from $5.50 in 1998 to
$6.40 in 1999.
- The market share for Imitrex(R) (sumatriptan injection, nasal spray and
tablets) continued to decline in 1999, dropping from 60.1 percent in 1998 to
52.0 percent in 1999. Lost market share has gone to Zomig(R) (zolmitriptan),
Amerge(R) (naratriptan) and Maxalt(R) (rizatriptan), which saw their
combined market share increase from 7.4 percent in 1998 to 19.0 percent in
1999.
- Motrin(R) Migraine Pain became the second OTC product to be labeled
specifically for the treatment of migraine headaches. It contains 200mg of
ibuprofen -- the same active ingredient as regular Motrin(R). A migraine
indication is also being sought for another non-prescription product,
Advil(R) (ibuprofen).
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FUTURE TRENDS
- Major news in the area of migraine headache treatment continues to center on
triptans. An approvable letter was issued in October 1999 for another oral
triptan, Relpax(R) (eletriptan). Expected to be introduced in 2000,
Relpax(R) would be the fifth product of its type to be made available for
the U.S. market. Another triptan, Miguard(R) (frovatriptan), was declared
"approvable" by the FDA in May 2000. Miguard(R) has a longer duration of
effectiveness than the other triptans, so it may prevent the rebound
headaches that affect up to 40 percent of patients treated with triptans. An
NDA has been filed for yet another triptan medication, Axert(R)
(almotriptan).
- In other research, an anticonvulsant medication, Depakene(R) (valproic
acid), prevented migraine attacks or sharply decreased their frequency among
patients in study groups. Depakote(R) (sodium valproate), a medication
closely related to Depakene(R), already has FDA approval for migraine
prevention. Neurontin(R) (gabapentin), another antiepileptic drug, shows
effectiveness in preventing or alleviating migraine attacks, as well. Other
drug classes that have been used successfully to prevent migraines are beta
blockers, calcium channel blockers and antidepressants.
- In ongoing trials, Botox(R) (botulinum toxin type A) has shown reductions in
both severity and frequency of migraines for approximately three months
after being injected directly into the foreheads of migraine sufferers.
Botox(R) is a neurotoxin that is already approved for certain conditions
that affect the eye. Botox(R) not only has orphan drug status in a number of
other neuromuscular conditions, it is also being studied for other types of
headaches as well as for other chronic pain syndromes.
- A fairly rare type of migraine appears to be caused by distinct genetic
mutations, leading researchers to speculate that other kinds of migraine may
also have hereditary causes. Other very preliminary studies seem to indicate
a link between migraines and H. pylori, the bacterium that causes stomach
ulcers. Additional research is needed in both areas, however, before any
cause and effect can be determined.
ANTICONVULSANTS
Seizures or convulsions result from many different causes, the most common being
epilepsy. Defined as a recurring disturbance of cerebral function, epilepsy
generally is characterized by sudden, usually brief interruptions of
consciousness, movement or sensory perception. Distinctly different types of
epilepsy are classified by the kind of seizures experienced. The majority of
people with epilepsy cannot identify one single cause of the condition. In other
cases, seizures result from stroke, infection, head injury, high fever,
congenital defects, metabolic abnormalities, brain tumors or CNS lesions.
Several classes of medications are used to prevent, abort or alleviate seizures.
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FIGURE A7: THERAPY CLASS DRUG MARKET SHARE TREND
ANTICONVULSANTS
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTICONVULSANTS LINE CHART]
- Anticonvulsant PMPY costs increased to $7.13 in 1999 -- a 29.0 percent rise
from 1998 due to increases in both use and cost per prescription.
- Neurontin(R) (gabapentin) continued to gain market share -- attaining a 17.1
percent level in 1999, while market share for generic products also grew to
29.1 percent. However, some generics may not be absorbed in the same ways as
their branded counterparts.
- The market share for Depakote(R), Dilantin(R)(phenytoin),
Tegretol(R)(carbamazepine), Tegretol(R) XR (carbamazepine extended release)
and Klonopin(R) (clonazepam) declined from 54 percent in 1998 to 45.2
percent in 1999.
- Of products with market shares above 4 percent, the average change in
prescription cost of Dilantin(R), Klonopin(R) and generic products was
virtually flat, while costs for Tegretol(R) XR, Depakote(R), Tegretol(R) and
Neurontin(R) rose by 11.3 percent, 7.7 percent, 7.7 percent and 3.7 percent
respectively.
FUTURE TRENDS
- A new antiepileptic medication that could be very promising is Keppra(R)
(levetiracetam). Approved in December 1999 for combination therapy in adults
with partial seizures, Keppra(R) has not shown any significant interactions
with other drugs, including other epilepsy medications.
- Zonegran(R) (zonisamide) has also been approved. An oral drug unrelated to
other anticonvulsants, Zonegran(R) is indicated for combination therapy in
adults with partial seizures.
- Neurontin(R) goes off patent in 2000.The makers of Neurontin(R) have
introduced new, higher dose tablets that simplify dosing regimens.
Neurontin(R) continues to be used extensively for the treatment of chronic
pain -- not yet an FDA-labeled indication.
- Trileptal(R)(oxcarbazepine) was approved Jan. 17, 2000, as monotherapy for
partial seizures in
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adults. It is also indicated as adjunctive therapy in adults and children 4
and older. In clinical trials, Trileptal(R) had fewer interactions and side
effects than older counterparts.
- A potentially important antiepileptic drug called pregabalin is in Phase III
clinical trials for both epilepsy and pain indications. Similar to
Neurontin(R), pregabalin may be marketed in the United States as early as
2001.
- In Europe, several anticonvulsants, including gabapentin, are in late stages
of clinical trials for bipolar disorder.
CARDIOVASCULAR
The multitude of conditions that can affect the heart and blood vessels has
prompted the discovery of drugs that act directly or indirectly to lower blood
pressure, improve heart function, relieve irregular heartbeats or reduce the
amount of cholesterol in the blood. Angiotensin-converting enzyme inhibitors
(ACEIs), angiotensin receptor blockers (ARBs), beta blockers, calcium channel
blocker (CCBs) and antihyperlipidemics are all discussed separately. Other kinds
of heart drugs include diuretics that reduce fluid load to relieve stress on the
heart; digitalis, which improves the pumping of the heart; nitrates that relieve
angina by relaxing the muscles in blood vessels; and anticoagulants, which
prevent blood clotting.
Aldactone(R) (spironolactone), a potassium-saving diuretic that has been in use
for years, gained new popularity as the result of 1999's RALES (Randomized
Aldactone(R) Evaluation Study). The progression of heart failure was prevented
so well in RALES participants that the study was stopped early.
New guidelines for the management of chronic stable angina written by a joint
task force of the American College of Cardiology and the American Heart
Association were published in June 1999. Among other recommendations, the
guidelines suggest the use of aspirin or beta blockers as first-line therapy to
prevent heart attacks in angina patients who have no contraindications.
Extended-release CCBs are the choice for patients who cannot take aspirin or
beta blockers.
In October 1999, an anti-arrhythmic agent, Tikosyn(R) (dofetilide), became the
first oral therapy in 10 years to receive FDA approval for atrial fibrillation.
A selective potassium channel blocker that can cause paradoxical arrhythmias,
Tikosyn(R) will be prescribed only by physicians who have completed specialized
training.
FUTURE TRENDS
- Concerns about possible side effects -- including angioedema -- prompted the
manufacturer of Vanlev(R) (omapatrilat) to withdraw the NDA. Vanlev(R) is a
vasopeptide inhibitor (VPI) -- one of a new class of medications that fight
hypertension by blocking both angiotensin-converting enzyme (ACE) and
another enzyme called neutral endopeptase (NEP). New studies will be done
for Vanlev(R), and its NDA may be re-filed as early as 2001.
- Another novel chemical compound, Natrecor(R) (nesiritide), is a human b-type
natriuretic peptide that has been filed for first-line IV use in patients
with heart failure (HF) needing rapid and sustained relief. An FDA Advisory
Committee has recommended that Natrecor(R) be approved, but the agency has
requested more information before proceeding with approval.
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ANTIHYPERTENSIVES
An ACEI is still the drug of choice for initial therapy in people with
hypertension who also have diabetes, HF or systolic dysfunction after a heart
attack. ARBs are a newer group of drugs that produce an antihypertensive effect
similar to the ACEIs, but they have yet to demonstrate long-term protective
effects on heart or kidney function.
FIGURE A8: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIHYPERTENSIVES
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIHYPERTENSIVES LINE CHART]
- From 1998 to 1999, PMPY costs for antihypertensives grew by 12.3 percent,
with rising utilization accounting for about two-thirds of this increase.
- Nearly 20 ACEIs and ACEI combination products are on the U.S. market.
Because most are therapeutically interchangeable for hypertension, favorable
price competition exists. Several of the more commonly used ACEIs are also
indicated for HF.
- The market share among the myriad of products in this class changed little
between 1998 and 1999. The only product having any appreciable market share
change (about 2 percent) was the most expensive drug, Vasotec(R)
(enalapril), which continued to decline to 6.5 percent in 1999.
- The results of several studies such as ATLAS (Assessment of Treatment with
Lisinopril), HOPE (Heart Outcomes Prevention Evaluation), the Studies of
Left Ventricular Dysfunction Trial and the Survival and Ventricular
Enlargement Trial prove that ACEIs used in higher doses not only improve
quality of life for HF patients but also reduce the risk of cardiovascular
events. Whether this protection is offered by all members of the class
remains to be tested, however.
- Approval was granted in May 1999 for once daily dosing of an ARB, Teveten(R)
(eprosartan), which had been approved in 1997 as a twice-a-day product.
Teveten(R) was not marketed in the United States until mid-1999.
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- Aceon(R) (perindopril erbumine), the American version of a once-daily ACEI
that has been used in Europe for several years, was launched in October
1999.
FUTURE TRENDS
- Although patent protection has been extended by six months due to ongoing
investigation for pediatric use, Vasotec(R) and Vaseretic(R) (enalapril and
hydrochlorothiazide) will still go generic in August 2000. Zestril(R)
(lisinopril), Prinivil(R) (lisinopril) and Accupril(R) (quinapril) are all
scheduled to go off patent in 2001, followed by Monopril(R) (fosinopril) in
2002.
CALCIUM BLOCKERS
Muscles contract and expand in response to stimulus from chemicals like sodium
and calcium. Drugs known as calcium channel blockers (CCBs) prevent the entry of
calcium into muscle cells, causing blood vessel walls to relax and reducing
resistance to blood flow. As a result, the heart does not have to pump with as
much force, so conditions like hypertension are relieved.
FIGURE A9: THERAPY CLASS DRUG MARKET SHARE TREND
CALCIUM BLOCKERS
[THERAPY CLASS DRUG MARKET SHARE TREND
CALCIUM BLOCKERS LINE CHART]
- Since 1994 the trend in both use and price of this therapy class has been
relatively flat. Between 1998 and 1999, overall PMPY costs rose by a modest
2.7 percent. During the same period, utilization of these products dropped
by 0.7 percent, while the per prescription cost rose by 3.4 percent.
- The market share for generic CCBs continued to increase reaching 23.5
percent in 1999.
- Norvasc(R) (amlodipine) continued to lead the class in 1999 as its market
share grew from 25 percent in 1998 to 28.6 percent in 1999. Norvasc(R)'s
manufacturer is attempting to shift market share from its older CCB,
Procardia(R) XL (nifedipine extended-release).
- Nifedipine extended-release, the first generic equivalent for Procardia(R)
XL, was approved in December 1999. However, the generic is BC rated to the
brand name product, which means
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that studies proving both the rate and the extent of the active ingredient's
absorption have not been submitted to the FDA, even though the generic
contains the same active ingredients as the branded product.
- The market share for Cardizem(R) CD (diltiazem extended-release capsules),
the third largest product in this class, continued to erode to 12.3 percent
in 1999. Virtually all other CCB products either lost or barely maintained
their respective market shares.
- Also in December 1999, a generic version of Cardizem(R) CD was FDA approved.
Generics for immediate-release diltiazem tablets and sustained-release
diltiazem tablets were already available on the U.S. market.
FUTURE TRENDS
- Plendil(R) (felodipine) will go off patent for its hypertension indication
in 2001.
BETA BLOCKERS
Beta blockers affect the cardiovascular system in several different ways. They
decrease both the speed and the force of heartbeats, and they relax muscles in
blood vessel walls. Not only do beta blockers reduce blood pressure, they are
also effective in angina and some kinds of arrhythmias. Many beta blockers are
available as generics.
FIGURE A10: THERAPY CLASS DRUG MARKET SHARE TREND
BETA BLOCKERS
[THERAPY CLASS DRUG MARKET SHARE TREND
BETA BLOCKERS LINE CHART]
- The overall 1999 PMPY cost increased by 11.2 percent over 1998 levels, most
of which is attributable to increased utilization.
- This class continued to be dominated by generics, which captured 76.1
percent of the 1999 market.
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- Among the branded products, Toprol(R) XL (metoprolol extended-release), is
the largest seller, growing steadily from a 3.1 percent market share in 1994
to 13.5 percent in 1999.
- New studies demonstrate that beta blockers can be beneficial in patients
with HF -- a reversal of previous recommendations. Two major studies -- the
MERIT-HF (The Mortality Effect of Metoprolol CR/XL in Patients with Heart
Failure) trial and the U.S. Carvedilol Heart Failure Study -- were ended
early because results were so good. Another trial, BEST (Beta Blocker
Evaluation of Survival Trial), also showed that beta blockers have value in
early stages of HF, particularly for Caucasian patients and people with
diabetes. Coreg(R) (carvedilol) is currently the only beta blocker to have
FDA approval for HF patients.
FUTURE TRENDS
- Betapace(R) AF (sotalol), a reformulated beta blocker already used for
ventricular arrhythmias, was approved in February 2000 for a more common and
less life-threatening condition -- atrial fibrillation. It must be given in
a clinical setting because it can actually precipitate arrhythmias.
ANTIHYPERLIPIDEMICS
In addition to the fats eaten in foods, certain types of fats or "lipids" are
manufactured by the body for use in essential body functions. Cholesterol, for
example, is necessary to make bile and steroid hormones. When the wrong kinds of
fat -- cholesterol, low density lipoproteins (LDLs) and triglycerides -- stay
in the blood, a condition variously called hyperlipidemia, hypercholesterolemia
or high cholesterol results. Fatty deposits can form on artery walls causing
narrowing, inflexibility and even blockages that contribute to heart disease.
High blood levels of another fat called high density lipoproteins (HDLs) are
desirable because they protect against heart disease.
When exercise, weight loss and the limitation of dietary fats fail to reduce
blood lipid levels, anti-hyperlipidemic medications can be added. By far the
most common drug type prescribed for high cholesterol is an HMG-CoA reductase
inhibitor -- commonly called a "statin." These oral drugs reduce cholesterol by
interfering with an enzyme that regulates cholesterol production in the liver.
An older class of medications, called bile acid sequestrants or ion exchange
resins, lowers cholesterol levels by attaching to bile and pulling it out of the
body. The creation of new bile requires that cholesterol be removed from the
blood. Since bile acid sequestrants are not absorbed by the body, they have few
side effects. A third group of drugs, fibric acid derivatives, is most effective
in reducing triglycerides by changing the metabolism of dietary fats.
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<PAGE> 74
FIGURE A11: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIHYPERLIPIDEMICS
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIHYPERLIPIDEMICS LINE CHART]
- 1999 PMPY expenditures for antihyperlipidemic medications continued to grow
substantially. Between 1998 and 1999, these costs grew by 20.9 percent to
$28.17, making it the third highest expenditure class. This overall cost
increase was driven almost exclusively by increased utilization -- 18.1
percent over 1998 levels. Prices for these products have not risen sharply
due to price competition among the many products in the statin market.
- Lipitor(R) (atorvastatin) continued its meteoric success since its March
1997 market entry. In 1997, Lipitor(R) claimed a 14.1 percent market share,
a level that rose to 43.9 percent in 1999.
- This growth in market share in turn decreased the market share for virtually
all other products in the class. For example, between 1998 and 1999, the
market share for Pravachol(R) (pravastatin) dropped from 16.4 percent to
15.0 percent, for Zocor(R) (simvastatin)/Mevacor(R) (lovastatin) from 31.6
percent to 24.2 percent and for Lescol(R) (fluvastatin) from 7.2 percent to
4.3 percent.
- In 1999 Zocor(R) became the first statin to be FDA-approved for raising HDL.
