<PAGE> 1
SCHEDULE 14A INFORMATION
Proxy Statement Pursuant to Section 14(a)
for the Securities Exchange Act of 1934
Filed by the Registrant /X/
Filed by a Party other than the Registrant / /
Check the appropriate box:
/ / Preliminary Proxy Statement
/ / Definitive Proxy Statement
/ / Definitive Additional Materials
/X/ Soliciting Material Pursuant 240.14a-11(c) or 240.14a-12
ICN PHARMACEUTICALS, INC.
(Name of Registrant as Specified in its Charter)
ICN PHARMACEUTICALS, INC.
(Name of Person(s) Filing Proxy Statement)
Payment of Filing Fee (Check the appropriate box):
/ / $125 per Exchange Act Rules 0-11(c)(1)(ii), 14a-6(i)(1), or 14a-7(i)(2).
/ / $500 per each party to the controversy pursuant to Exchange Act Rule
14a-6(i)(3).
/ / Fee computed on table below per Exchange Act Rules 14a-6(i)(4) and 0-11.
1) Title of each class of securities to which transaction applies:
2) Aggregate number of securities to which transaction applies:
3) Per unit price or other underlying value of transaction computed pursuant
to Exchange Act Rule 0-11.*
4) Proposed maximum aggregate value of transaction:
*Set forth the amount on which the filing fee is calculated and state how it
was determined.
/ / Check box if any part of the fee is offset as provided by Exchange Act
Rule 0-11(a)(2) and identify the filing for which the offsetting fee was
paid previously. Identify the previous filing by registration statement
number of the Form or Schedule and the date of its filing.
(1) Amount Previously Paid:
(2) Form, Schedule or Registration Statement No.:
(3) Filing Party:
(4) Date Filed:
<PAGE> 2
[ICN Logo]
ICN Pharmaceuticals, Inc. International Headquarters Telephone: 714/545-0100
ICN Plaza FAX: 714/556-0131
3300 Hyland Avenue Telex: 57-0413
Costa Mesa, California 92626
December 19, 1993
Dear Shareholder/Investor:
Enclosed for your information are new materials that exemplify the solid
science behind the company's antiviral Virazole (ribavirin) and its research
and development programs:
1) Four investigational studies of ribavirin capsules in the treatment of
hepatitis C from the October, 1993 issue of the medical journal HEPATOLOGY.
It includes an abstract from the National Institutes of Health Liver Unit
that preliminarily reports that in 16 patients receiving ribavirin
". . . prolonged ribavirin therapy was associated with significant
improvement in serum ALT levels (despite unchanged serum HCV RNA levels)
and in hepatic lobular necrosis" (Vol. 18, No. 4, Pt. 2, 1993). Serum
ALT levels and the degree of hepatic lobular necrosis are key parameters
for monitoring chronic hepatitis C. Ribavirin is not yet approved for the
indication of hepatitis C by the FDA.
2) An article entitled "antiviral therapy of hepatitis C - present and future"
from the JOURNAL OF HEPATOLOGY (1933: 17, Suppl. 3).
3) New treatment guidelines from the American Academy of Pediatrics on the use
of aerosolized Virazole to treat severe lower respiratory tract
infections caused by respiratory syncytial virus (RSV). They are authored
by the Academy's Committee on Infectious Diseases, which includes liaison
representatives from NIH, CDC and FDA. The Academy recommends Virazole as
the standard of care in all high-risk RSV babies, including those with a
number of underlying medical conditions. The new guideline is based on the
safe and efficacious use of aerosolized Virazole in more than 100,000
babies since it was introduced in the U.S. in 1986.
Sincerely,
Jack Sholl
Senior Vice President
Public Relations
<PAGE> 3
VOL. 18, NO. 4, PT.2 OCTOBER 1993
PROGRAM ISSUE
======================================================================
HEPATOLOGY
THE
AMERICAN ASSOCIATION
FOR THE
STUDY OF LIVER DISEASES
POSTGRADUATE COURSE
& 44TH ANNUAL MEETING
NOVEMBER 4-7, 1993
CHICAGO MARRIOTT HOTEL
CHICAGO, ILLINOIS
OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
<PAGE> 4
HEPATOLOGY Vol. 18, No. 4, Pt. 2, 1993
145 RANDOMIZED, DOUBLE BLIND PLACEBO-CONTROLLED TRIAL OF RIBAVIRIN THERAPY
FOR CHRONIC HEPATITIS C.
AM Di Bisceglie, MW Fried, MG Swain, NV Bergasa, C Yurdaydin, LH
Simpson, R Sallie, H Conjeevaram, D Kleiner, Y Park, JH Hoofnagle. Liver
Diseases Section and Lab. of Pathology, NIH, Bethesda Md.
58 pts with chronic hepatitis C entered a randomized, double-blind
controlled trial of ribavirin (600mg BID orally for 12 mos) vs placebo.
All had HCV RNA in serum (by PCR) with elevated serum ALT values (>2X ULN)
for >6 mos and chronic hepatitis on liver biopsy. To date, 32 pts have
completed therapy, 16 on ribavirin and 16 placebo. The 2 groups were well
matched with regard to age, gender, duration and source of hepatitis,
liver histology, serum ALT and HCV RNA levels. During therapy with
ribavirin, ALT values became and remained normal in 4 pts (25%,
responders). ALTs fell by more than 50% in 7 pts (44%, partial
responders); overall mean values decreased by 47% (p<.01) by the end of
therapy (Table). No pt lost serum HCV RNA and mean levels of HCV RNA did
not change (branched DNA assay, Chiron). After stopping therapy, ALT
values rose in most pts, including 2 of 4 responders. The histologic
activity index (HAI) decreased with ribavirin, hepatic lobular necrosis
improving most (mean 3.3 vs 2.3, p<.05).
<TABLE>
<CAPTION>
Time ALT AST HCT WBC HAI HCV RNA (ag/ml)
-------------------------------------------------------------------
<S> <C> <C> <C> <C> <C> <C>
Pre 186 130 44.7 6.6 12.5 2273
Post 88* 69 38.9* 5.5* 11.4 1947
-------------------------------------------------------------------
</TABLE>
(*p<.01) Only 1 placebo-treated pt had a partial response, none lost
HCV RNA and liver histology appeared to worsen (mean HAI 11.1 vs 12.3,
p=ns). Ribavirin was associated with hemolysis requiring dose reduction in
2 pts and a mild decrease in lymphocyte counts (2401 vs 1506/mm3, p<.01).
The dose was reduced in 2 pts for non-specific constitutional symptoms.
Thus, prolonged ribavirin therapy was associated with significant
improvement in serum ALT levels (despite unchanged serum HCV RNA levels)
and in hepatic lobular necrosis.
<PAGE> 5
AASLD ABSTRACTS 93A
146 COMBINATION THERAPY OF a-INTERFERON AND RIBAVIRIN IN PATIENTS WITH
CHRONIC HEPATITIS C: AN INTERIM REPORT.
MY Lai, PM Yang, JH Kao, JT Wang, HS Lee, and DS Chen. Grad. Inst. Clin.
Med., Dept. Int. Med., and Hepatitis Research Center, National Taiwan
University Hospital, Taipei, Taiwan.
For chronic hepatitis C. treatment with a-interferon alone can
induce long-term normalization of serum ALT activities in only about
15-25% of the patients after cessation of the drug. Ribavirin is a
nucleoside analog which has significant antiviral activity against HCV. To
improve the efficacy of treatment for chronic hepatitis C, we designed a
combination therapy with a-interferon and ribavin. Sixty patients with
positive anti-HCV, persistently elevated serum ALT for more than 6 mo with
levels at least twice the upper limit of the normal range before therapy,
chronic hepatitis without cirrhosis of liver histology, were recruited.
There were 34 males and 26 females, with mean age of 51 yr (range: 31 to
69 yr). They were randomized into 3 groups: (1) Group A received
interferon-a-2a (Roferon-A) (3 million units thrice weekly) and ribavirin
(1200 mg/day) for 6 mo; (2) Group B received interferon-a-2a 3 million
units thrice weekly alone for 6 mo; (3) Group C were controls. Up to now,
9 patients in either group A or B have completed the treatment. In group
A, normalization of serum ALT activities was rapidly achieved in all
patients. By the end of therapy (6 mo), 7 (78%) had normal ALT activity
and the result have sustained up to 5 mo after cessation of the therapy.
In contrast, in group B, only 3 (33%) patients had normalization of serum
ALT activities at the end of therapy, and all suffered from relapse of
elevated serum ALT one mo after cessation of the drug. In group C, all
patients had persistent abnormal serum ALT levels. Only mild and tolerable
side effects were encountered in the treated patients. We conclude that
combination therapy of a-interferon and ribavirin for chronic hepatitis C
can remarkably increase the response rate during therapy. The long-term
effect of this novel regimen seems promising but awaits further
observation.
<PAGE> 6
375 COMBINATION THERAPY WITH RIBAVIRIN AND a-INTERFERON IN PATIENTS WITH
CHRONIC HEPATITIS C RESISTANT TO a-INTERFERON TREATMENT.
S. Brillanti, C. Masci, M. Miglioli and L. Barbara, Dept. of Internal
Medicine and Gastroenterology, University of Bologna, Bologna, Italy.