FUTURE TRENDS
- Patent protection for both major bile acid sequestrants, Questran(R)
(cholestyramine) and Colestid(R) (colestipol), has expired. Generic
equivalents for Questran(R) are marketed in the United States under the
names Prevalite(R), LoCholest(R) and cholestyramine. No generic is currently
available for Colestid(R).
- An NDA for Welchol(R) -- formerly named Cholestagel(R) (colesevelam) -- is
under FDA review. A polymer-based product that is not absorbed,
Cholestagel(R) can be used as monotherapy or in combination with a statin.
Additionally, it can be taken with meals either once or twice a day.
- An application for the approval of a new, 80mg extended-release form of
Lescol(R) was submitted to the FDA in December 1999.
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- The patent for Mevacor(R) is scheduled to expire in 2001. All other branded
statin products have several more years of patent protection.
- A new statin called ZD 4522, currently in clinical trials, is expected to be
approved in 2002 or 2003. Preliminary data show that ZD 4522 produces
greater lowering of LDL than statins presently available in the U.S.
- In research news, a gene called ABC1 has been identified as being involved
in the production of HDL cholesterol. In preclinical lab experiments,
increased ABC1 levels resulted in lowered total cholesterol levels in
cultured cells. Despite large amounts of evidence that reducing LDLs can
lower heart attack risk substantially, a recent study found that many
high-risk patients do not receive cholesterol-lowering medications. Women
especially are not likely to be given drugs to control cholesterol,
according to the research which was published in the February 2000 Archives
of Internal Medicine.
RESPIRATORY
Respiratory conditions can be as mild as an annoying seasonal allergy or as
serious as a life-threatening asthma attack. Medications for respiratory
conditions -- available in oral and inhaled dosage forms -- include
antihistamines, corticosteroids, beta agonists, decongestants and various
combination products. Inhaled medications that are used to treat asthma get into
the lungs faster to open constricted bronchioles.
During the past few years, worldwide environmental initiatives have emphasized
the removal of ozone-damaging chlorofluorocarbons (CFCs) from the propellants
used in inhalers. As a result, new kinds of inhaler devices are available that
deliver dry powdered medications or a finer aerosol spray than the metered dose
inhalers (MDIs) that are being replaced.
The FDA approved three new anti-allergy eye drops in 1999. Alamast(R)
(pemirolast potassium ophthalmic solution) and Alocril(R) (nedocromil sodium
ophthalmic solution 2%) are mast cell stabilizers. Zaditor(R) (ketotifen
fumarate ophthalmic solution) combines mast cell stabilization with a histamine
blocker. All three relieve itchy eyes associated with allergies.
ANTIASTHMATICS
In asthma, chronic inflammation of lung tissues causes sensitive and blocked air
passages called bronchioles. Symptoms of asthma include wheezing, coughing and
shortness of breath. Acute asthma attacks can be triggered by numerous factors
such as exercise, allergens or stress. People with asthma usually need two types
of medications: controllers to suppress inflammation and relievers to alleviate
acute asthma attacks. Controllers must be taken on a regular basis. Some classes
of controller medications are long-acting beta agonists, leukotriene modifiers,
mast call stabilizers, inhaled corticosteroids (ICSs) and oral corticosteroids.
Relievers such as short-acting beta agonists and anticholinergic agents are
taken to stop an attack.
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FIGURE A12: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIASTHMATICS
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIASTHMATICS LINE CHART]
- In 1999 PMPY cost of antiasthmatics grew by 11.6 percent to $13.57, although
PMPY utilization rose by only 4.3 percent.
- Albuterol (brand name Proventil(R) or Ventolin(R)) is the most widely used
beta agonist. Albuterol inhalers have been available generically since early
1996. The market share for the generic forms remained stable at 26 percent
in 1999.
- The use of the long-acting beta agonist, Serevent(R) (salmeterol) -- often
considered a niche product for nocturnal asthma symptoms -- maintained its
market share of 7.3 percent. Because Serevent(R) has a slow (15-30 minute)
onset of action, it should not be used to treat acute asthma symptoms. It is
used instead as a daily controller medication, often in combination with an
anti-inflammatory agent.
- The newest controller medications for asthma are the leukotriene modifiers
-- Accolate(R) (zafirlukast), Zyflo(R) (zileuton) and Singulair(R)
(montelukast). The National Asthma Education and Prevention Program (NAEPP)
guidelines list these products as an alternative to ICSs in mild persistent
asthma. Taken as tablets, all the leukotriene modifiers are for long-term
control of asthma so they must be taken continually. These products have low
overall market share because they are usually either prescribed in
combination with other products or used as a second-line therapy. The market
share for Singulair(R) grew from 2.2 percent in 1998 to 6.5 percent in 1999,
while the market for Accolate(R) declined slightly to 3.2 percent.
- Flovent(R) (fluticasone) Rotadisk(R), Serevent(R), Diskus(R) and
Pulmicort(R) (budesonide) Turbohaler(R) are some of the currently available
dry powder dosage forms. Designed not only to eliminate the need for CFC
propellants, they also simplify the administration of inhaled medications.
Their redesigned inhaler style eliminates much of the hand-eye-breath
coordination that makes liquid inhalers difficult to use for children,
elderly and disabled
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patients. In 1999 Flovent(R) increased its market share to 7.1 percent,
whereas Pulmicort(R) increased its share to 1.1 percent.
- Vanceril(R) and Beclovent(R), the two brand-name products of an orally
inhaled corticosteroid called beclomethasone dipropionate, went off patent
in 1999. However, the FDA does not recognize the generic version of
beclomethasone dipropionate as therapeutically equivalent to the branded
products. Both have market shares of less than 2 percent.
FUTURE TRENDS
- An FDA Advisory Committee recommended Advair(R) for approval in November
1999. Administered with a patented Diskus(R) device, Advair(R) combines a
long-acting beta agonist (salmeterol) with a corticosteroid (fluticasone).
- An NDA was submitted in November 1999 for Asmanex(R) (mometasone furoate
inhalation powder). If used regularly for the prevention of asthma attacks,
Asmanex(R) may reduce the need for oral steroids in some asthma patients. A
version of the same active drug in a metered-dose inhaler is still in Phase
III clinical trials, but it seems to offer no advantage over existing
products.
- Singulair(R) received a new indication for children as young as two years
old. Approved in March 2000, the new cherry-flavored 4mg tablet is meant to
be given once a day. Singulair(R) was previously available only as 10mg
tablets for adults and as 5mg chewable tablets for children from 6 years -
14 years of age.
- The NDA for a CFC-free beclomethasone inhaler has been filed with the FDA.
The medication, Qvar(R) (hydrofluoroalkane-134a beclomethasone
dipropionate), uses a "press-and-breathe" (P&B) inhaler device that delivers
a smaller particle size and uses less force than earlier inhaler sprays. As
a result, the inhaler is easier to use. Patients may require smaller doses
as well, since more active drug will reach their lungs.
- Formoterol is a beta agonist with both rapid onset and long duration, so it
can be used not only to prevent asthma attacks but also to treat an attack
once it has begun. The European Union approved a type of formoterol called
Oxis(R) Turbuhaler(R) in January 2000. In the United States, formoterol --
with the brand name Foradil(R) -- was taken under consideration by the FDA
in late 1997. Approval has been delayed, however, by questions about the
manufacturing processes used in Foradil(R)'s production.
- In a completely new approach to asthma therapy, researchers have reported
positive results from Phase III trials of a biological, anti-IgE. IgE
(immunoglobulin epsilon) is a protein made by cells in the respiratory
tract. It provokes the release of histamines, leukotrienes and
prostaglandins that in turn cause allergic reactions. Anti-IgE, also called
rhuMAb-E25 or olizumab, is a humanized monoclonal antibody that interferes
with the action of IgE. Anti-IgE will be injected twice a week for allergic
asthma and for seasonal allergic rhinitis. U.S. filing for approval is
anticipated in 2000.
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ANTIHISTAMINES
Allergies are acquired, exaggerated sensitivities to substances called allergens
which normally do not produce reactions. Allergic rhinitis is a common form of
allergy produced primarily by airborne allergens. Typical symptoms of allergic
rhinitis like sneezing, nasal congestion and itchy eyes can be seasonal or
chronic. Other types of allergy may show as rashes, wheezing or, rarely, as very
severe swelling of the throat. Oral antihistamine tablets and capsules are the
most popular type of medication to treat systemic allergy symptoms. Newer
non-sedating products have virtually replaced first-generation antihistamines
that cause drowsiness.
FIGURE A13: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIHISTAMINES
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIHISTAMINES LINE CHART]
- After growing 38.5 percent between 1996 and 1997, another 25.2 percent in
1998, PMPY costs for antihistamines grew 25.8 percent more in 1999. In all
of these years, the cost increases were largely due to substantial increases
in utilization. Most of the increase in cost took place among the
non-sedating antihistamines Claritin(R) (loratidine) and Allegra(R)
(fexofenadine) and the low-sedating product Zyrtec(R) (cetirizine). All of
these products have been promoted heavily through DTC advertising.
- The use of Claritin(R), the market leader, increased from 28.3 percent in
1994 to 50.6 percent in 1998, before declining somewhat to 48.8 percent in
1999. The AWP per prescription for Claritin(R) was $66.41 in 1999, a 5.9
percent rise over 1998 levels. Allegra(R)'s market share rose to 19.0
percent in 1999. Allegra(R) has an average cost of $51.68 per prescription,
11.9 percent over 1998 costs. Zyrtec(R), although relatively new, is
increasing in use, reaching a 19.9 percent market share. It had an AWP of
$52.40 in 1999 -- 3.5 percent over 1998 costs.
- Hismanal(R) (astemizole) was taken off the U.S. market June 28, 1999, due to
sharply declined sales after the FDA cautioned in February about potentially
dangerous reactions when it was taken with certain other drugs or when it
was used in higher than recommended doses.
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- The FDA has approved two new strengths and one new indication for
Allegra(R). In addition to the original 60mg tablet indicated for
twice-a-day adult dosing, it is now available as a 180mg tablet for
once-a-day dosing in adults and as a 30mg tablet that can be given up to
twice daily to children between 6 and 11 years of age. Allegra(R) is also
indicated for the treatment of chronic idiopathic urticaria -- an
unexplained skin condition characterized by itchy hives.
FUTURE TRENDS
- The makers of Claritin(R) hope that a loratidine metabolite, desloratadine,
will win FDA approval for the treatment of seasonal allergic rhinitis in
2000. Desloratadine was filed for approval in both the United States and the
European Union in November 1999.
- Phase III clinical trials are nearing completion for norastemizole, a
metabolite of astemizole. Research has shown that norastemizole provides a
non-sedating antihistamine effect without the interaction or side effect
problems associated with astemizole. An NDA could be filed with the FDA by
the end of the year for this once-a-day allergy medication.
- Development of Kestine(R) (ebastine), an oral non-sedating antihistamine,
was essentially stopped after a not-approvable letter was issued by the FDA
in April 1999.
DECONGESTANTS (NASAL STEROIDS)
Nasal corticosteroids (NCSs) are often used for localized allergic rhinitis
symptoms. Sprayed directly into the nose, they reach inflamed passages quickly
to reduce swelling and to decrease nasal secretions. Because very little of the
drug is absorbed, nasal steroids do not produce the side effects associated with
oral corticosteroids.
FIGURE A14: THERAPY CLASS DRUG MARKET SHARE TREND
DECONGESTANTS (NASAL STEROIDS)
[THERAPY CLASS DRUG MARKET SHARE TREND
DECONGESTANTS (NASAL STEROIDS) LINE CHART]
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- NCSs include only branded products at this time. The most commonly used
products are Flonase(R) (fluticasone), which increased its 1999 market share
to 33 percent, and Nasonex(R) (mometasone), which captured a 14.4 percent
market share in 1999. In contrast, market shares for other products either
grew marginally or declined. Vancenase(R)AQ (beclomethasone aqueous) saw its
market share drop from 18.4 percent in 1998 to 11.3 percent in 1999.
Beconase(R) AQ's (beclomethasone aqueous) market share declined by about
one-third to 6.3 percent, Nasacort(R)'s (triamcinolone) market share
increased slightly to 12.5 percent and Rhinocort(R)'s (budesonide) market
share fell to 10.5 percent.
- The patent for Beconase(R) and regular-strength Vancenase(R) expired in
1999. Although a generic has been introduced, it is not rated as
therapeutically equivalent by the FDA. Vancenase(R) DS (beclomethasone
dipropionate monohydrate inhalation 0.084mg/inhalation) is still only
available as a branded product.
COUGH AND COLD
Most cough and cold therapies are available over the counter. The few
prescription medications available to treat upper respiratory conditions consist
mainly of products that combine prescription antihistamines with decongestants.
FIGURE A15: THERAPY CLASS DRUG MARKET SHARE TREND
COUGH AND COLD
[THERAPY CLASS DRUG MARKET SHARE TREND
COUGH AND COLD LINE CHART]
- PMPY costs grew by 21.1 percent, with utilization increases accounting for
about 13 percent of this increase.
- This class of drugs consists primarily of generic products that represent a
flat 60 percent of the 1998-1999 market. Claritin(R)-D (loratidine and
pseudoephedrine), a combination product that includes a non-sedating
antihistamine, made up 17.9 percent of the 1999 market, a decrease from the
19.6 percent share it enjoyed in 1998. The only other branded combination
product of any importance in this class is Allegra(R)-D (fexofenadine and
pseudoephedrine),
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which doubled its market share to 6.2 percent in 1999. Whereas the average
AWP cost per prescription is $10.45 for generic products (an increase of 8.9
percent over 1998 levels), it is $63.60 for Claritin(R)-D and $49.63 for
Allegra(R)-D. Average prescription costs grew by 8.4 percent for
Claritin(R)-D and by 12.7 percent for Allegra(R)-D.
FUTURE TRENDS
- A generic version of Claritin(R)-D 24-hour was submitted for FDA approval in
February 2000. If approved, it will be the first equivalent to the branded
product to be approved under provisions of the Hatch-Waxman Act, and it will
have a six-month period of exclusivity.
- An NDA for Zyrtec-D(R) (cetirizine and pseudoephedrine) is expected to be
filed with the FDA during 2000.
ANTI-INFECTIVES
Drugs used to treat bacterial infections either destroy bacteria (bactericides)
or slow down bacterial replication (bacteriostats). Some antibacterial agents
are only effective against certain types of bacteria or for specific types of
infections. Most, however, have a broad-spectrum of activity, which means they
can be used for a number of different infections.
The overuse of antibiotics has lead to mutations that make some bacteria
resistant to previously effective medications, especially in developing areas of
the world. To combat the worldwide problem of bacterial resistance,
pharmaceutical manufacturers are studying completely new chemical classes. For
example, Synercid(R) (quinupristin and dalfopristin) is the first agent to be
approved in a new class of antibiotics called streptogramins. Given as an
injection, Synercid(R) will be reserved for infections that are resistant to
vancomycin--currently the most potent antibiotic available in the United States.
FUTURE TRENDS
- A completely new antibiotic product approved in 2000 is Zyvox(R)
(linezolid), which represents a class called oxazolidinones. Like
Synercid(R), Zyvox(R) will be used for pneumonia, skin infections and some
serious systemic infections that do not respond to other antibiotic
therapies. It will be available in both oral and IV formulations.
- An NDA for Ketek(R) (telithromycin), the first antibiotic in a new class
known as ketolides, was filed with the FDA in March 2000. Ketolides are
similar to macrolides. Ketek(R) has been formulated for once-a-day oral
dosing in the treatment of four common respiratory infections.
- A fourth new class of antibiotics is designated BPIs
(bactericidal/permeability-increasing proteins). Derived from a protein
found in human white blood cells, BPIs are biologic products that will
probably be used only in a hospital setting. The drug that is closest to
general marketing in the United States is Neuprex(R) (rBPI-21). Neuprex(R)
has already received an orphan designation for the treatment of
meningococcemia, a very serious systemic infection caused by a type of
bacteria that also causes meningitis.
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CEPHALOSPORINS
Similar to the penicillins in structure, cephalosporins kill bacterial cells by
disrupting the formation of viable bacterial cell walls. At least four distinct
"generations" of cephalosporins have specific activity against different groups
of bacteria that cause respiratory, genital, urinary and skin infections.
FIGURE A16: THERAPY CLASS DRUG MARKET SHARE TREND
CEPHALOSPORINS
[THERAPY CLASS DRUG MARKET SHARE TREND
CEPHALOSPORINS LINE CHART]
- PMPY expenditures for cephalosporins rose by a nominal 3.8 percent. This
slight increase was due to increased prescription costs as utilization for
this drug class actually declined by 1.4 percent.
- The market share for generic cephalexin remained stable at 45.8 percent. The
use of another generic, cefaclor, (often used to treat otitis media)
continued to decline from a peak of 14.5 percent in 1996 to 6.2 percent in
1999 owing to the availability of more effective second-line antibiotics.
- The preference for two "second generation" branded cephalosporins, Cefzil(R)
(cefprozil) and Ceftin(R) (cefuroxime), continued slow growth. The market
share for Cefzil(R) rose marginally to 16.2 percent, while the share for
Ceftin(R) increased to 14.1 percent in 1999. "Third generation"
cephalosporins, Suprax(R) (cefixime), Vantin(R) (cefpodoxime) and Cedax(R)
(ceftibuten), have relatively low use, which seems to be declining.
Omnicef(R) (cefdinir), a "third generation" cephalosporin introduced to the
U.S. market in October 1998, offered nothing new to the already crowded
class but still managed to grow in market share from 0.3 percent in 1998 to
1.7 percent in 1999.
- A number of brand name cephalosporins either just lost patent protection or
face patent loss in 2000. Among them are Vantin(R) (cefpodoxime proxetil
suspension and tablets), Suprax(R) (cefixime suspension and tablets) and
Duricef(R) (cefadroxil capsules). Patents for hospital products Cefobid(R)
(cefoperazone for injection), Mefoxin(R) (cefoxitin for injection) and
Fortaz(R) and Tazicef(R) (ceftazidime for injection) have all expired.
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FUTURE TRENDS
- In January 2000 an NDA was submitted for Spectracef(R) (cefditoren pivoxil)
a new broad spectrum oral cephalosporin for the treatment of respiratory and
skin infections in adults. Clinical trials for the effectiveness of
Spectracef(R) in pediatric patients are still being conducted.
MACROLIDES
Macrolides belong to an antibiotic class that was named for the large or "macro"
chemical structure they share. Erythromycin, the oldest currently used member of
the group, is derived from Streptomyces erythraeus -- an organism found in soil.
Macrolides are "bacteriostats", which means they stop bacteria from reproducing
rather than killing bacteria like some other types of antibiotics do. Drugs in
the Macrolide class are particularly effective against opportunistic infections
in immuno-compromised patients. Macrolides are also used as a part of the triple
therapy regimens for eradicating H. pylori.
FIGURE A17: THERAPY CLASS DRUG MARKET SHARE TREND
MACROLIDES
[THERAPY CLASS DRUG MARKET SHARE TREND
MACROLIDES LINE CHART]
- Overall the rate of growth in PMPY cost for macrolides grew by 19 percent in
1999, after growing by only 7.7 percent between 1997 and 1998. About
two-thirds of this growth was attributable to rising utilization rates.
- Zithromax(R) (azithromycin), Biaxin(R) (clarithromycin) and generic
macrolides account for about 94 percent of all drug use in this category.
Zithromax(R) dominates this therapy class with a 1999 market share of 57.2
percent -- more than double its 1996 share. This increased market share came
at the expense of both generic erythromycins, which continued to decline
from a 26.7 percent market share in 1996 to 14.5 percent in 1999, and
Biaxin(R) whose market share declined from a peak 34.6 percent in 1996 to
22.4 percent in 1999.
- In first quarter 1998, Dynabac(R) (dirithromycin) was given approval for
additional indications, as well as approval for shorter dosing periods.
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FUTURE TRENDS
- Biaxin XL(R), a once-a-day version of clarithromycin, was approved and
launched in the first half of 2000. Biaxin(R) was previously formulated for
twice-a-day dosing.
PENICILLINS
Penicillins work by disrupting bacterial ability to make cell walls and to keep
them intact. Penicillins are widely used as first-line treatment against common
childhood infections like otitis media, as well as in multiple respiratory and
urinary tract infections in adults. As one of the first classes of antibacterial
medications to be discovered, many of the penicillins are available in generic
form.
FIGURE A18: THERAPY CLASS DRUG MARKET SHARE TREND
PENICILLINS
[THERAPY CLASS DRUG MARKET SHARE TREND
PENICILLINS LINE CHART]
- After growing by a modest 4.3 percent between 1997 and 1998, the PMPY cost
of this class rose by 19.2 percent in 1999, almost all of which is
attributable to increased costs per prescription.
- Augmentin(R) (amoxicillin and sodium clavulanate) is the only branded
product in this class with significant use. Its average prescription price
grew by 8.2 percent to $72.73 in 1999 compared with the 3.7 percent rise to
a $7.84 average price for generic products. The use of Augmentin(R) had been
steady at approximately 13 percent from 1993 through 1996. In 1997, its
market share increased to 17.1 percent, then continued to grow -- reaching
21.7 percent in 1999.
- During summer 1999, a shortage of penicillin G, an injectable form of
penicillin used mainly in hospitals, called attention to a larger potential
problem. A combination of factors caused supplies of the raw materials that
are needed for several penicillins, cephalosporins and other antibiotics to
become scarce. Alternatives exist for most of the medications in short
supply, but not all the substitutes work as well as the drugs they are
replacing.
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FUTURE TRENDS
- The U.S. patent on Augmentin(R) was due to expire in 2002, but the company
that makes it received a new patent -- apparently based on new antibacterial
activity recently discovered in its clavulanate component.
QUINOLONES
Fluoroquinolones, usually called quinolones, were synthesized from an older
class of antibiotics used primarily to treat urinary tract infections. Beginning
in 1987, several "second" or "third" generation quinolones have been introduced
into the U.S. market. The newer fluoroquinolones have a broad range of activity
against multiple micro-organisms -- including some that are resistant to other
antibiotics -- and a lower incidence of adverse effects compared with the older
agents. Fluoroquinolones kill bacterial cells by interfering with enzymes called
topoisomerase II (DNA gyrase) and topoisomerase IV.
FIGURE A19: THERAPY CLASS DRUG MARKET SHARE TREND
QUINOLONES
[THERAPY CLASS DRUG MARKET SHARE TREND
QUINOLONES LINE CHART]
- Cipro(R)'s (ciprofloxacin) dominant market share continued to decline in
1999. After reaching a 76.4 percent market share in 1995, Cipro(R)'s share
dropped to 60.2 percent in 1999. Floxin(R)'s (ofloxacin) maximum market
share of 19.8 percent achieved in 1996, decreased to only 5.3 percent in
1999. The lost market shares for Cipro(R) and Floxin(R) went to Levaquin(R)
(levofloxacin), whose market share grew from 8.9 percent in 1997, when it
was introduced, to 27.4 percent in 1999. At $82.94, Levaquin(R)'s average
prescription cost is the highest among these three products.
- Tequin(R) (gatifloxacin) and Avelox(R) (moxifloxacin) were FDA approved in
December 1999 for once-daily oral dosing in bronchitis, community-acquired
pneumonias and sinusitis. Neither Tequin(R) nor Avelox(R) seems to cause
photosensitivity, liver toxicity or interaction problems that are associated
with other fluoroquinolones.
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- Less than two years after it was approved by the FDA, Raxar(R)
(grepafloxacin) was voluntarily withdrawn from the world market in October
1999 after reports suggested that a rare but serious arrhythmia was
associated with its use. In similar action, the European Community withdrew
Trovan(R) (trovafloxacin) because of its potential to cause liver toxicity.
Trovan(R) was introduced to the U.S. market in 1998 and it is still being
used in this country, although cautiously.
FUTURE TRENDS
- An NDA for Factive(R) (gemifloxacin) to be used against respiratory
infections was filed with the FDA in December 1999.
- Patent protection for injectable forms of Floxin(R) will begin to run out
next year. Patents for the oral forms of both Floxin(R) and Cipro(R) expire
in 2003.
ANTIVIRALS
Infections caused by viral organisms range from merely annoying head colds to
life threatening illnesses like Acquired Immune Deficiency Syndrome (AIDS).
Other viral illnesses include measles, mumps, chicken pox, shingles, influenza
and chronic fatigue syndrome (CFS), as well as most types of hepatitis and some
forms of meningitis.
Intense research for treatments, vaccines and ultimately for cures effective
against the human immunodeficiency viruses (HIV) that cause AIDS has also lead
to the discovery of agents effective against other types of viruses. Drugs now
available for the treatment of AIDS do not cure HIV infection, they only
decrease viral duplication. Current anti-AIDS drugs fall into two broad therapy
classes called protease inhibitors and reverse transcriptase inhibitors (RTIs).
RTIs are either nucleosides (NRTIs) or non-nucleosides (NNRTIs). Each class
represses an enzyme that is critical to the viral replication process, thereby
decreasing the amount of virus in the blood, which is known as the "viral load."
For HIV-positive adults and adolescents, the goal is to suppress viral load for
as long as possible. According to updated Guidelines for the Use of
Antiretroviral Agents in HIV-Infected Adults and Adolescents, treatment should
be available to all patients with acute or symptomatic HIV infection.
Recommended therapy combinations are either a protease inhibitor or the NNRTI
Sustiva(R) (efavirenz) along with two NRTIs or one of the protease inhibitors
Fortovase(R) (saquinavir) or Norvir(R) (ritonavir) along with one or two NRTIs.
Some physicians are beginning to prescribe two protease inhibitors together to
enhance effectiveness and improve adherence. New research suggests that
non-compliance with complicated and lengthy treatment regimens may be as
important as viral mutation in the development of resistance.
Although vaccines are effective against quite a few viral diseases, a problem
with developing vaccines to protect against some viral infections -- especially
HIV -- is that viruses are constantly mutating. Antibodies produced by a vaccine
may only work against some strains of a particular virus. As viruses change,
they may also develop resistance to treatments that were once effective.
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FIGURE A20: THERAPY CLASS DRUG MARKET SHARE TREND
ANTIVIRALS
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTIVIRALS LINE CHART]
- The 1999 PMPY cost of antivirals grew at a faster rate, 39.9 percent, than
any other class of drug. The introduction of new drugs, the increasing
popularity of combination therapy and the growing number of patients in
therapy caused PMPY costs to reach $10.29 in 1999. The average cost per
prescription grew by more than 22 percent, suggesting that use of higher
cost drugs account more than rising utilization for this dramatic PMPY cost
increase.
- After growing dramatically between 1997 and 1998, the market share for
generics declined somewhat to 30.3 percent in 1999.
- Two drugs for the treatment of herpes, Valtrex(R) (valacyclovir) and
Famvir(R) (famciclovir), are the most widely used branded products in
this category with a combined 32.6 percent market share in 1999,
moderately above 1998 levels.
- After growing its market share to 7.1 percent in 1997, Epivir(R)'s
(lamivudine) share continued to drop to 3.2 percent in 1999. Zerit(R)
(stavudine) saw its market share decrease slightly to 3.5 percent in
1999.
- Among the protease inhibitors, Crixivan(R) (indinavir) continued to
experience a slight market share decline to 1.9 percent, while
Norvir(R) (ritonavir) dropped to a 0.8 percent market share.
- The hot topic in antiviral medications for the 1999-2000 winter season
was the release of two new flu drugs, Tamiflu(R) (oseltamivir oral
tablets) and Relenza(R) (zanamivir powder for inhalation). Both
medications block an enzyme that keeps influenza viruses from
reproducing and infecting new cells. Now indicated for treatment of flu
symptoms within 48 hours of onset, Tamiflu(R) and Relenza(R) may be
approved for the prevention of influenza as well by next flu season.
- In the battle against AIDS, a protease inhibitor called Agenerase(R)
(amprenavir) was given accelerated approval by the FDA and marketed in
the United States during 1999. A soft
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capsule form of the protease inhibitor, Norvir(R) (ritonavir), was
approved in July for twice daily dosing and Videx(R) (didanosine), an
NRTI, received approval for once-daily dosing in October 1999. A
warning has been added to labeling for the NRTI Ziagen(R) (abacavir) to
caution about fatal hypersensitivity reactions that have been
associated with its use. In addition, a new film-coated tablet dosage
form and a new twice daily dosing schedule have been approved for the
protease inhibitor, Viracept(R) (nelfinavir).
- In October 1999, RotaShield(R) (rotavirus vaccine) was taken off the
market by the manufacturer due to reports that the vaccine caused bowel
obstruction in some of the infants who had received it.
FUTURE TRENDS
- Guidelines for the treatment of AIDS in children -- first proposed in
1993 -- were revised by the Working Group on Antiretroviral Therapy and
Medical Management of HIV-infected Children. Released in January 2000,
the new guidelines recommend that antiretroviral therapy should be
started for children younger than 1 year old as soon as they are
diagnosed and for children of any age as soon as symptoms appear.
HIV-positive children who are older than a year and who do not exhibit
symptoms of AIDS should either be given drug therapy or be monitored
for symptoms. Triple therapy with two NRTIs and one protease inhibitor
appears to be most effective.
- In November 1999 an FDA committee recommended against accelerated
approval for Preveon(R) (adefovir), the first agent in a new class
called nucleotide analogs, for the treatment of HIV infection. Clinical
trials and an expanded access program in the United States were stopped
for the seemingly promising drug after researchers noted both kidney
and liver problems among the study participants. Adefovir is still
under investigation, however, in this country for the treatment of
Hepatitis B (HVB) and in Europe for several indications. A similar, but
more potent, chemical called tenofovir disoproxil fumarate or PMPA
began Phase III clinical trials for AIDS in late 1999.
- Coactinon(R) (emivirine, formerly called MKC-442) is currently in Phase
II and Phase III trials in the United States, Africa and Europe. A NRTI
that acts more like a NNRTI, Coactinon(R) will be used in combination
with other AIDS medications. Coviracil(R) (emtricitabine or FTC),
another NRTI that was in advanced trials for HIV and in Phase II trials
for HVB, has been placed on "clinical hold" by the FDA after more than
the expected number of trial participants developed liver problems.
- Another group of compounds currently under investigation for AIDS
affects HIV in a way that is different from other classes of drugs.
These drugs, called fusion inhibitors, keep HIV cells from attaching or
"fusing" to host cells. The first one to be tested in humans, T-20
(pentafuside), is in Phase II trials; at least four others are in Phase
I or Phase II. A potential disadvantage of fusion inhibitors is that
they must be injected or infused because they are degraded by stomach
acid.
- A vaccine for the virus group that causes AIDS is still elusive. The
agents most advanced in studies are AIDSVax(R), a glycoprotein obtained
from HIV coats, and Remune(R), a specially treated form of inactivated
HIV that is to be injected four times a year. A mixture of the
glycoproteins, gp41 and gp120 also shows promise in earlier phases of
study.
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- An experimental agent that could be effective treatment for the common
cold is pleconaril, previously called VP 63843. Intended for oral use,
pleconaril has shown enough effectiveness against viral meningitis to
be available through a compassionate use program while Phase III trials
for meningitis continue in the United States. Pleconaril is also being
studied in Phase II trials to treat severe respiratory infections in
high-risk patients, although more recent results from trials in both
indications have been disappointing.
- Peg-Intron(R) (pegylated interferon alfa 2b) was filed late in 1999 for
FDA approval and Pegasys(R) (peginterferon alfa-2a) is in late stages
of clinical trials. Both are long-acting interferons that can be
injected fewer times a week for the treatment of chronic hepatitis C.
- Twinrix(R) (inactivated hepatitis A and recombinant DNA hepatitis B
vaccine), the first single agent to combine the two vaccines, is in
Phase III clinical trials in the United States. This vaccine has been
approved for both adults and children in the European Community since
1996.
- Ampligen(R) is a second-generation interferon that appears to have
broad activity against many different types of viruses. Available in
Canada under a compassionate use program for the treatment of Chronic
Fatigue Syndrome, Ampligen(R) is in several U.S. clinical trials --
Phase III for Chronic Fatigue Syndrome and Phase II for HVB and HIV.
- A whole new area of research for people with damaged immune systems
centers on agents to restore the immune function. Thymic peptides,
natural and synthetic compounds that mimic normal thymus activity, have
been studied most. For over 30 years, the thymus gland has been known
to be the center for T-cell production and regulation. T-cells are
specialized blood cells that ordinarily fight infections. Viruses
invade and destroy T-cells, so the body's natural defenses are
weakened. The first commercially available thymic peptide, Zadaxin(R)
(thymosin alpha 1 or thymalfasin), has been approved in several Asian,
Middle Eastern and South American countries for HVB and HVC. In the
United States, Zadaxin(R) is in Phase III clinical trials for HVC.
- Some interesting preliminary research shows that fatty acids destroy
the coatings that surround infective organisms -- particularly viruses.
Oral forms of one fatty acid known as monolaurin are still in early
stages of research, but a topical form called Glylorin(R) has been
granted FDA approval for orphan status in the treatment of a relatively
rare skin condition called congenital primary ichthyosis.