The aim of this pilot study was to evaluate the role of combination
therapy with ribavirin and a-interferon (IFN) in patients with chromic
hepatitis C who failed to respond to IFN therapy (NR) or who had a relapse
from response to IFN therapy (RR). Ten consecutive NR patients and 10
consecutive RR patients entered into the study. In each patient, IFN
therapy had been stopped at least 12 months before entry. All patients were
positive for anti-HCV (ELISA-2 and RIBA-2), serum HCV-RNA (PCR) and had
chronic active hepatitis on liver biopsy. They were randomly assigned to
receive other combination of ribavirin, 800 mg a day, with IFN, 3 MU
tiw, for 6 mo., (10 patients), or IFN alone. 3 MU tiw, for 6 mo., (10
patients). The two groups were comparable concerning age (43.3+/-6.1 vs.
48.3+/-4.4 yr.), sex (6 vs. 5 males), pre-therapy ALT levels (110.1+/-28.6
vs. 151.3+/-32.6 U/L), and liver histology (5 vs. 4 cirrhosis). All
patients were prospectively observed for at least 12 mo. Results are
summarized in the table:
<TABLE>
<CAPTION>
IFN + Ribavirin IFN alone p
(n=10) (n=10)
<S> <C> <C> <C>
Normal ALT
Initial 0 0 NS
Final 7 4 NS
6 mo. later 5 0 <0.02
</TABLE>
In the combination therapy group: (a) The sustained normalization of ALT levels
occurred in 3/5 (60%) RR patients and in 2/5 (40%) NR patients: (b) The
sustained normalization of ALT levels was always accompanied by sustained loss
of serum HCV-RNA. Mild hemolytic anemia was observed in some patients treated
with combination therapy. In conclusion, combination therapy with ribavirin and
IFN seems able to induce a sustained biochemical and virological response in
patients with chronic hepatitis C resistant to a-interferon treatment.
<PAGE> 7
1144 TREATMENT OF HEPATITIS C VIRAL INFECTION (HCV) IN THE TRANSPLANTED
PATIENT WITH RIBAVARIN.
M. Rezieg, I. Altraif, C. Roach, P. Greig, E. Cole, M. Kraiden, G. Levy.
Multi-Organ Transplant Unit, Univ. of Toronto, Canada.
It has been suggested that post-transplant HCV infection can lead to
serious, rapidly progressive and ultimately fatal liver disease.
Immunosuppression has been reported to accelerate the severity and course
of this infection as compared to HCV infection in non-immunosuppressed
patients. Ribavarin is a nucleoside analogue with a broad spectrum of
anti-viral activity for both RNA and DNA viruses. We investigated the
efficacy of Ribavarin in 6 patients who have developed chronic hepatitis C
infection post-transplant. Patient characteristics are described in the
table below.
<TABLE>
<CAPTION>
BILIRUBIN
SERUM HCV AST (IU/L) (umol/L)
PCR ------------ ------------
PT.# AGE SEX TX. RNA EIA II PRE POST PRE POST
- -------------------------------------------------------------------------------
<S> <C> <C> <C> <C> <C> <C> <C> <C> <C>
1 59 M Liver/ + + 115 27 145 24
Kidney
2 58 M Kidney + + 73 24 38 20
3 28 M Kidney + + 107 66 14 17
4 56 M Liver + + 131 32 34 13
5 23 M Kidney + + 74 24 16 8
6 18 M Liver + + 846 72 180 22
</TABLE>
TX = transplant
All patients were male with a mean age of 45.3 +/- 15.9 years.
Patients were treated with Ribavarin (1 gram per day in 2 divided doses for
3 months). Liver biopsies at initiation of therapy showed moderate to
severe chronic active hepatitis and fibrosis. Liver biochemistry and
hematology were followed weekly and patients assessed monthly. All patients
developed mild to moderate hemolysis, and in one patient the medication had
to be stopped. The mean AST and bilirubin prior to treatment were 224 +/-
305 IU/L and 76.1 +/- 68.4 umol/L respectively. At discontinuation, the AST
and bilirubin decreased to 40.8 +/- 22 IU/L and 17.3 +/- 5.9 umol/L
respectively. Patients clinically felt better and to date there have been
no biochemical relapses. In conclusion a 3 month course of Ribavarin
appears to be efficacious for chronic HCV infection in the setting of organ
transplantation although longer follow up and larger trials must be
performed in order to firmly conclude this.
Consent of publication has not been received from the American
Association for the Study of Liver Diseases as of the date of this filing.