WOMEN'S HEALTH
Health concerns specific to women include the prevention of pregnancy, the
reversal of infertility, and the replacement of female hormones after menopause.
An increasingly important problem in an aging population is the prevention and
treatment of osteoporosis -- more common in women than in men.
ORAL CONTRACEPTIVES
Methods for contraception have begun to evolve as more women seek different
options for protection from untimely pregnancies. The "Pill" is still the most
popular form of birth control, but newer delivery systems under investigation
include a transdermal patch, a monthly estrogen-progestin injection, a long-term
progestin implant similar to Norplant(R) (levonorgestrel implant) and even a
once-a-day topical gel formulation combining estradiol and levonorgestrel.
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FIGURE A21: THERAPY CLASS DRUG MARKET SHARE TREND
ORAL CONTRACEPTIVES
[THERAPY CLASS DRUG MARKET SHARE TREND
ORAL CONTRACEPTIVES LINE CHART]
- PMPY costs for oral contraceptives grew 13.7 percent between 1998 and
1999. This growth rate is equally attributable to growing use and
rising average per prescription costs.
- Even though many are available generically, overall use of the
estrogen-progestin combinations that were the most popular over the
last decade is declining. The Ortho-Novum(R) product line, for example,
continued its market share decline, dropping from 17.3 percent in 1997
to 14.9 percent in 1998 then to 12.2 percent in 1999. Market share for
generic versions of the most popular branded combinations increased
only slightly, despite lower cost. Low, but sustained growth, has been
seen with some newer products and formulations. Most notably, Ortho
Tri-Cyclen(R) (ethinyl estradiol and norgestimate) increased its market
share from 12.2 percent in 1998 to 16.8 percent in 1999. The
manufacturer of Ortho Tri-Cyclen(R) is heavily marketing this product,
promoting its acne indication to young women.
- Plan B(R), an emergency contraceptive pill that contains only a
progesterone (levonorgestrel), was approved in July and launched in the
fourth quarter of 1999.
FUTURE TRENDS
- Tri-Norinyl(R) (ethinyl estradiol and norethindrone) will go off patent
in 2001.
- Lunelle(R) (estradiol cypionate and medroxyprogesterone acetate), a new
contraceptive to be given as a monthly injection, has completed Phase
III clinical trials in the United States and is awaiting FDA approval.
Initially intended for administration only in clinics or physicians'
offices, Lunelle(R) is expected to be approved eventually for
self-administration at home. Another new dosage form to complete Phase
III trials successfully in the United States, Evra(R) (ethinyl
estradiol and deacetylnorgestimate), is a transdermal patch made to be
worn on the arm, abdomen or buttocks. Evra(R) needs to be changed only
once a week.
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- Implanon(R) (etonorgestrel) is a single rod-shaped implant that
releases a progestin continuously for 24 months, as reported in the
results of recent clinical trials. Norplant(R) (levonorgestrel) is also
being reformulated so that the newer version, tentatively named
Norplant(R) II, will use only one rod instead of the six that are now
needed to ensure contraceptive protection for up to five years.
- After years of uncertainty, mifepristone, also known as RU-486, is
closer to being released to the U.S. market for emergency
contraception. The FDA is considering aspects of manufacture and
distribution before final approval is granted. A progesterone
antagonist, mifepristone is intended to be used in combination with
misoprostol, a prostaglandin.
ESTROGENS
Hormone replacement therapy (HRT) with estrogen and progesterone not only helps
to prevent osteoporosis and to relieve the symptoms associated with menopause
but may also reduce the risk of cardiovascular diseases in some postmenopausal
women. Troublesome side effects of HRT, however, cause a significant percentage
of women to stop therapy.
Most postmenopausal women who receive HRT are prescribed both estrogens and
progestin, while others need replacement only for estrogens (ERT). A group of
hormones produced primarily by the ovaries, estrogens are responsible for female
characteristics.
FIGURE A22: THERAPY CLASS DRUG MARKET SHARE TREND
ESTROGENS
[THERAPY CLASS DRUG MARKET SHARE TREND
ESTROGENS LINE CHART]
- 1999 PMPY costs for estrogens grew by 15.7 percent, slightly more than
the 14.5 percent rise in cost between 1997 and 1998. About two-thirds
of this growth rate is attributable to a 10.5 percent increase in the
average cost per prescription.
- Premarin(R) (conjugated estrogens), the best known branded estrogen
product, continued its dramatic decline in market share, dropping from
71.8 percent in 1994 to 47.2 percent in 1998 and sliding even further
to 44.6 percent in 1999. In contrast, Prempro(R) (conjugated estrogens
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and medroxyprogesterone acetate fixed-dose tablets) grew its market
share from 20.7 percent to 22.7 percent between 1998 and 1999. Market
share changes for other products in this class were marginal.
- Branded products that contain several types of estrogen have dominated
the market, mainly because bioequivalence cannot be documented for some
generics. Generics currently have only a 10.5 percent market share.
- Two new estrogen/progestin combinations are now being marketed in the
United States. FemHRT(R) (ethinyl estradiol and norethindrone) and
Ortho Prefest(R) (ethinyl estradiol and norgestimate) are oral
alternatives to Prempro(R) and other estrogen-progesterone regimens. A
tablet containing both Cenestin(R) (synthetic conjugated estrogens) and
a progestin is also under development.
- New estrogen patches also became available for distribution in the
United States during 1999. With five different strengths, Esclim(R)
(estradiol transdermal patch) offers the widest range of dosing options
among topical estrogen forms. Vivelle-Dot(R) (estradiol transdermal
patch), a smaller sized version of Vivelle(R), is more convenient for
some women to use.
FUTURE TRENDS
- Patents for Estraderm(R) (estradiol transdermal patch), the
"grandmother" of estrogen patches, will expire in 2001. Generic
estradiol transdermal patches are already available on the U.S. market
but not in all strengths.
- Lower doses and different formulations of Premarin(R), Prempro(R) and
Premphase(R) (conjugated estrogens and medroxyprogesterone acetate
phased-dose tablets) are expected to be submitted for FDA approval in
2000. The new combinations will address the concern that a higher risk
of breast cancer may be associated with long-term use of HRT.
- Ongoing research suggests that estrogen replacement not only has a
protective effect against colorectal cancer, it may be effective
against Alzheimer's disease as well. Premarin(R) is now in Phase III
clinical trials for Alzheimer's.
MISCELLANEOUS ENDOCRINES
Drugs in this class treat a number of conditions that result from deficiencies
in hormones normally produced by the endocrine system. Treatments for nocturnal
enuresis (bedwetting), infertility and growth hormone deficiency all fall into
this diverse group.
The top three endocrine drugs are all different in activity, but they all
prevent or treat osteoporosis. Fosamax(R) (alendronate) is a bisphosphonate, a
relatively new class of drugs which inhibit bone resorption. Evista(R)
(raloxifene) is a selective estrogen receptor modulator (SERM). Drugs of this
type protect bone mass in the same general ways that HRT does but they do not
increase the chance of breast or endometrial cancers like estrogens do. The
third drug for osteoporosis is Miacalcin(R) (calcitonin-salmon), which is
marketed as both an injection and a nasal spray. Miacalcin(R) is usually
reserved for women who cannot take estrogens.
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FIGURE A23: THERAPY CLASS DRUG MARKET SHARE TREND
MISCELLANEOUS ENDOCRINES
[THERAPY CLASS DRUG MARKET SHARE TREND MISCELLANEOUS ENDOCRINES LINE GRAPH]
- PMPY expenditures for miscellaneous endocrines rose by a substantial
31.4 percent. This increase is due totally to increased utilization
because average per prescription costs actually declined by 1.3
percent.
- In 1999 Fosamax(R) received a new indication for the treatment of
osteoporosis that is caused by taking steroid drugs. A much-publicized
study released in November 1999 reported that a large weekly dose of
Fosamax(R) was as effective in the treatment of osteoporosis as the
currently recommended dose of 10mg once a day. Whether GI side effects
are inordinately increased with the larger dose remains to be seen.
- Evista(R)'s market share grew dramatically from 15 percent in 1998 to
26.9 percent in 1999, while the market share for Fosamax(R) declined
from 47.9 percent in 1998 to 43.1 percent in 1999.
FUTURE TRENDS
- In April 2000 Actonel(R) (risendronate), a bisphosphonate already
approved for Paget's disease, received additional indications for
prevention and treatment of osteoporosis. It will compete directly
with Fosamax(R).
- Several new therapies are currently under investigation for prevention
and/or treatment of osteoporosis. Already in clinical trials are
several SERMs as well as oral and inhaled forms of calcitonin.
- An injectable version of human parathyroid hormone -- called ALX1-11 --
is in Phase III trials for osteoporosis. While currently available
medications merely stop the progression of bone loss in osteoporosis,
ALX1-11 is the first in a class of drugs that potentially can reverse
osteoporosis.
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DERMATOLOGICALS
The medications used to treat skin conditions come in an assortment of topical
formulations including creams, gels, lotions, ointments, powders and solutions.
A few, such as some antifungal medications and Accutane(R) (isotretinoin), a
medication for severe acne in males, are available in oral forms. Dermatological
medications treat all sorts of conditions that affect the skin surface. Many
dermatological preparations, especially antibiotics and antifungals, are
available without prescription, and many are also generic.
FIGURE A24: THERAPY CLASS DRUG MARKET SHARE TREND
DERMATOLOGICALS
[THERAPY CLASS DRUG MARKET SHARE TREND
DERMATOLOGICALS LINE CHART]
- Between 1998 and 1999, the PMPY cost of the class grew by 14.6 percent
to $11.79. The entire increase was due to higher costs per prescription
since no growth in utilization occurred.
- Continuing a pattern seen throughout the 1990s, the market share for
generics continued to rise -- reaching 30.4 percent in 1999.
- Levulan(R) (aminolevulinic acid) Kerastik(R) was approved in December
1999 for the treatment of actinic keratoses -- a type of skin lesion
that could develop into cancer. Using a unique new photodynamic
therapy, the active drug is applied in liquid form directly to skin
lesions, where it is absorbed into abnormal cells making them sensitive
to light. Fourteen to 18 hours later, the areas are exposed to a
specific kind of light that disrupts the cell membranes of treated
cells but does not damage normal cells.
- The gel form of Loprox(R) (ciclopirox 0.77%) has been approved for
superficial fungal infections and for seborrhea. Patent approval for
Loprox(R) gel expires in July 2000. Loprox(R) cream and lotion are
already off patent, but a completely new dosage form has been approved.
Penlac(R), a colorless nail polish containing ciclopirox, is indicated
for the topical treatment of fingernail and toenail fungus.
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- Nizoral(R) A-D (ketoconazole 1%) has become the first OTC shampoo
marketed for fungal dandruff. Oral and lotion forms of Nizoral(R) are
still prescription-only, as is a 2% shampoo. The patent for Nizoral(R)
tablets expired in 1999 and a generic is available. A topical mousse
form of ketoconazole is in development.
- Aldara(R) (imiquimod 5% cream) is being used for common and plantar
warts even though it is approved only for genital warts. High oral
doses of Tagamet(R) (cimetidine) are also being used off label for the
treatment of warts in both adults and children. Adult doses in the
range of 1200mg to 2400mg a day for three months or longer are needed
to see improvement. Unlike other wart treatments that are applied
externally to disintegrate warty tissue, Aldara(R) and cimetidine are
used internally to enhance immune system function.
FUTURE TRENDS
- Novel topical dosage forms continue to be a big focus of investigation.
In an effort to more precisely deliver medications to target areas,
researchers are also discovering delivery systems that are less
irritating and longer acting than conventional topical dosage forms.
One experimental technique incorporates medications into polymers that
apply like gels but then dry to form clear, water-resistant reservoirs
that release active drugs. Photodynamic procedures are being expanded
for use in diagnosis. When exposed to the right wavelengths of light,
for example, specially treated cancer cells have been made to fluoresce
-- pinpointing the location of main tumors and metastases.
- The patent on a widely-used combination steroid and antifungal cream,
Lotrisone(R) (betamethasone dipropionate 0.05% and clotrimazole 1%)
will expire fourth quarter 2000. The ointment formulation of
Diprolene(R) (augmented betamethasone dipropionate 0.05% ointment) is
already off patent. Diprolene(R) cream, gel and lotion will be losing
patent protection between 2000 and 2007, depending on the indication.
Another popular steroid Elocon(R) (mometasone fumarate 0.1% cream,
lotion and ointment), begins to go generic in 2001.
- A topical NSAID, diclofenac gel, is widely available in other countries
for the pain associated with arthritis as well as for the topical
treatment of actinic keratoses. Although it is being compounded at
local pharmacies, diclofenac gel is still not available commercially in
the United States. Pennsaid(R), a diclofenac lotion, is finishing
clinical trials and it will be submitted for FDA review in 2000.
Topical forms of NSAIDs provide localized relief without the systemic
side effects -- particularly GI upset -- that accompany the oral use of
NSAIDs.
- OLUX(R) ViaFoam(R), a mousse formulation of the high-potency steroid,
clobetasol propionate 0.05%, has been filed for FDA approval in
treating severe scalp conditions. Other topical forms of clobetasol are
available generically.
- An NDA for tacrolimus ointment to be used in the treatment of eczema
was submitted to the FDA in September 1999. The ointment is marketed
under the trade name Protopic(R) in Japan, but the U.S. product may
have a different brand name.
- In March 2000 an oral inhibitor of collagen synthesis, halofuginone,
was given orphan status for the treatment of scleroderma.
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ANTIDIABETICS
Diabetes is really a set of conditions characterized by the inability to
metabolize carbohydrates or "sugars" normally. Untreated diabetes is a major
cause of blindness, kidney disease and nerve damage. The best way to prevent or
postpone long-term complications from diabetes is to keep blood glucose levels
as close to the normal range of 64mg/dL to 112mg/dL as possible.
The most prevalent forms of diabetes are diabetes mellitus Types 1 and 2. People
with Type 2 diabetes either do not produce enough of their own "endogenous"
insulin to counterbalance the carbohydrates in foods that they eat or they have
a resistance to the effects of the insulin that their bodies do produce. Oral
antidiabetes drugs, manufactured "exogenous" insulin or a combination of both
can be used to treat Type 2 diabetes. Exogenous insulin, however, is essential
for people with Type 1 diabetes because they do not make endogenous insulin at
all. People with Type 1 diabetes depend on two kinds of exogenous insulin -- one
that acts rapidly to control blood sugar changes caused by meals and exercise,
and a long-acting insulin to maintain baseline blood glucose levels. The goal is
to keep blood sugar from becoming dangerously high or low.
While research has lead to the development of improved formulations and dosage
forms of insulin, the range of oral antidiabetic medications is also expanding.
In addition, new products are currently being studied to treat the long-term
complications of diabetes. For instance, Pimagedine(R) (amino-quanidine
hydrochloride), a product nearing FDA approval, preserves kidney function in
patients with kidney damage.
- PMPY costs for antidiabetic drugs, both oral and insulins, rose 22.2
percent in 1999 to $14.82. Utilization growth and average cost per
prescription increases accounted for about equal proportions of these
increases.
ORAL HYPOGLYCEMICS
People with Type 2 diabetes do not always have to take insulin. Often, they can
use oral medication with or without supplemental insulin to help use their
endogenous insulin more effectively. Beginning in the 1950s, the sulfonylurea
class of drugs offered an oral alternative to injected insulin. A second
generation of better acting, more refined sulfonylureas came to market during
the 1980s. Nearly all of those products are now available in generic forms.
At least four new classes of oral antidiabetic agents have been introduced in
the United States during the past few years. Each class works differently. For
example, an alpha-glucosidase inhibitor, Precose(R) (acarbose), delays
carbohydrate absorption. Biguanides increase the usefulness of naturally
produced insulin and also reduce glucose production. Glucophage(R) (metformin)
is the only biguanide currently marketed in the United States. Prandin(R)
(repaglinide) is a meglitinide; it promotes endogenous insulin production.
Thiazolidinediones or "glitazones" increase insulin sensitivity. Oral
antidiabetic medications are often used in combination with one another or with
insulin.
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FIGURE A25: THERAPY CLASS DRUG MARKET SHARE TREND
ORAL HYPOGLYCEMICS
[THERAPY CLASS DRUG MARKET SHARE TREND
ORAL HYPOGLYCEMICS LINE CHART]
- As second generation oral sulfonylurea medications become available
generically, the original brand name products are declining in use. One
exception is Glucotrol(R) XL (glipizide sustained-release), which is
not available generically. The use of Glucotrol(R) XL increased from 11
percent to 11.2 percent between 1998 and 1999.