<PAGE> 8
AMERICAN ACADEMY OF PEDIATRICS
USE OF RIBAVIRIN IN THE TREATMENT OF RESPIRATORY SYNCYTIAL VIRUS INFECTION
RE9329
Committee on Infectious Diseases
Ribavirin is an antiviral drug that was approved by the Food and Drug
Administration in 1986 for aerosol treatment of serious respiratory syncytial
virus (RSV) infections in hospitalized children. Ribavirin has a broad spectrum
of antiviral activity in vitro, where it inhibits replication of RSV,
influenza, parainfluenza, adenovirus, measles, Lassa fever, and Hantaan
viruses. Proof of efficacy for human infection has been obtained in
double-blind placebo-controlled studies of RSV,(1,2) Lassa fever, and Korean
hemorrhagic fever. Presently, only anecdotal reports support the efficacy of
this drug for treatment of measles of parainfluenza. Ribavirin treatment for
RSV infections has been controversial because of the aerosol route of
administration, concern for potential toxicity for exposed persons, cost, and
the unpredictable and highly variable course of illness in the absence of
specific therapy. These issues necessitate ongoing review of ribavirin therapy
and the following updated recommendations by the American Academy of
Pediatrics.
BACKGROUND
RSV DISEASE
Respiratory syncytial virus is the most important cause of lower respiratory
tract disease in infants and young children. Disease usually appears in yearly
outbreaks in the winter or spring, and essentially all children become infected
during their first 3 years of life. The number of infected infants who require
hospitalization has been estimated to range from 1 to 50 per 1000 in different
locations. Currently, the mortality rate in hospitalized infants who previously
were healthy is low (less than 1%). In infants with underlying diseases,
however, the mortality can be much higher. Conditions that increase the risk of
severe or fatal RSV infection are cyanotic or complicated congenital heart
disease (including pulmonary hypertension); underlying pulmonary disease,
especially bronchopulmonary dysplasia; prematurity; and immunodeficiency
disease or therapy causing immunosupression at any age.
Most previously healthy infants infected with RSV do not require
hospitalization, and many who are hospitalized improve within a few days with
supportive care and are discharged after a stay ranging from 3 to 5 days.
Long-term sequelae of RSV infec-
The recommendations in this statement do not indicate an exclusive course of
treatment or procedure to be followed. Variations, taking into account
individual circumstances, may be appropriate.
Received for publication May 11, 1993; accepted May 11, 1993.
PEDIATRICS (ISSN 0031 4005). Copyright 1993 by the American Academy of
Pediatrics.
<PAGE> 9
tion are difficult to assess. Evidence recently has accumulated suggesting that
some infected children develop long-term abnormalities in pulmonary
function.(3) Although these abnormalities may be subclinical in most children,
some subjects have recurrent wheezing. Whether treatment of the initial
respiratory syncytial virus infection can alter the rate or severity of such
sequelae is unknown.
RIBAVIRIN
Aerosolized ribavirin is the first specific drug available for treatment
of RSV infections. It is a synthetic nucleoside analogue
(1-B-d-ribafuranosynl-1,2,4-triazole-3-carboxamide) resembling guanosine and
inosine; it appears to interfere with the expression of messenger RNA and to
inhibit viral protein synthesis. It is not significantly incorporated into host
cell RNA or DNA.
CLINICAL STUDIES
Ribavirn is administered as aerosolized particles small enough (median
aerosol diameter, 1 to 2 pm) to reach the lower respiratory tract.It is
delivered via an oxygen hood, tent, or mask for 12 to 20 hours each day for a
mean of 4 days. In controlled studies involving both healthy infants and those
with underlying disease, clinical improvement was greater in ribavirin
recipients than in placebo recipients. Ribavirin had a beneficial effect on
some signs, such as retraction and rales, but not on others, such as fever and
wheezing. However, these latter signs were present in only a minority of
patients. Improvement in arterial blood oxygenation following ribavirin therapy
has been substantial. In one study, the treated group had a mean arterial
oxygen pressure (Pao2) of 49.4 mm Hg at the start of therapy and 62.4 mm Hg at
the end, a mean increase of 13 mm Hg, which was significantly greater than the
comparable values for the placebo group (at the start and end of therapy 52 mm
Hg and 56 mm Hg, respectively).(4) The effect of therapy on persistence of
virus in secretions differed in various studies.
No appreciable toxicity has been observed in any of the controlled
trials or in other follow-up studies. Although reversible bronchospasm has been
observed occasionally (less than 0.1%), hyperactivity of the airways has not
been demonstrated in studies of pulmonary function during administration of
ribavirin aerosol.(4-6) The effect of ribavirin aerosol on pulmonary function
was examined in adult volunteers infected with RSV in a controlled, double-
blind study. Serial pulmonary function tests, which included carbachol
challenge, showed no alterations in volunteers during ribavirin therapy or
when tested]
PEDIATRICS Vol. 92 No. 3 September 1993 501
<PAGE> 10
month later. The long-term effects of ribavirin on pulmonary function and on
the sequelae of RSV infection require further investigation.
In mechanically ventilated infants, most of whom were previously healthy,
ribavirin treatment was safe and was associated with a reduced need for
mechanical ventilation and supplemental oxygen, shorter duration of
hospitalization, and cost-effectiveness.(7)
One potential problem is deposition of the drug in the ventilator delivery
system, which appears to be dependent on temperature, humidity, and
electrostatic forces. This deposition can lead to malfunction or obstruction of
the expiratory valve, resulting in inadvertently high positive end-expiratory
pressures. The use of one-way valves in the inspiratory lines, a breathing
circuit filter in the expiratory line, and frequent monitoring and filter
replacement by trained staff have been effective in preventing these problems.
Experience with antiviral agents used to treat other viruses has raised the
additional concern of development of resistance to ribavirin by RSV. To date,
no change in susceptibility of any viral isolate to ribavirin has been
observed, even with prolonged administration.
SAFETY FOR HEALTH CARE PERSONNEL
Although mucous membrane irritation has been reported following exposure to
ribavirin (especially in the eyes of contact lens wearers), it occurs in a
small percentage of exposed personnel and is reverisble.(8) Reproductive and
teratogenic toxicities were observed in pregnant rodents administered oral
ribavirin. These effects were not reproduced in baboons and have not been
reported in humans. Studies have indicated that although absorption of ribavrin
can occur in health care personnel from environmental exposure, no deleterious
effects have been reported. Concern about the safety of ribavirin has led some
hospitals to apply strict precautions for use of ribavirin to minimize exposure
of health care workers.
A review of animal and human data on ribavirin safety is summarized and
interpreted as follows:(9)
1. In hamsters after a single oral dose of 2.5 mg/kg, and in rats after a
daily oral dose of 10 mg/kg for 60 days or longer, fetal malformations have
been noted. In rabbits, the species most sensitive to the effects of
ribavirin, skeletal malformations were observed after daily oral
administration of 0.1 to 0.3 mg/kg for 12 days. In contrast, seven pregnant
baboons were treated orally with 60 to 120 mg/kg of ribavirin for 4
consecutive days, during the time of fetal organogenesis. The offspring of
six of seven of these baboons showed no evidence of teratogenicity. The
seventh animal aborted at day 45 (60-mg dose) but no traces of implantation
were recovered, implying fetal death and resorption prior to organogenesis
and prior to ribavirin therapy.(9)(10)
2. Extrapolation from these animal experiments involving oral
administration of ribavirin to circumstances of human exposure to ribavirin
aerosol is difficult, especially in view of species differences in
teratogenicity and the high doses administered.
502 RIBAVIRIN FOR RESPIRATORY SYNCYTIAL VIRUS
<PAGE> 11
3. During treatment with aerosolized ribavirin, dissemination of the drug
in the environment of the patient can occur, with the potential for
inhalation by those caring for treated children. However, while 60% to 70%
of the inhaled drug may be deposited in the airways, absorption from the
respiratory tract into the circulation is minimal. In infants receiving
aerosolized ribavirin, the mean peak plasma concentration was less than 1
umol/L at a time when the peak concentrations in endotracheal secretions
were greater than 1700 umol/L.(11)
Studies of health care personnel also have demonstrated minimal
absorption. In one study of 19 non-pregnant nurses who were caring for infants
receiving ribavirin by aerosol treatment via an oxygen tent, hood, or
ventilator, nurses were exposed for a mean of 8 hours per day during a 3-day
period (a total of 20 to 35 hours).(12) Total air exchanges occurred 5.4 to 24
times per hour in the patients' rooms. Blood samples for analysis of ribavirin
were obtained 1 day before exposure, 1 hour after the final exposure, and 3 to
5 days later; urine was collected before and 3 to 5 days after exposure.
Ribavirin was not detected in any sample of plasma, erythrocytes, or urine. The
lower limit of sensitivity of the radioimmunoassay used to measure ribavirin in
the study was 0.02 ug/mL. In a similar study of health care personnel caring
for infants treated with ribavirin, 90 samples of serum, urine, and
erythrocytes were assayed for ribavirin.(13) Ribavirin was detected in a
concentration of 0.44 ug/mL in only one erythrocyte sample. (The minimum level
of detection of the test used was 0.02 ug/mL.) The concurrent serum and urine
samples were negative. No symptoms were reported by any health care workers in
this study.