- While the market shares for Precose(R) and Prandin(R) remain at about 1
percent each, Glucophage(R)'s market share continued to rise from 18.8
percent in 1997 to 21.5 percent in 1998 then to 25.5 percent in 1999.
- Amid concerns about liver toxicity associated with the use of the
earliest "glitazone", Rezulin(R) (troglitazone), it was removed from
the U.S. market in March 2000.
- Two new "glitazones" were introduced to the U.S. market during 1999.
Avandia(R) (rosiglitazone) was approved in May, and Actos(R)
(pioglitazone) received FDA approval in July. Although liver function
testing is recommended for patients taking either Avandia(R) or
Actos(R), neither drug has yet produced the same types of liver damage
that Rezulin(R) has caused. Avandia(R) and Actos(R) achieved 1999
market shares of 1.1 percent and 0.4 percent, respectively.
- In August 1999 the company that was experimenting with Alond(R)
(zopolrestat), an aldose reductase inhibitor, decided not to continue
clinical investigation for the treatment of peripheral diabetic
neuropathy. Trials are continuing for the effectiveness of zopolrestat
in treating kidney and heart damage caused by diabetes.
FUTURE TRENDS
- Starlix(R) (nateglinide 1) is an insulin secretagogue, another new
class of oral medications that stimulate the pancreas to produce more
insulin. In December 1999 an NDA was submitted for its review, and the
FDA may have a decision on Starlix(R) by mid-2000. Derived from an
amino acid (phenylalanine), Starlix(R) has a mechanism of action
different from other oral antidiabetic
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medications. With both a fast onset and a short duration of action, it
can be taken close to mealtimes -- making it more convenient for
patients to use.
- Glucophage(R) was scheduled to go off patent early in 2000, but a
six-month extension was granted because clinical trials for pediatric
indications are being conducted. In other efforts to prolong its
profitability, the company that makes Glucophage(R) has filed not only
for a new controlled-release dosage form -- to be called Glucophage(R)
XR, but also for a new combination tablet, Glucovance(R), containing
both metformin and glyburide, which is one of the sulfonylureas.
- Voglibose, an alpha glucosidase inhibitor, is in Phase III clinical
trials in the U.S. Under the brand name Basen(R), voglibose has been
approved in Japan since 1994.
INSULINS
People who have Type 1 diabetes mellitus require the injection of exogenous
insulin because they do not make insulin naturally. The earliest exogenous
insulins were obtained from beef or pork tissues, but recombinant DNA (rDNA)
technology changed insulin production completely. Semi-synthetic rDNA insulins
more closely match the insulin naturally produced by humans. Today insulin is
available in many different formulations -- some act quickly but for short
lengths of time; others are slow in onset but long lasting. Insulins currently
on the market require injection.
FIGURE A26: THERAPY CLASS DRUG MARKET SHARE TREND
INSULINS
[THERAPY CLASS DRUG MARKET SHARE TREND
INSULINS LINE CHART]
- Partly due to unsubstantiated fears that Mad Cow Disease may be
transmitted through beef insulin, the manufacturer no longer makes
Iletin(R) I. Although beef insulin may be imported for personal use,
importation involves cumbersome paperwork. Purified insulins derived
from pork are still available for people who prefer an animal product
to the recombinant DNA insulins.
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FUTURE TRENDS
- Humulin(R) (rDNA human insulin) is losing patent protection this year.
- In April 2000 the FDA approved Lantus(R) (insulin glargine), a new
recombinant human insulin product for treatment of type 1 and type 2
diabetes. Lantus(R) is injected once daily at bedtime to release a
relatively constant level of insulin over 24 hours. Its slower, more
prolonged absorption is less likely to produce pronounced high or low
blood-glucose levels than is NPH insulin.
- On the other end of the insulin activity spectrum is insulin aspart, a
very rapid-acting insulin designed to be effective even when taken at
mealtime. Insulin aspart has been approved in Europe as NovoRapid(R);
in the United States it will probably be called Novolog(R) after FDA
approval.
- New mixtures of insulin types that can be taken with only one injection
are appearing, as well. Mixtures like Humulin(R) 70/30 (70 percent
human insulin isophane suspension and 30 percent human insulin
injection [rDNA origin]) have been available for several years. They
will now be joined by combinations that contain a rapid-acting insulin.
Humalog(R) Mix 75/25(R) (75 percent human lispro protamine suspension
and 25 percent insulin lispro injection [rDNA origin]) is the first new
combination insulin to be approved by the FDA.
- Oral forms of insulin continue to be tested. One form in clinical
trials would be dissolved in the mouth to enter the bloodstream
directly through the cheek lining. Oralin(R), a liquid insulin
administered through an inhaler similar to the ones used for asthma
medications, is in Phase II and Phase III trials in Canada. Liquid
insulin particles must be exactly the right size or they will not reach
lung tissues where they are absorbed. Another investigational method of
delivering insulin orally uses a mechanical device to spray dry
powdered insulin called Exubera(R) into the lungs. Exubera(R) may be
marketed in the United States as early as 2001. A transdermal insulin
patch is in very early stages of development.
ANTICANCER
Although over 100 distinctly different diseases are all classified as cancers,
they can be grouped into four general types. Most frequently diagnosed are
carcinomas, tumors that begin in the surface layers of the body's organs or
cavities. Common sites of carcinomas include the lungs, breast, colon and
prostate. Leukemias are cancers of the blood. In leukemias, white blood cells
multiply uncontrollably, interfering with normal blood production and function.
A similar problem occurs with lymphomas -- specialized white blood cells called
lymphocytes are overproduced, displacing normal cells and spreading through the
lymphatic system. The fourth major type of cancer, sarcoma, is relatively rare.
Sarcomas originate in connective tissues like muscles or bones. Any type of
cancer can spread -- or metastasize -- to other parts of the body.
The exact cause of cancer is not usually known. Some cancers do have clear links
to environmental factors -- such as lung cancers in people who smoke cigarettes.
Genetic predisposition appears to be involved in other cancers. Daughters of a
man who has colon cancer, for instance, are more likely than other women to
develop cancers of the breast.
Early detection of cancer offers the best chance of survival. Treatment usually
involves surgery to remove solid tumor tissue, followed by radiation and drugs
(chemotherapy) to kill any remaining cancer cells. Often, more than one drug is
used at the same time, and cancer medications are
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<PAGE> 100
frequently used off-label to treat forms of cancer for which they are not
specifically indicated. The ongoing discovery of cancer's genetic markers is
leading not only to new treatments, but also to new diagnostic procedures that
can identify cancers before they spread.
In the past, medications -- especially those for the various types of cancer --
were developed according to the shape of chemical receptors in the body. More
recently research has focused on the interruption of functions that are
essential for cancer cell replication. A prime example is the use of monoclonal
antibodies designated as "MAb" or as the suffix "-mab" in generic drug names.
Antibodies are extremely specific -- each type inhibits one particular antigen
so only one exact type of tissue is affected. Once activated, antibodies prevent
recurrence of the cells they are programmed to fight.
Another promising area of anticancer research is the development of angiogenesis
inhibitors, which prevent tumors from developing new blood vessels. Other
studies center on antisense compounds, which keep cancer cells from forming
proteins they need to grow. Anticancer vaccines are also beginning to be used.
Unlike traditional vaccines that prevent specific diseases, cancer vaccines are
for people who already have cancer. In general, cancer vaccines are derived from
tumor cells taken from an individual patient, changed to make them invoke that
patient's immune system then re-introduced into the patient's body. An immune
response similar to that seen in organ transplant rejection causes the body to
reject the cancer cells.
Since they are much more targeted to cancer cells, emerging therapies promise to
produce fewer and milder side effects than older classes of anticancer drugs. In
addition, many of the new medications are available in oral formulations. As a
result, patients who used to be hospitalized for intravenous therapy or for the
major systemic side effects associated with earlier anticancer chemotherapy will
now be able to receive effective treatment at home.
FIGURE A27: THERAPY CLASS DRUG MARKET SHARE TREND
ANTICANCER
[THERAPY CLASS DRUG MARKET SHARE TREND
ANTICANCER LINE CHART]
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- The use of some expensive injectable anticancer agents and injectable
adjuvant therapies (e.g., granulocyte stimulating factors) is growing.
The costs of these drugs generally are reflected in the medical portion
of the health care budget.
- Approved in February 1999, Ontak(R) (denileukin diftitox) is composed
of diphtheria toxin pieces that are joined genetically to
Interleukin-2, an immune modulator that promotes the production of
cells to fight infection. Ontak(R) is approved to treat a type of
lymphoma that persists or recurs after treatment with other anticancer
agents.
- After being granted orphan approval in September, Ellence(R)
(epirubicin injection) was fully FDA approved in December 1999 for the
adjuvant treatment of early node-positive breast cancer.
- Temodar(R) (temozolomide capsules) was launched in fourth quarter 1999
for the treatment of refractory anaplastic astrocytoma, a type of brain
tumor.
- In November 1999, the FDA approved Aromasin(R) (exemestane tablets)
which permanently inhibits a specific enzyme. Used in oral form,
Aromasin(R) is indicated for postmenopausal women with advanced breast
cancers that have not responded to other therapy.
- Previously approved only for breast cancer, Taxotere(R) (docitaxel)
received an additional indication for non-small cell lung cancer in
December 1999.
- An oral form of Targretin(R) (bexarotene capsules) was approved in
December 1999 for one type of lymphoma. Approval of a topical gel form
for cancerous skin lesions was pending under a six-month priority
review filed in December of 1999.
- A number of investigational cancer agents have been designated as
orphan products by the FDA. Orphan approval is granted as an incentive
to pharmaceutical manufacturers so they will develop drugs for rare
diseases. A medication may have more than one orphan indication or it
may have full approval for certain conditions and orphan status in
others. Drugs that received orphan designations for cancer during 1999
include Hepacid(R) (pegylated arginine deiminase) for a type of liver
cancer, Melanocid(R) (pegylated arginine deiminase) for invasive
malignant melanoma; Nipent(R) (pentostatin) for certain lymphomas and
Theragyn(R) (Murine MAb to polymorphic epithelial mucin, human milk fat
globule 1) for adjuvant treatment of ovarian cancer.
FUTURE TRENDS
- In April 1999 M-Vax(R), a vaccine for a kind of skin tumor called
malignant melanoma, received approval for orphan status from the FDA. A
second melanoma vaccine, Melacine(R) (melanoma therapeutic vaccine) has
been approved fully in Canada. O-Vax(R) for late-stage ovarian cancers
and possible vaccines for breast, colon, lung and prostate cancers are
in various early phases of development.
- An application for FDA approval was filed in the summer of 1999 for
Bexxar(R) (tositumomab, iodine I 131 tositumomab), which combines a
radioactive isotope of iodine with a monoclonal antibody. Additional
data were requested before the FDA takes action on the application.
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- Viadur(R), an implantable form of leuprolide acetate, was approved for the
treatment of prostate cancer in March 2000. One Viadur(R) implant per year
can replace the daily or monthly injections that some prostate cancer
patients currently must take.
- An application for arsenic trioxide as treatment for an acute type of
leukemia was put on fast-track approval mode by the FDA after being filed in
March 2000.
- Novantrone(R) (mitoxantrone for injection concentrate), previously indicated
for Multiple Sclerosis (MS) patients, was also approved in March 2000 for
the alleviation of pain associated with advanced prostate cancer.
- Early in 2000, the FDA gave both orphan approval and priority status to
Mylotarg(R) (gemtuzamab zogamicin) for the treatment of relapsed adult acute
myeloid leukemia. A unique combination of a synthesized antibody and a
chemotherapeutic agent, Mylotarg(R) is specifically targeted at an antigen
released by leukemia cells.
- Extensive lawsuits are delaying the introduction of generic Taxol(R)
(paclitaxel). Widely used to treat both ovarian cancers and Kaposi's
Sarcoma, a complication of AIDS, Taxol(R) has several original patents with
different expiration dates.
- Zometa(R) (zoledronic acid for injection), a bisphosphonate, is in
accelerated review for the treatment of hypercalcemia -- high levels of
calcium in the blood. Hypercalcemia is a metastatic bone complication of
some cancers.
- Marimastat, the oral angiogenesis inhibitor closest to general marketing in
the United States, has been involved in at least eight Phase III trials
around the world for the past 12 years. Despite disappointing results from
some of the studies, marimastat and similar chemicals still show promise in
treating a wide range of solid tumor-type cancers. They inhibit enzymes
called matrix metalloproteinases (MMPs), which may break down the body's own
natural immunity allowing cancers to grow and spread. MMPs may also be
involved in the development of new blood vessels that feed tumors.
- Rubitecan (9-nitrocamptothecin [9NC] for oral administration) is a
topoisomerase I inhibitor that is in Phase III clinical trials for
pancreatic cancer and Phase II trials for a number of other cancers. Under
its former designation, RF 2000, rubitecan already has orphan approval for
cancer of the pancreas. An inhaled dosage form is also being developed.
- Other research involves a composite of DNA with antigens and lipids.
Injected directly into tumor tissue, these compounds -- sometimes called
vectins -- work locally on tumor cells but not on normal cells. The most
advanced product in the class, Allovectin-7(R) (HLA-B7/Beta2M DNA Lipid
DMRIE/DOPE Complex), was designated as an orphan drug for the treatment of
metastatic melanoma by the FDA in October 1999.
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[BLANK PAGE]
100
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Drug Utilization
and Cost
by Sex and Age
APPENDIX B
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DRUG UTILIZATION AND COST BY SEX AND AGE
The number, type and cost of prescription drugs differ by the sex and age of
members in a given population. Appendix B of the Drug Trend Report details drug
utilization and cost as they vary by sex and age. The first section of Appendix
B discusses the most frequently used therapy classes; the second section
examines overall utilization and cost; and the third section details drug
utilization by therapy class for male and female members of varying age groups.
METHODS
Systematic sampling was used to select a representative subset of pharmaceutical
claims from the same database that has been used elsewhere in the Drug Trend
Report. Using this method, every 60th claim was selected from the Express
Scripts Drug Trend database. This resulted in a total of 1,380,069 pharmacy
claims with each claim representing a prescription filled between Jan. 1, 1999
and Dec. 31, 1999. Claims for prescriptions processed through the mail pharmacy
service were converted to 30-day network equivalents. Each claim included
information on the member's sex and age, the drug dispensed, the date the
prescription was filled and the days supply of medication the member received.
Drug utilization and cost were then compared between females and males, and
among members of various age groups.
MOST FREQUENTLY USED THERAPY CLASSES BY SEX AND AGE
TABLE B1: MOST FREQUENTLY USED THERAPY CLASSES BY SEX
<TABLE>
<CAPTION>
FEMALES MALES
RANK THERAPY CLASS PERCENT OF RANK THERAPY CLASS PERCENT OF
PRESCRIPTIONS PRESCRIPTIONS
<S> <C> <C> <C> <C> <C>
1 Estrogens 8.1 1 Antihypertensives 9.1
2 Antidepressants 6.3 2 Antihyperlipidemics 6.0
3 Oral Contraceptives 5.6 3 Antidiabetics 5.0
4 Antihypertensives 4.5 4 Narcotic Analgesics 4.7
5 Narcotic Analgesics 4.3 5 Ulcer/Gastrointestinal 4.4
6 Cough/Cold 4.3 6 Cough/Cold 4.4
7 Antirheumatics/NSAIDs 3.7 7 Antiasthmatics 4.2
8 Ulcer/Gastrointestinal 3.6 8 Antidepressants 4.2
9 Thyroid 3.5 9 Penicillins 4.2
10 Penicillins 3.3 10 Calcium Blockers 4.0
</TABLE>
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Table B1 shows the 10 most frequently used therapy classes for females and
males, along with the percentage of prescriptions filled for drugs in each class
by each sex. As this table shows, the use of prescription drugs differed between
women and men.