These findings and the lack of validated reports of adverse effects in
human fetuses after 7 years of clinical use of the drug in the United States
suggest that the teratogenic risk of ribavirin exposure in humans is extremely
low. The National Institute for Occupational Safety and Health (NIOSH) recently
conducted a study at a Florida Hospital, where the technique they employed
consistently found small concentrations of ribavirin in the postshift urine of
nurses. No clinical findings were reported in association with these
observations.(14) NIOSH recommends review of work policies and institution of
engineering controls in order to reduce environmental concentration of
ribavirin in the patient's room.
RECOMMENDATIONS
Experience in more than 100,000 patients indicates that aerosolized
ribavirin treatment for RSV infection is both safe and effective. As with other
antiviral therapy, the maximum benefit will be derived by early treatment of
high-risk patients. The route of administration, cost, and need for
hospitalization support a strategy of selective use of ribavirin as follows:
1. Patients at High Risk for Complications Due to Other Conditions.
Ribavirin treatment is recom-
<PAGE> 12
mended for the following patients hospitalized with RSV lower respiratory
tract disease:
a. Infants at high risk for severe or complicated RSV infection, including
those with complicated congenital heart disease (including pulmonary
hypertension); those with bronchopulmonary dysplasia, cystic fibrosis,
and other chronic lung conditions; premature infants; children with
immunodeficiency (especially those with acquired immunodeficiency
syndrome or severe combined immunodeficiency disease); recent transplant
recipients; and patients undergoing chemotherapy for malignancy.
b. Infants who are severely ill. Because severity of illness is often
difficult to judge clinically in infants with RSV infection,
determination of blood gas concentrations is often necessary. Values for
PaO2 of less than 65 mm Hg (ie, oximetry reading less than 90%) and
increasing concentration of carbon dioxide arterial pressure (PaCO2) are
useful indicators of severity.
c. All patients mechanically ventilated for RSV infection.
2. Treatment for Hospitalized Infants. Ribavirin treatment should also be
considered for hospitalized infants who may be at increased risk of
progressing from a mild to a more complicated course by virtue of young age
(less than 6 weeks) or underlying condition, such as multiple congenital
anomalies or certain neurologic or metabolic diseases (eg, severe cerebral
palsy, myasthenia).
3. Diagnosis of RSV Infection. Rapid diagnostic techniques to identify RSV
antigen in respiratory secretions should be performed when the child is
admitted to the hospital. Tissue culture isolation requires 3 to 5 days. If
rapid tests are not available, patients in the recommended categories who
have bronchiolitis or pneumonia clinically compatible with RSV infection and
who are admitted during the RSV season (generally November to April) should
be considered for ribavirin therapy. If the etiology of the infant's
pulmonary disease is subsequently found to be an agent other than RSV,
ribavirin therapy can be discontinued. If no agent is identified initially
as the cause of the lower respiratory tract disease, but the most likely
clinically diagnosis remains RSV infection and the infant is severely ill,
continuation of treatment is reasonable. Further diagnostic efforts to
ascertain the causative agent should be undertaken, recognizing that false-
negative rapid diagnostic test results have been noted in 5% to 20% of
cases.
4. Administration. Ribavirin is nebulized by a small-particle aerosol generator
into an oxygen hood, tent, or mask from a solution containing 20 mg of
ribavirin per milliliter of water. The generator is supplied with the drug
by the manufacturer. The aerosol is administered for 12 to 20 hours per day,
usually for 3 to 5 days depending on the patient's clinical course; a longer
duration of therapy may be useful in immunodeficient patients. A recent
study noted good patient tolerance and favorable ribavirin pharmacokinetics
when a regimen of 60
<PAGE> 13
mg/mL for 2 hours three times daily was used; however, the efficacy of this
dosage has not been proven.(11) Maximal therapeutic responses usually are
not noted after 2 to 4 days of treatment.
5. Isolation of Patients. Treatment with ribavirin does not eliminate the need
for contact isolation of patients with RSV.(15)
6. Precautions for Health Care Personnel and Visitors. Health care personnel
and visitors should be informed about the potential but unknown risks of
environmental exposure to ribavirin. In-service education for hospital
personnel is most effective just prior to the RSV season. While evidence of
human teratogenicity is lacking, in view of the embryopathic effects in
nonprimate animals, pregnant women should be advised not to care directly
for patients who are receiving ribavirin.(16) Several methods have been
employed to lower environmental exposure. For example, aerosol
administration should be stopped temporarily when the hood or tent is open.
Also, the drug should be administered in well-ventilated rooms (at least six
air changes per hour).
No additional precautions to protect patients, visitors, or hospital workers
in the room are required. Masks designed to block absorption of 1- to 2-ug
particulate droplets may reduce inhalation of ribavirin, but clinical studies
are lacking. Standard surgical masks do not block particles of this size.
Gloves and gowns are not essential since dermal absorption of ribavirin appears
to be negligible. However, gloves and gowns may lower the risk of nosocomial
spread of RSV. Scavanger devices to lower the escape of aerosolized ribavirin
into a room also can be used.(17) Additional research and clinical experience
are needed to establish more specific guidelines regarding occupational
exposure.
Committee on Infectious Diseases, 1992 to 1993
Caroline B. Hall, MD, Chairperson
Dan M. Granoff, MD
Donald S. Gromisch, MD
Neal A. Halsey, MD
Steve Kohl, MD
Edgar K. Marcuse, MD
Melvin I. Marks, MD
George A. Nankervis, MD
Larry K. Pickering, MD
Gwendolyn B. Scott, MD
Russell W. Steele, MD
Ram Yogev, MD
Ex-Officio
Georges Peter, MD
Liaison Representatives
Kenneth J. Bart, MD, MPH, National
Vaccine Program
Claire Broome, MD, Centers for Disease
Control
M. Carolyn Hardegree, MD, Food and Drug
Administration
Richard F. Jacobs, MD, American Thoracic
Society
Noni E. MacDonald, MD, Canadian
Paediatric Society
AMERICAN ACADEMY OF PEDIATRICS 503
<PAGE> 14
Walter A. Orenstein, MD, Centers for Disease Control
Gina Rabinovich, MD, National Institutes of Health
REFERENCES
1. Snell NJ, Economic and long-term benefits of ribavirin therapy on
respiratory syncytial virus infection. Lung. 1990;168:S422-429
2. Marks MI, Wald E. Ribavirin therapy for respiratory syncytial virus
infections; a scientific workshop. Pediatr Infect Dis J. 1990;9:S67-S124
3. Hall CB, Hall WJ, Gala CL, Magill FB, Leddy JP. Long-term prospective study
in children after respiratory syncytial virus infection. J Pediatr.
1984;105:358-364
4. Hiatt P, Treece D, Tabar L. Pulmonary function following treatment with
ribavirin in infants hospitalized with RSV bronchiolitis. Am Rev Respir Dis.
1990;141(part 2):A624
5. Hall CB, Walsh EE, Hruska JF, Betts RF, Hall WJ. Ribavirin treatment of
experimental respiratory syncytial viral infection. JAMA. 1983;
249:266-2670
6. Janai HK, Stutman HR, Zaleska M, et al. Possible mechanisms of ribavirin
effect in young infants with respiratory syncytial virus bronchiolitis,
Pediatr Infect Dis J. April 1993
7. Smith DW, Frankel LR, Mathers LH, Tang ATS, Ariagno RL, Prober CG. A
controlled trial of aerosolized ribavirin in infants receiving mechanical
ventilation for severe respiratory syncytial virus infection. N Engl J
Med. 1991;325:24-29
8. Janai HK, Marks MI, Zaleska M, Stutman HR. Ribavirin; adverse drug
reactions, 1986 to 1988. Pediatr Infect Dis J. 1990;9:209-211
<PAGE> 15
9. Johnson EM. The effects of ribavirin on development and
reproduction: a critical review of published and unpublished studies in
experimental animals. J Am Coll Toxicol. 1990,9;551-561
10. Hillyard I Preclinical toxicology and safety of ribavirin. In: Smith
R. Kirkpatrick W, eds. Ribavirin: A Broad Spectrum Antiviral Agent. New
York, NY: Academic Press; 1990
11. Englund J, Piedra PA, Jefferson LS, Wilson SZ, Taber LH, Gilbert BE.
High-dose, short-duration ribavirin aerosol therapy in children with
suspected respiratory syncytial virus infection. J. Pediatr.
1990;117:313-320
12. Rodriguez WJ, Dang Bui RH, Connor JD, et al. Environmental
exposure of primary care personnel to ribavirin aerosol when supervising
treatment of infants with respiratory syncytial virus infections.
Antimicrob Agents Chemother. 1987;31:1143-1146
13. Harrison R. Bellows J, Rempel D. Assessing exposures of
health-care personnel to aerosols of ribavirin -- California. MMWR.
1988;37:560-563
14. Decker JA, Shults RA (NIOSH Investigators). Hazard evaluation and
technical assistance. Interim report HETA 91-104, Florida Hospital,
January 1992
15. American Academy of Pediatrics, Committee on Infectious Diseases.
Respiratory syncytial virus. In: Report of the Committee on Infectious
Diseases, 1991. 22nd ed. Elk Grove Village, IL: American Academy of
Pediatrics; 1991:400-401
16. Ito S. Koren G. Exposure of pregnant women to ribavirin-contaminated
air: risk assessment and recommendations. Pediatr Infect Dis J. 1993;
12:2-5
17. Charney W. Corkeryl J. Kraemer R. Wugofskil L. Engineering and
administrative controls to contain aerosolized ribavirin: results
of simulation and application to one patient. Respir Care.