Estrogens ranked highest among the most frequently used therapy classes by
female members. Used primarily by women to replace hormones lost with menopause
and to decrease the risk of osteoporosis, estrogens accounted for 8.1 percent of
all prescriptions filled among members of this sex. Other therapy classes used
more frequently, and in some cases exclusively, by females included oral
contraceptives, antirheumatics/NSAIDs and thyroid medications. NSAIDs are often
used to treat arthritis and the pain associated with osteoporosis, conditions
that have a higher rate of prevalence among women(1,2). Thyroid disease also
occurs more commonly in women, particularly among the elderly.(3)
The antidepressant class was ranked second for female members, although it was
the eighth most-frequently used therapy class among males. This may be because
women are twice as likely to be affected by depression as men are, particularly
during adolescence and the reproductive years.(4) There is also some evidence
that doctors are more likely to prescribe psychotropic medications like
antidepressants to women, even when factors such as morbidity, age and use of
other medications are controlled.(5)
Antihypertensives, antihyperlipidemics and antidiabetics are the three therapy
classes used most frequently by males. High blood pressure and high cholesterol
affect more men than women, especially those men who are less than 55 years of
age and who have a family history of heart disease.(6,7) Both of these
conditions can increase the risk for developing diabetes. However, statistics
indicate that diabetes affects men and women almost equally.(8)
Antihypertensives ranked fourth on the list among female members while
antihyperlipidemics and, surprisingly, antidiabetics did not make it into the
top 10. Calcium channel blockers, which are used to treat a variety of
conditions ranging from high blood pressure to migraine headaches, was another
therapy class that ranked among the top 10 for male members but not for females.
Other therapy classes that were included in the top 10 list for both females and
males included narcotic analgesics, cough/cold, ulcer/gastrointestinal and
penicillins. Although appearing on both lists, the rankings for these therapy
classes differed slightly between the two groups.
(1) National Institute of Arthritis and Musculoskeletal and Skin Diseases.
"Questions and Answers about Arthritis and Rheumatic Disease,"
www.nih.gov/niams/healthinfo/artrheu.htm#art_d
(2) National Osteoporosis Foundation. "Osteoporosis: Fast Facts,"
www.nof.org/osteoporosis/stats.htm
(3) Guide to Clinical Preventive Services, Second Edition, Metabolic,
Nutritional, and Environmental Disorders; "Screening for Thyroid
Disease," cpmcnet.columbia.edu/texts/gcps/gcps0030.html
(4) National Mental Health Association. "Depression in Women,"
www.nmha.org/infoctr/factsheets/23.cfm
(5) Sayer GP, Britt H. Sex differences in prescribed medications: Another
case of discrimination in general practice. Soc Sci Med
1997;10:1581-7.c
(6) National Institutes of Health. National Heart, Lung, and Blood
Institute. National High Blood Pressure Education Program. "The Sixth
Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure,"
www.nhlbi.nih.gov/guidelines/hypertension/jnc6.pdf
(7) National Institutes of Health. National Heart, Lung, and Blood
Institute. National Cholesterol Education Program. "2nd Report of the
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults,"
www.nhlbi.nih.gov/guidelines/cholesterol/atp.txt
(8) National Diabetes Information Clearinghouse. "Diabetes overview,"
www.niddk.nih.gov/health/diabetes/pubs/dmover/dmover.htm
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TABLE B2. Most Frequently Used Therapy Classes by Age
<TABLE>
<CAPTION>
AGE GROUP RANK THERAPY CLASS PERCENT OF PRESCRIPTIONS
<S> <C> <C> <C>
BIRTH TO 9 YEARS 1 Penicillins 22.5
2 Cough/Cold 9.4
3 Antiasthmatics 9.3
4 Cephalosporins 8.0
5 Macrolides 7.3
10 TO 19 YEARS 1 Dermatologicals 11.4
2 Penicillins 8.5
3 Cough/Cold 7.5
4 Antiasthmatics 7.3
5 Stimulants/Anti-obesity 7.1
20 TO 29 YEARS 1 Oral Contraceptives 19.5
2 Cough/Cold 6.5
3 Narcotic Analgesics 6.3
4 Dermatologicals 5.4
5 Antidepressants 5.4
30 TO 39 YEARS 1 Oral Contraceptives 9.3
2 Antidepressants 7.8
3 Narcotic Analgesics 7.1
4 Cough/Cold 6.3
5 Antirheumatics/NSAIDs 4.1
40 TO 49 YEARS 1 Antidepressants 7.9
2 Antihypertensives 6.3
3 Narcotic Analgesics 6.0
4 Estrogens 5.7
5 Cough/Cold 4.6
50 TO 59 YEARS 1 Estrogens 10.7
2 Antihypertensives 8.9
3 Antihyperlipidemics 5.9
4 Antidepressants 5.3
5 Antidiabetics 4.9
60 TO 69 YEARS 1 Antihypertensives 10.3
2 Antihyperlipidemics 7.7
3 Estrogens 6.3
4 Antidiabetics 5.8
5 Calcium Blockers 5.5
70 TO 79 YEARS 1 Antihypertensives 9.7
2 Antihyperlipidemics 6.8
3 Diuretics 5.9
4 Calcium Blockers 5.9
5 Antidiabetics 5.1
80 YEARS AND ABOVE 1 Antihypertensives 8.9
2 Diuretics 8.2
3 Calcium Blockers 5.8
4 Ulcer/Gastrointestinals 4.7
5 Beta Blockers 4.3
</TABLE>
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TABLE B3. Most Frequently Used Therapy Classes by Sex and Age
<TABLE>
<CAPTION>
FEMALES MALES
AGE GROUP RANK THERAPY CLASS PERCENT OF RANK THERAPY CLASS PERCENT OF
PRESCRIPTIONS PRESCRIPTIONS
<S> <C> <C> <C> <C> <C> <C>
BIRTH TO 9 YEARS 1 Penicillins 23.8 1 Penicillins 21.3
2 Cough/Cold 9.8 2 Antiasthmatics 10.6
3 Cephalosporins 8.4 3 Cough/Cold 9.1
4 Antiasthmatics 7.9 4 Cephalosporins 7.6
5 Macrolides 7.4 5 Macrolides 7.3
10 TO 19 YEARS 1 Dermatologicals 11.0 1 Dermatologicals 11.8
2 Oral Contraceptives 9.9 2 Stimulants/Anti-obesity 11.5
3 Penicillins 8.9 3 Antiasthmatics 8.7
4 Cough/Cold 7.5 4 Penicillins 8.1
5 Antiasthmatics 6.0 5 Cough/Cold 7.4
20 TO 29 YEARS 1 Oral Contraceptives 26.0 1 Cough/Cold 9.0
2 Cough/Cold 5.6 2 Narcotic Analgesics 8.8
3 Narcotic Analgesics 5.5 3 Dermatologicals 6.8
4 Antidepressants 5.4 4 Penicillins 6.1
5 Dermatologicals 5.0 5 Antidepressants 5.6
30 TO 39 YEARS 1 Oral Contraceptives 13.6 1 Narcotic Analgesics 8.6
2 Antidepressants 8.4 2 Cough/Cold 7.3
3 Narcotic Analgesics 6.4 3 Antidepressants 6.4
4 Cough/Cold 5.9 4 Antihypertensives 5.5
5 Antirheumatics/NSAIDs 3.8 5 Ulcer/Gastrointestinals 5.3
40 TO 49 YEARS 1 Antidepressants 8.9 1 Antihypertensives 9.7
2 Estrogens 8.8 2 Narcotic Analgesics 6.8
3 Narcotic Analgesics 5.5 3 Antihyperlipidemics 6.4
4 Cough/Cold 4.7 4 Antidepressants 5.9
5 Antihypertensives 4.4 5 Ulcer/Gastrointestinals 5.6
50 TO 59 YEARS 1 Estrogens 16.8 1 Antihypertensives 13.1
2 Antihypertensives 6.5 2 Antihyperlipidemics 9.6
3 Antidepressants 6.1 3 Antidiabetics 7.2
4 Ulcer/Gastrointestinals 4.2 4 Calcium Blockers 5.6
5 Diuretics 4.1 5 Beta Blockers 5.3
60 TO 69 YEARS 1 Estrogens 11.1 1 Antihypertensives 13.4
2 Antihypertensives 8.0 2 Antihyperlipidemics 9.8
3 Antihyperlipidemics 6.0 3 Antidiabetics 7.7
4 Diuretics 5.5 4 Calcium Blockers 6.5
5 Calcium Blockers 4.7 5 Beta Blockers 5.7
70 TO 79 YEARS 1 Antihypertensives 8.1 1 Antihypertensives 11.7
2 Diuretics 6.3 2 Antihyperlipidemics 7.5
3 Antihyperlipidemics 6.2 3 Antidiabetics 6.2
4 Calcium Blockers 5.7 4 Calcium Blockers 6.0
5 Beta Blockers 4.8 5 Diuretics 5.5
80 YEARS 1 Diuretics 8.4 1 Antihypertensives 10.6
AND ABOVE 2 Antihypertensives 7.8 2 Diuretics 7.9
3 Calcium Blockers 6.2 3 Calcium Blockers 5.2
4 Ulcer/Gastrointestinals 4.7 4 Ulcer/Gastrointestinals 4.5
5 Opthalmic Products 4.3 5 Beta Blockers 4.5
</TABLE>
105
<PAGE> 109
Table B2 categorizes the drug use of Express Scripts members by age groupings.
For each of the nine age groups, the five most frequently used therapy classes
are listed along with the percentage of prescriptions filled for drugs in that
class.
As one might expect, drugs used to treat infections, coughs and colds, and
respiratory conditions dominated the list for children from birth through 9
years of age. In fact, the top five therapy classes accounted for more than 50
percent of all the prescriptions filled for children in this age group.
Although most of these same therapy classes are still widely used by preteens
and teenagers, the most commonly used therapy class among 10-19 year olds was
the dermatologicals. This is likely to be related to the treatment of acne,
which affects about 85 percent of individuals in this age group.(9) One
surprising finding is that drugs in the stimulant/anti-obesity class were used
almost as often as drugs for cough/colds and respiratory conditions among
members aged 10-19 years.
Table B3, which categorizes drug use by both sex and age, showed that drugs in
the stimulant/ anti-obesity class were used with great frequency by males in
the 10-19 age group but did not rank among the top five therapy classes for
females in any age group. Further analysis showed that methylphenidate HCl
(Ritalin(R)) accounted for 7.4 percent of all prescriptions filled for males in
this age group, primarily attributed to the treatment of Attention Deficit
Hyperactivity Disorder (ADHD). Although some medical professionals and
consumers believe stimulant drugs are being overused in children with ADHD,
reports suggest that fewer children are treated for ADHD than prevalence rates
indicate may actually suffer from it -- specifically in regard to females and
children in certain minority groups. One explanation for an increase in the use
of stimulant drugs is that ADHD may be diagnosed inappropriately in children
who have not fully meet the diagnostic criteria.(10)
The drugs that were dispensed most commonly among all members in their 20s and
30s were the oral contraceptives. Although not apparent in Table B2, Table B3
shows that oral contraceptives accounted for 9.9 percent of the prescriptions
used by females in the 10-19 year age group. Narcotic analgesics, which are
used to treat various types of pain, entered the top five therapy classes for
the 20-29 age group. For individuals in their 30s, the narcotic analgesics were
joined by antirheumatics/NSAIDs -- another class of drugs used for pain.
Antidepressants were the fifth most frequently used therapy class among members
aged 20-29. They leapt to number two in the rankings for members in their 30s,
and were the most common therapy class used among members in their 40s.
Antidepressants were fourth-ranked among members in their 50s, finally
disappearing from the top five for members aged 60 and above.
Linked to the arrival of menopause, estrogens were used frequently by members
aged 40-49 and were the most commonly prescribed therapy class among members in
their 50s. Estrogens were ranked third on the list for members aged 60-69 years
and disappeared completely from the top five rankings thereafter.
(9) National Institute of Arthritis and Musculoskeletal and Skin Diseases.
"Questions and Answers about Acne,"
www.nih.gov/niams/healthinfo/acne/acne.htm#acne_d
(10) National Institute of Mental Health. "Mental Health: A Report of the
Surgeon General on Attention-Deficit/Hyperactivity Disorder,"
www.nimh.nih.gov/mhsgrpt/chapter3/sec4.html
106
<PAGE> 110
The antihypertensive therapy class began to be used extensively among members
in their 40s, ranking second to antidepressants in that age stratum.
Antihypertensives continued to play an important role throughout the rest of
the adult years, ranking as the second most frequently used therapy class among
members in their 50s and occupying the top ranking in the remaining age
categories. Like the antihypertensives, calcium channel blockers are used to
treat high blood pressure. Frequent use of calcium channel blockers occurred
later in the lifespan than for antihypertensives, however, and only began to
appear among the top five therapy classes for members 60 years of age and
older. Frequent use of diuretics and beta blockers, also used in the treatment
of high blood pressure, was associated with the older adult years as well.
Antihyperlipidemics and antidiabetics were frequently used among members in
their 50s, 60s, and 70s while ulcer/gastrointestinal drugs were commonly used
by those who were 80 years of age and older.
OVERALL UTILIZATION AND COST BY SEX AND AGE
Since these analyses are based on a systematic sampling of claims from the
Express Scripts Drug Trend database, the underlying sex and age distribution of
sample members is unavailable. For that reason, these analyses are for
descriptive purposes only and do not provide the reason(s) for relatively high
or low utilization by a sex/age category. That is, particularly high or low
utilization within a sex/age category could be due to the relative number of
members in that category, to the relative usage of drugs per category member or
to a combination of both factors.
TABLE B4: Overall Drug Utilization by Sex and Age
<TABLE>
<CAPTION>
# OF PRESCRIPTIONS % OF PRESCRIPTIONS(11)
AGE GROUP FEMALES MALES TOTAL FEMALES MALES TOTAL
<S> <C> <C> <C> <C> <C> <C>
Birth-9 years 34,528 40,930 75,458 2.5 3.0 5.5
10-19 years 42,252 38,444 80,696 3.1 2.8 5.8
20-29 years 74,431 24,741 99,172 5.4 1.8 7.2
30-39 years 128,555 58,983 187,538 9.3 4.3 13.6
40-49 years 189,777 101,337 291,114 13.8 7.3 21.1
50-59 years 211,871 123,872 335,743 15.4 9.0 24.3
60-69 years 106,824 81,985 188,809 7.7 5.9 13.7
70-79 years 48,070 38,394 86,464 3.5 2.8 6.3
80+ years 21,787 13,288 35,075 1.6 1.0 2.5
TOTAL 858,095 521,974 1,380,069 62.2 37.8 100.0
</TABLE>
(11) Due to rounding error, the sum of the percentage of prescriptions used
by males and females within an age group may not exactly equal the
total percentage of prescriptions filled by that age group. Likewise,
also due to rounding error, the sum of the percentages of prescriptions
filled by females or males of each age group may not exactly equal the
total percentage of prescriptions filled by that sex.
107
<PAGE> 111
Table B4 shows the number as well as the percentage of prescriptions for all
therapy classes combined that were attributable to females, males and members of
each age group.
FIGURE B1 : PERCENT OF PRESCRIPTIONS FILLED BY MEMBERS OF EACH
SEX AND AGE CATEGORY
[PERCENT OF PRESCRIPTIONS FILLED BY MEMBERS OF EACH
SEX AND AGE CATEGORY BAR CHART]
<TABLE>
<CAPTION>
% OF PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 2.5 3.0
10-19 years 3.1 2.8
20-29 years 5.4 1.8
30-39 years 9.3 4.3
40-49 years 13.8 7.3
50-59 years 15.4 9.0
60-69 years 7.7 5.9
70-79 years 3.5 2.8
80+ years 1.6 1.0
</TABLE>
There were no significant changes from 1998 to 1999 in the distribution of
prescriptions overall as a function of age and sex (Figure B1). Females
accounted for more prescriptions than males, with a greater disparity in the
proportion of prescriptions attributable to males and females occurring for
members aged 20 through 59 years. In 1999, 62.2 percent of all prescriptions
were filled for females, although other analyses showed that females made up
only 51.2 percent of the population of Express Scripts members. This indicates
that females filled more prescriptions per member than males. Both female and
male members between 30 and 69 years of age were responsible for the bulk of the
more than 1.3 million prescriptions in this sample.
95-percent confidence intervals were calculated for each of the sample
percentages shown in Table B4. Confidence intervals are used to estimate how
closely values based on a sample represent the population values (in this case,
the values that would have resulted if the entire Express Scripts Drug Trend
database had been used in these analyses). The 95-percent confidence interval
calculations showed that each of the sample percentages is accurate to within
plus minus 0.1 percentage points. For example, Table B4 states that females aged
0 to 9 years accounted for 2.5 percent of sample prescriptions. The confidence
interval calculation indicates that there is a 95-percent probability that the
percentage of prescriptions attributable to females between the ages of birth
and 9 years the entire Express Scripts database lies somewhere between 2.4
percent and 2.6 percent.
108
<PAGE> 112
TABLE B5: Percent of Total AWP, Mean AWP Per Prescription, and Percent Change in
Mean AWP Per Prescription by Sex and Age Groups
<TABLE>
<CAPTION>
% OF TOTAL AWP(12) MEAN AWP PER PRESCRIPTION % CHANGE IN MEAN AWP
FROM 1998 TO 1999
AGE GROUP FEMALES MALES TOTAL FEMALES MALES TOTAL FEMALES MALES TOTAL
<S> <C> <C> <C> <C> <C> <C> <C> <C> <C>
Birth-9 years 1.4 1.9 3.3 $26.54 $29.69 $28.25 8.30 11.52 10.13
10-19 years 2.7 3.0 5.7 $41.84 $50.41 $45.93 11.85 5.84 8.65
20-29 years 4.4 1.8 6.2 $37.97 $46.75 $40.16 10.10 8.24 9.60
30-39 years 8.7 4.8 13.6 $43.90 $52.68 $46.66 9.94 6.18 8.67
40-49 years 13.7 8.6 22.3 $46.59 $54.88 $49.48 8.61 6.71 7.95
50-59 years 14.7 10.4 25.1 $44.65 $54.19 $48.17 10.34 5.50 8.44
60-69 years 7.7 6.8 14.5 $46.35 $53.75 $49.57 12.25 6.87 9.77
70-79 years 3.7 3.2 6.8 $49.39 $52.92 $50.95 18.20 9.45 14.04
80+ years 1.5 1.0 2.5 $44.84 $48.97 $46.41 20.25 10.90 16.37
TOTALS 58.5 41.5 100.0 $44.01 $51.30 $46.77 10.96 7.24 9.58
</TABLE>
Average Wholesale Price (AWP) was used to reflect ingredient cost in these
analyses to ensure comparability across time and for all clients. The percent of
AWP costs accounted for by each sex/age group combination is presented in Table
B5, together with the mean AWP per prescription for 1999. Table B5 also shows
the percent change in mean AWP per prescription from 1998 to 1999 as a function
of age and sex. The percentage of total pharmacy costs (percent of total AWP)
borne by each of the sex/age group categories in 1999 was similar to that shown
in 1998. The majority of costs were attributable to members aged 20-59 years.
Females accounted for 62.2 percent of all prescriptions filled by Express
Scripts members but only 58.5 percent of costs. This disparity indicates that
the mean cost per prescription is less for females than males, a fact that is
confirmed by the mean AWP per prescription figures of $44.01 for females and
$51.30 for males. Prescriptions for children from birth through age 9 were the
least expensive ($28.25 per prescription) and those for adults aged 70-79 years
were the most expensive ($50.95 per prescription), a difference of $22.70 per
prescription between these age groups.
95-percent confidence interval calculations indicate that there is a 95-percent
probability that each of the sample percentages listed under the heading "% of
Total AWP" in Table B4 were within (plus/minus) 0.1 percentage points of the
corresponding percentage values which would have resulted if the entire Express
Scripts Drug Trend database had been analyzed. Likewise, 95-percent confidence
interval calculations indicate that for each of the mean AWP values calculated
from the sample (Table B5), there is a 95-percent probability that the
corresponding mean AWP value in the entire Express Scripts Drug Trend database
lies within (plus/minus) $1.51 of the sample mean.
(12) Due to rounding error, the sum of the percentage of AWP attributed to
males and females within an age group may not exactly equal the total
percentage of AWP attributed to that age group. Likewise, also due to
rounding error, the sum of the percentages of AWP attributed to females
or males of each age group may not exactly equal the total percentage
of AWP attributed to that sex.
109
<PAGE> 113
FIGURE B2: MEAN AWP PERCENT CHANGE FROM 1998 TO 1999
BY SEX AND AGE
[MEAN AWP PERCENT CHANGE FROM 1998 TO 1999
BY SEX AND AGE BAR CHART]
<TABLE>
<CAPTION>
1998-1999 % OF CHANGE
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 8.3 11.5
10-19 years 11.9 5.8
20-29 years 10.1 8.2
30-39 years 10.0 6.2
40-49 years 8.6 6.7
50-59 years 10.3 5.5
60-69 years 12.3 6.9
70-79 years 18.2 9.5
80+ years 20.3 10.9
</TABLE>
The mean AWP per prescription overall rose from $42.68 in 1998 to $46.77 in
1999, an increase of 9.58 percent (Table B5). The percent change in mean AWP
per prescription from 1998 to 1999 varied as a function of sex and age (Figure
B2). There was a greater percent change in cost per prescription for females
(+10.96 percent) than for males (+7.24 percent), and cost increases impacted
elderly members to a greater degree than younger members. The mean AWP per
prescription increased 14.04 percent and 16.37 percent for members aged 70-79
years and those 80 years of age and above, respectively.
As Figure B2 shows, 1998-1999 increases in cost per prescription hit elderly
females disproportionately hard. Mean AWP per prescription increased 18.2
percent for women in their 70s, and 20.25 percent for women 80 years of age and
older. In contrast, the percent increase for every other sex/age group
combination was less than 13 percent. In dollar terms, women 70 years of age
and older were paying approximately $7.50 more per prescription in 1999
compared with 1998 on average. The mean dollar increase for each of the other
sex/age group strata was on the order of $5 or less per prescription.
110
<PAGE> 114
UTILIZATION OF EACH THERAPY CLASS BY SEX AND AGE(13)
This section examines the percentage of prescriptions attributed to members of
each sex/age grouping for each therapy class.
GASTROINTESTINAL
FIGURE B3: GASTROINTESTINAL DRUGS.
[GASTROINTESTINAL DRUGS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.7 0.7
10-19 years 1.2 0.9
20-29 years 2.4 1.8
30-39 years 7.1 5.8
40-49 years 14.0 10.5
50-59 years 16.4 11.8
60-69 years 9.2 7.2
70-79 years 4.2 3.3
80+ years 1.9 1.1
</TABLE>
The majority of prescriptions for gastrointestinal drugs were filled by females
(57 percent) although males also filled a respectable percentage of
prescriptions (43 percent). As might be expected, individuals aged 40-79 years
used the bulk of prescriptions in this class. Research suggests that there may
still be discrepancies in the way that medical professionals treat Peptic Ulcer
Disease (PUD), with specialists being more likely to prescribe eradication
therapy for Helicobacter pylori.(14) Current efforts focus on improving existing
therapies for PUD. Another important area of development is in the treatment of
Irritable Bowel Syndrome (IBS), a condition that affects up to 20 percent of
Americans at some time in their lives and that appears to be more prevalent
among women.(15)
(13) 95%-confidence interval calculations indicate that for each of the
sample percentages (in every therapy class examined), there is a 95%
probability that the corresponding percentage value in the entire
Express Scripts Drug Trend database lies within (plus/minus) 1.1
percentage points of the sample percentages.
(14) Fendrick AM., et al. Differences between generalist and specialist
physicians regarding Helicobacter pylori and peptic ulcer
disease. American Journal of Gastroenterology 1996; 91(8):1544-8.
(15) Heitkemper M., et al. Evidence for autonomic nervous system imbalance
in women with irritable bowel syndrome. Digestive Diseases & Sciences
1998;43(9):2093-8.
111
<PAGE> 115
CENTRAL NERVOUS SYSTEM
FIGURE B4: ANTIDEPRESSANTS
[ANTIDEPRESSANTS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.3 0.6
10-19 years 2.5 2.6
20-29 years 5.3 1.8
30-39 years 14.3 4.9
40-49 years 22.3 7.9
50-59 years 17.0 6.7
60-69 years 6.0 2.8
70-79 years 2.3 1.1
80+ years 1.1 0.5
</TABLE>
More than two-thirds of all prescriptions for antidepressants were used by
females, especially women in their middle years. Over 50 percent of all 1999
prescriptions for antidepressants (53.6 percent) were filled by women age 30-59
years. A recent report from the Surgeon General indicates that nearly half of
all Americans who suffer from a mental illness, such as depression, fail to seek
treatment. Goals for the future include increasing public awareness about mental
illnesses and the available treatment options as well as overcoming the stigma
of these illnesses. Ongoing research will look at tailoring therapies to
individuals based on age, gender, race and culture.(16)
FIGURE B5: ANTIANXIETY AGENTS
[ANTIANXIETY AGENTS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.8 1.0
10-19 years 0.9 0.8
20-29 years 3.2 1.5
30-39 years 11.2 4.8
40-49 years 19.0 8.4
50-59 years 17.5 8.2
60-69 years 8.8 4.5
70-79 years 4.3 2.5
80+ years 2.0 0.9
</TABLE>
(16) "Scientific Revolution" In Mental Health Research And Services Declared
In First Surgeon General's Report On Mental Health. HHS News, December
1999. www.nimh.nih.gov/events/prsurgeon.cfm
112
<PAGE> 116
The distribution of prescriptions for antianxiety agents by sex and age is
similar to that shown for antidepressants. Like antidepressants, the majority of
antianxiety agents were used by females. Most prescriptions for these agents
were dispensed to members age 30-69 years. A number of drugs are now available
to treat anxiety disorders and, with proper treatment, many people will
experience significant improvement in their symptoms. Behavioral therapies play
an important part as well, which is why researchers are looking at the use of
combined therapies.(17)
CARDIOVASCULAR
FIGURE B6: ANTIHYPERTENSIVES
[ANTIHYPERTENSIVES BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.1 0.4
10-19 years 0.1 0.5
20-29 years 0.4 0.6
30-39 years 2.6 3.7
40-49 years 9.8 11.3
50-59 years 15.9 18.8
60-69 years 9.9 12.7
70-79 years 4.5 5.2
80+ years 2.0 1.6
</TABLE>
The antihypertensive therapy class was one of only three classes in which males
filled more prescriptions than females (54.9 percent versus 45.1 percent). More
than three-fourths of all prescriptions in this class (78.3 percent) were filled
by members age 40-69 years. The past decade has seen an alarming decrease in the
rates of awareness and control of high blood pressure, despite evidence that
detection and proper treatment can reduce the number of deaths and disabilities
associated with uncontrolled high blood pressure. It is not yet known if medical
professionals and consumers have merely become indifferent about the treatment
of high blood pressure or if factors such as the cost of therapy have had a
significant influence.(18)
(17) National Institute of Mental Health. Anxiety Disorders Research at the
National Institute of Mental Health. Fact Sheet.
www.nimh.nih.gov/publicat/anxresfact.cfm
(18) "Decline in awareness and treatment of high blood pressure could pose a
serious public health threat." American Heart Association News Release
August 1999.
www.americanheart.org/Whats_News/AHA_News_Releases/08-19-99_1-comment.html
113
<PAGE> 117
FIGURE B7: CALCIUM CHANNEL BLOCKERS
[CALCIUM CHANNEL BLOCKERS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.0 0.0
10-19 years 0.1 0.1
20-29 years 0.5 0.4
30-39 years 2.7 3.0
40-49 years 9.6 9.7
50-59 years 16.7 16.3
60-69 years 11.8 12.4
70-79 years 6.4 5.5
80+ years 3.2 1.6
</TABLE>
FIGURE B8: BETA BLOCKERS
[BETA BLOCKERS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.1 0.1
10-19 years 0.4 0.3
20-29 years 1.3 0.7
30-39 years 4.0 3.3
40-49 years 11.5 10.0
50-59 years 16.3 16.0
60-69 years 10.5 11.3
70-79 years 5.6 5.1
80+ years 2.2 1.4
</TABLE>
Calcium channel blockers and beta blockers are typically used for the same
purposes as drugs in the antihypertensive class, and the pattern of use by age
associated with these classes is similar to that of antihypertensives. Unlike
antihypertensives, however, slightly greater percentages of prescriptions for
calcium channel blockers and beta blockers were filled for females than for
males. Based on their ability to decrease mortality, beta blockers remain a
treatment of choice for the initial therapy of uncomplicated hypertension and
for the prevention of a second heart attack in patients who have previously
experienced a heart attack.(19,20) In addition, both beta blockers and calcium
channel blockers play an important role in the prevention of migraine
headaches.(21)
(19) National Institutes of Health. National Heart, Lung, and Blood
Institute. National High Blood Pressure Education Program. "The Sixth
Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure,"
www.nhlbi.nih.gov/guidelines/hypertension/jnc6.pdf
(20) American Heart Association; "Recommendations for Secondary Prevention
of Heart Attack,"
www.americanheart.org/Heart_and_Stroke_A_Z_Guide/prevsec.html
(21) William E.M., et al. Guidelines for the diagnosis and management of
migraine in clinical practice.CMAJ 1997;156:1273-87
114
<PAGE> 118
FIGURE B9: ANTIHYPERLIPIDEMICS
[ANTIHYPERLIPIDEMICS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.0 0.0
10-19 years 0.0 0.0
20-29 years 0.2 0.3
30-39 years 1.4 2.9
40-49 years 6.4 12.0
50-59 years 14.8 22.0
60-69 years 12.0 15.0
70-79 years 5.5 5.4
80+ years 1.2 0.9
</TABLE>
Antihyperlipidemic prescriptions were most often filled by males and by
individuals 40 years of age and above. Results from a large study conducted in
the United States indicate that more than 60 percent of those receiving
lipid-lowing therapy fail to meet National Cholesterol Education Program (NCEP)
treatment goals, suggesting a need for more aggressive therapy.(22)
INFLAMMATION AND PAIN MANAGEMENT
FIGURE B10: ANTIRHEUMATICS/NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDS)
[ANTIRHEUMATICS/NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDS) BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.2 0.2
10-19 years 2.3 1.5
20-29 years 4.4 2.4
30-39 years 9.5 5.7
40-49 years 15.4 9.0
50-59 years 16.4 10.0
60-69 years 8.6 6.0
70-79 years 3.9 2.4
80+ years 1.5 0.7
</TABLE>
(22) Pearson TA., et al. The lipid treatment assessment project (L-TAP). A
multicenter survey to evaluate the percentages of dyslipidemic
patients receiving lipid-lowering therapy and achieving low-density
lipoprotein cholesterol goals. Arch Intern Med 2000;160:459-467.
115
<PAGE> 119
FIGURE B11: NARCOTIC ANALGESICS
[NARCOTIC ANALGESICS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.6 0.7
10-19 years 2.5 2.0
20-29 years 6.7 3.5
30-39 years 13.3 8.3
40-49 years 17.0 11.2
50-59 years 11.5 8.0
60-69 years 5.1 3.9
70-79 years 2.4 1.6
80+ years 1.2 0.6
</TABLE>
Females accounted for a greater percentage of prescriptions than males for both
the antirheumatic/NSAIDs and narcotic analgesic therapy classes. However, the
shape of each distribution indicates that narcotic analgesic users are slightly
younger on average than are users of antirheumatics/NSAIDs. Adequate pain
management is now recognized as an integral part of the treatment of cancer and
other conditions involving chronic pain. Current guidelines recommend early and
aggressive treatment measures, including the use of narcotic analgesics when
necessary, and dispel the notion that addiction and abuse are common among pain
sufferers.(23)
FIGURE B12: MIGRAINE PRODUCTS
[MIGRAINE PRODUCTS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.1 0.1
10-19 years 2.7 1.2
20-29 years 7.8 1.4
30-39 years 19.4 3.7
40-49 years 30.2 5.5
50-59 years 19.6 3.4
60-69 years 3.3 0.9
70-79 years 0.5 0.2
80+ years 0.1 0.1
</TABLE>
(23) Management of Cancer Pain. Clinical Practice Guideline No. 9 (AHCPR
Publication No. 94-0592).
http://text.nlm.nih.gov/ftrs/pick?collect=ahcpr&dbName=0&cc=1&t=955673335
116
<PAGE> 120
Four out of every five prescriptions for a migraine drug are filled by females,
with women in their 40s accounting for almost one-third of all prescriptions. A
recent study suggests the incidence of migraines is on the rise, particularly
among women 20-29 years of age. Based on the review of medical records for more
than 1,300 patients, the number of women newly diagnosed with migraine between
1980 and 1989 increased by 56 percent with a corresponding increase of 34
percent among men. Interestingly, the increase among women has been attributed
in part to changes in the social environment. Notable factors include the rise
in the number of single-parent households, increased stress in the workplace and
the pressures of dieting for weight loss.(24)
RESPIRATORY
FIGURE B13: ANTIASTHMATICS
[ANTIASTHMATICS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 5.5 8.8
10-19 years 5.1 6.7
20-29 years 4.2 2.7
30-39 years 7.4 4.2
40-49 years 10.9 5.7
50-59 years 11.3 5.4
60-69 years 6.5 5.9
70-79 years 3.1 3.4
80+ years 1.0 1.1
</TABLE>
Unlike most classes examined, a large proportion of antiasthmatic prescriptions
was accounted for by children. At younger ages (birth through age 19), boys
accounted for the greatest percentage of prescriptions. Conversely, women filled
more prescriptions than men did across the 20-59 year age range. The prevalence
of asthma has increased among all patient groups over the past 20 years,
regardless of age, sex or race. Even so, a report by the National Heart, Lung
and Blood Institute (NHLBI) suggests that asthma is still under-treated or
inappropriately treated in many cases -- primarily due to the inadequate use of
anti-inflammatory drugs. Special attention is now being focused on minority
children, the elderly and pregnant women with asthma.(25)
(24) Rozen TD, et al. Increasing incidence of medically recognized migraine
headache in a United States population. Neurology 1999;53(7):1468-73.
(25) National Asthma Education and Prevention: Practical Guide for the
Diagnosis and Management of Asthma 1997. NIH Publication No. 97-4053.
www.nhlbi.nih.gov/health/prof/lung/asthma/practgde/practgde.pdf
117
<PAGE> 121
FIGURE B14: ANTIHISTAMINES
[ANTIHISTAMINES BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 5.1 6.7
10-19 years 6.0 5.8
20-29 years 6.2 2.6
30-39 years 10.5 5.2
40-49 years 14.9 6.9
50-59 years 12.8 5.3
60-69 years 5.1 2.9
70-79 years 1.5 0.9
80+ years 0.5 0.3
</TABLE>
FIGURE B15: DECONGESTANTS
[DECONGESTANTS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 2.3 3.3
10-19 years 4.1 4.2
20-29 years 4.6 2.8
30-39 years 11.1 7.3
40-49 years 15.6 9.6
50-59 years 13.4 8.1
60-69 years 5.3 4.2
70-79 years 1.6 1.6
80+ years 0.6 0.4
</TABLE>
FIGURE B16: COUGH AND COLD PRODUCTS
[COUGH AND COLD PRODUCTS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 5.7 6.3
10-19 years 5.3 4.8
20-29 years 7.1 3.8
30-39 years 12.7 7.2
40-49 years 14.8 7.5
50-59 years 10.5 5.6
60-69 years 3.8 2.5
70-79 years 1.2 0.8
80+ years 0.4 0.2
</TABLE>
118
<PAGE> 122
The antihistamines, decongestants and cough/cold therapy classes are
characterized by relatively high use among young people (between 21.3 percent
and 32.9 percent of prescriptions filled by members less than 30 years of age)
and greater use by females than males, particularly in the years following
childhood. More than 40 million Americans suffer from allergic rhinitis, the
most common type of allergic condition. If left untreated, allergic rhinitis can
have a significant impact on a person's quality of life and may lead to more
serious conditions such as asthma, sinusitis and otitis media.(26)
ANTI-INFECTIVES
FIGURE B17: PENICILLINS
[PENICILLINS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 16.2 17.2
10-19 years 7.4 6.1
20-29 years 6.3 3.0
30-39 years 8.9 5.0
40-49 years 8.7 5.4
50-59 years 5.8 3.9
60-69 years 2.2 1.8
70-79 years 0.8 0.8
80+ years 0.3 0.2
</TABLE>
FIGURE B18: CEPHALOSPORINS
[CEPHALOSPORINS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 11.2 12.1
10-19 years 6.7 6.1
20-29 years 6.3 3.4
30-39 years 10.0 5.9
40-49 years 10.9 6.3
50-59 years 7.6 5.1
60-69 years 2.9 2.3
70-79 years 1.2 1.1
80+ years 0.6 0.4
</TABLE>
(26) The Allergy Report. Overview of Allergic Diseases: Diagnosis,
Management, and Barriers to Care. Volume 1. American Academy of
Allergy, Asthma, and Immunology. www.aaaai.org/ar/volume1.pdf
119
<PAGE> 123
FIGURE B19: MACROLIDES
[MACROLIDES BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 7.6 8.9
10-19 years 6.7 5.7
20-29 years 7.4 3.6
30-39 years 11.8 6.6
40-49 years 12.2 6.8
50-59 years 9.2 5.0
60-69 years 3.5 2.4
70-79 years 1.2 0.8
80+ years 0.3 0.3
</TABLE>
Like those therapy classes used to treat respiratory conditions, the
anti-infective classes show high use by younger persons. Children from birth
through age 9 accounted for more than one-third of all claims for penicillins.
Infectious diseases are a serious challenge to the world population. Since 1976,
scientists have identified approximately 30 new pathogens that have the ability
to cause disease in humans. Moreover, previously identified micro-organisms have
been shown to undergo changes that make them resistant to drugs that were once
effective. As a result, the medical community has established guidelines to
promote the judicious use of antibiotic therapy.(27)
WOMEN'S HEALTH
FIGURE B20: ORAL CONTRACEPTIVES
[ORAL CONTRACEPTIVES BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES
<S> <C>
0-9 years 0.1
10-19 years 8.7
20-29 years 40.2
30-39 years 36.2
40-49 years 13.7
50-59 years 1.0
60-69 years 0.0
70-79 years 0.0
80+ years 0.0
</TABLE>
(27) National Institute of Allergy and Infectious Diseases (NIAID) Emerging
Infectious Disease Research: Meeting the Challenge. May 1997
www.niaid.nih.gov/eidr/intro.htm
120
<PAGE> 124
FIGURE B21: ESTROGENS
[ESTROGENS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.0 0.0
10-19 years 0.0 0.0
20-29 years 0.3 0.0
30-39 years 3.2 0.0
40-49 years 23.8 0.2
50-59 years 51.1 0.3
60-69 years 17.0 0.1
70-79 years 3.3 0.0
80+ years 0.7 0.0
</TABLE>
Use of these therapy classes corresponds to reproductive milestones in the lives
of women. Women of childbearing age (those in their 20s, 30s and 40s) account
for the majority of prescriptions filled for oral contraceptives. Oral
contraceptives are the preferred method of pregnancy prevention among women
under 30 years of age, although they are not as widely used by women in higher
age groups.(28) Studies indicate the new low-dose oral contraceptives are safe
and may even be beneficial for use by healthy non-smoking women over 40 years of
age who are not otherwise at risk for heart disease. Additional
non-contraceptive benefits include improvements in acne and reductions in the
incidence of benign heart disease as well as endometrial and ovarian cancer.(29)
Menopausal women (age 40-60 years) are responsible for most estrogen use.
Because estrogen is sometimes used to retard the growth of prostate or breast
cancer, a small number of estrogen prescriptions were filled by men. Although
estrogen alone or in combination with a progestin has been proven effective in
alleviating symptoms of menopause and reducing the risk of osteoporosis, up to
50 percent of eligible women either discontinue taking hormone replacement
therapy (HRT) after as little as one year or choose not to take it at all.
Reasons include the occurrence of undesirable side effects such as cyclic
bleeding and the fear of breast cancer.(30)
(28) National Center for Health Statistics. Fastats A-Z. Contraceptive Use
in the U.S. April 1999. www.cdc.gov/nchs/fastats/usecontr.htm
(29) Journal of the American Medical Association. Women's Health:
Contraception Information Center. Oral Contraceptives in the
Perimenopause. February 1998.
www.ama-assn.org/special/contra/newsline/briefing/peri.htm#n1b
(30) Okon MA, et al. A study to examine women's knowledge, perception and
acceptability of hormone replacement therapy.Eur Menopause J
1996;3(2):47-52.
121
<PAGE> 125
FIGURE B22: DERMATOLOGICALS
[DERMATOLOGICALS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 4.8 4.2
10-19 years 10.2 10.0
20-29 years 8.1 3.7
30-39 years 10.1 5.4
40-49 years 10.7 6.5
50-59 years 8.2 5.9
60-69 years 3.7 3.5
70-79 years 1.7 1.6
80+ years 1.0 0.6
</TABLE>
Compared with many other classes, dermatologicals are used by a relatively
young population. Across the 20-59 year age span, a greater percentage of
dermatological prescriptions are filled by women than men. Some skin conditions
are generally associated with a specific age group such as diaper rash in
infants, acne in adolescents and shingles in the elderly. Others, like atopic
dermatitis and psoriasis, can affect individuals throughout their entire lives.
Common seasonal conditions include sunburns and allergic rashes from poison
ivy, poison oak and poison sumac. Atopic dermatitis is thought to affect 15
million Americans -- an increase in incidence of nearly 30 percent over the
past 30 years -- while psoriasis affects more than 5 million. Contributing
factors include environmental irritants and infectious agents that trigger an
immune response as well as emotional stress.(31, 32) Nail disorders account for
about 10 percent of all skin conditions.(33)
FIGURE B23: ANTIDIABETICS
[ANTIDIABETICS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.2 0.2
10-19 years 0.9 0.9
20-29 years 1.2 1.1
30-39 years 3.5 3.4
40-49 years 9.7 10.7
50-59 years 15.6 18.4
60-69 years 9.8 13.0
70-79 years 4.2 4.9
80+ years 1.2 1.1
</TABLE>
(31) 15 Million American Kids and Adults are Itchy, Irritable and Exhausted
- The Villian is Eczema and It's on the Rise. American Academy of
Dermatology Press Release - February 2000.
www.aad.org/PressReleasesIndex.html
(32) Psoriasis Causes Disability That Equals Other Major Medical Diseases.
American Academy of Dermatology Press Release - December 1999.
www.aad.org/PressReleasesIndex.html
(33) Anonymous. Guidelines of care for nail disorders. American Academy of
Dermatology.Journal of the American Academy of Dermatology
1996;34(3):529-33.
122
<PAGE> 126
Males were responsible for the majority of antidiabetic prescriptions overall,
although the sex difference was typically small at each age category. Most
prescriptions in this class were dispensed to adults 40-69 years. By recent
estimates, more than 10 million Americans currently have diabetes and an
additional 5 million people with diabetes are believed to be undiagnosed.(34) An
alarming number of children and adolescents are now being diagnosed with Type 2
non-insulin-dependent diabetes, a form of diabetes that was previously thought
to be rare in this age group. Because an increasing number of American children
are overweight, experts predict that this condition will become even more
prevalent in the coming years. Children with Type 2 diabetes are generally more
than 10 years of age, are overweight, belong to certain ethnic groups (African
American, Inuit, Native American, Asian, Pacific Islander or Hispanic) and have
a family history of diabetes. Additional characteristics include being female
and having an apple-shaped figure (i.e., centrally distributed body fat).(35)
FIGURE B24: ANTICANCER
[ANTICANCER BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 0.5 0.5
10-19 years 0.8 0.4
20-29 years 2.5 0.7
30-39 years 7.5 3.0
40-49 years 15.9 4.2
50-59 years 21.9 5.4
60-69 years 13.7 5.8
70-79 years 7.0 4.1
80+ years 3.4 1.8
</TABLE>
Almost three-quarters of prescriptions in this class were filled by females.
Individuals in their 40s and 50s accounted for the majority of prescriptions in
this therapy class. Cancer is the second leading cause of death in the United
States. More than 12 million new cases of cancer have been diagnosed since 1990,
with skin cancer being the most common.(36) Advances in genetic and molecular
technologies are expected to help researchers identify the genes that predispose
people to certain types of cancer and gain a better understanding of the impact
of environmental factors.
(34) Diabetes Facts and Figures. American Diabetes Association 1999.
www.diabetes.org/ada/facts.asp
(35) Dabelea D., et al. Type 2 diabetes mellitus in minority children and
adolescents. An emerging problem. Endocrinology & Metabolism Clinics of
North America 1999;28(4):709-29.
(36) Cancer Facts and Figures. American Cancer Society 2000.
www.cancer.org/statistics/index.html?Language=ENGLISH
123
<PAGE> 127
FIGURE B25: ANTIVIRALS
[ANTIVIRALS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 1.1 1.0
10-19 years 2.7 1.5
20-29 years 9.3 4.4
30-39 years 14.9 14.4
40-49 years 15.0 14.3
50-59 years 7.5 7.6
60-69 years 2.3 2.5
70-79 years 0.5 0.6
80+ years 0.2 0.2
</TABLE>
Members in their 20s and 30s accounted for almost 60 percent of prescriptions
filled in this class. Although females filled a greater percentage of
prescriptions overall, a marked sex difference appears to be present only for
those in their 20s. Each year in the United States, 10 percent-20 percent of the
population is affected by the influenza virus -- with infection rates varying
somewhat among the different age groups. About 1 percent of those with influenza
require hospitalization, and approximately 20,000 die each year due to
respiratory complications. Although the rate of vaccinations against the
influenza virus has increased among individuals older than 65, hospitalizations
for pneumonia and influenza still appear to be on the rise.(37) The estimated
number of new AIDS cases declined by 11 percent between 1997 and 1998, however a
greater number of these cases were reported among women than ever before.
Advances in available drug therapies resulted in a 10 percent increase in the
number of Americans who are currently living with the disease. AIDS is now
recognized as the fifth leading cause of death among Americans 25-44 years of
age.(38)
(37) Overview of Influenza Surveillance. Centers for Disease Control and
Prevention 2000. www.cdc.gov/ncidod/diseases/flu/flusurv.htm
(38) Centers for Disease Control and Prevention (CDC). HIV/AIDS Surveillance
Report 1999;11(no.1):1-44.
124
<PAGE> 128
FIGURE B26: ANTICONVULSANTS
[ANTICONVULSANTS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 1.5 1.8
10-19 years 3.9 4.9
20-29 years 4.4 4.0
30-39 years 10.8 7.0
40-49 years 16.9 9.2
50-59 years 11.7 7.8
60-69 years 4.9 4.6
70-79 years 2.7 2.2
80+ years 1.2 0.7
</TABLE>
The largest percentage of anticonvulsant prescriptions were dispensed to
middle-aged members, those 30-59 years. Within these middle-age ranges, women
accounted for a greater percentage of claims than men did, although there was
little difference between the sexes for the other age groups. An estimated 2
million Americans suffer from epilepsy, with more than 50 percent of all cases
affecting children and adults younger than 25 years of age. Although the number
of drugs available for the treatment of epilepsy has nearly doubled in the past
10 years, a disturbing percentage of individuals with epilepsy are unable to
achieve complete control of their seizures. In addition to the treatment of
epilepsy, anti-epileptic drugs are widely used for the relief of pain associated
with migraine headaches, diabetic neuropathy and trigeminal neuralgia.(39)
(39) Hansen HC. Treatment of Chronic Pain With Antiepileptic Drugs: A New
Era.Southern Medical Journal 1999;92(7):642-649.
125
<PAGE> 129
FIGURE B27: ANTIFUNGALS
[ANTIFUNGALS BAR CHART]
<TABLE>
<CAPTION>
% of PRESCRIPTIONS
AGE GROUP FEMALES MALES
<S> <C> <C>
0-9 years 2.0 2.7
10-19 years 3.3 1.6
20-29 years 12.0 2.1
30-39 years 19.0 4.6
40-49 years 20.5 5.5
50-59 years 12.5 5.7
60-69 years 3.6 2.6
70-79 years 1.1 0.8
80+ years 0.3 0.2
</TABLE>
Three out of every four prescriptions filled in 1999 for an antifungal was
received by a female. Most of the prescriptions in this class were dispensed to
members 20-59 years. The prevalence of fungal infections has increased over the
last several decades, particularly in those individuals who have a compromised
immune system. It is estimated that 90 percent of people who have AIDS will
develop at least one fungal infection as a result of their condition.(40)
Moreover, 10 percent-20 percent of the general population will experience a
superficial fungal infection at some time during their lives. Whether fungal
infections are superficial (affecting the skin or nails) or deeply invasive
(affecting an internal organ such as the lungs or the brain), they are
difficult to treat and often require prolonged therapy. About 70 percent of all
superficial fungal infections recur, due to either reinfection or the failure
to completely eliminate the original fungal infection.(41)
(40) THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs) January 1997.
www.aidsinfonyc.org/tag/ois/histo.html
(41) Guidelines of care for superficial mycotic infections of the skin:
Tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea
pedis.J Am Acad Dermatol 1996;34:282-6.
126
<PAGE> 130
EXPRESS SCRIPTS
DRUG TREND REPORT
(Please copy and fax or mail back.)
<TABLE>
<CAPTION>
Quantity Item Amount
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SUBTOTAL
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MO residents add $5.975% sales tax
TOTAL
</TABLE>
Discounts available for volume orders; call for information.
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127
<PAGE> 131
NOTES
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<PAGE> 132
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<PAGE> 135
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<PAGE> 136
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EXPRESS SCRIPTS, INC.
Date: October 31, 2000 By: /s/ Thomas M. Boudreau
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