1990;35:1042-1048
504 RIBAVIRIN FOR RESPIRATORY SYNCYTIAL VIRUS
Consent of publication has not been received from the American Academy of
Pediatrics as of the date of this filing.
<PAGE> 16
Journal of Hepatology, 1993; 17 (Suppl. 3):
Antiviral therapy of hepatitis C - present and future
Jay H. Hoofnagle, Adrian M. Di Bisceglie and Michiko Shindo
Liver Diseases Section, Digestive Diseases Branch, National Institute
of Diabetes and Kidney Diseases. National Institutes of Health,
Bethesda, MD, United States of America
- -------------------------------------------------------------------------------
The current recommendations for therapy of chronic hepatitis C are a 6-month
course of alpha-interferon in doses of 3 million units 3 times weekly. Patients
should have compensated chronic liver disease with elevations in serum
aminotransferases, serologic evidence of hepatitis C virus (HCV) infection and
chronic hepatitis by liver biopsy. At present, a long-term beneficial response
to alpha-interferon occurs in only 10-25% of patients. The modest long-term
response rate and the restricted recommendations for use of interferon leave
several unresolved issues regarding therapy of this disease. Do patients with
atypical, severe or advanced disease warrant therapy? What is the optimal dose
and duration of treatment? How can one increase the response rate to
interferon? How can one predict which patients are likely to benefit from
therapy? Which patients are likely to relapse if therapy is stopped?
Ultimately, what is needed to answer these issues are better techniques to
assess HCV infection and monitor therapy as well as more effective and
better-tolerated agents that can be used alone or in combination with
alpha-interferon.
Key words: Chronic hepatitis; Cirrhosis; Hepatitis C virus; Controlled trials;
Antiviral therapy; Inteferon; Ribavirin; Polymerase chain reaction
- -------------------------------------------------------------------------------
Pilot studies (1) followed by multiple randomized controlled trials (2-10)
have documented that alpha-interferon is effective in suppressing disease
activity and inducing remissions in disease in a high proportion of patients
with chronic hepatitis C. Treatment with doses of 3-5 million units (MU) of
alpha-interferon subcutaneously thrice weekly has been associated with a serum
biochemical response in 40-70% of patients and a long-term, sustained
improvement in aminotransierases in 10-25% of patients. In several trials, this
improvement in serum biochemical tests has been shown to correlate well with
improvements in liver histology and function 13-61. More recently,
retrospective analyses have shown that improvements in clinical features of
disease are associated with a decrease or loss of serum hepatitis C virus (HCV)
RNA from the serum and liver (11). These studies have provided the basis for
the licensing and approval of alpha-interferon as therapy for chronic hepatitis
C in most countries of the world.
These initial controlled trials provided the basis for current
recommendations for the use of alpha-interferon as therapy of chronic hepatitis
C. Treatment is recommended for patients with compensated chronic hepati-
<PAGE> 17
tis C if serum aminotransferases are at least 1.3 times the upper limit of
normal and liver biopsy demonstrates chronic hepatitis disease activity.
Interferon should be given at a dose of 3 MU subcutaneously thrice weekly for 6
months. If improvements in aminotransferases has not occurred after 2-3 months
of treatment, therapy can be discontinued early. The dose of interferon can be
increased to 5 MU thrice weekly if a partial response occurs. However, side
effects of interferon are common, and are often dose-limiting. Indeed, a
sizeable proportion of patients receiving 3 MU of interferon will require a
decrease in dose because of intractable fatigue, anxiety, depression,
leukopenia or other side effects. This approach to treatment should lead to
improvements in approximately 50% of patients and sustained responses in
10-25%.
UNRESOLVED ISSUES
Although alpha-interferon is now considered standard therapy for chronic
hepatitis C, there are several unresolved issues concerning its use. Some major
issues are
<PAGE> 18
ANTIVIRAL THERAPY OF HEPATITIS C
TABLE 1
Therapy in chronic hepatitis C: unresolved issues
- --------------------------------------------------------------------
How to treat patients with atypical or severe disease?
What is the optimal dose and duration of therapy?
What are the predictors of a response to therapy?
What are the predictors of a relapse after therapy?
How can one increase the response rate?
- --------------------------------------------------------------------
TABLE 2
Alpha-interferon therapy in chronic hepatitus C: atypical patients
- --------------------------------------------------------------------
Decompensated cirrhosis
Children
Atypical serology ianti-HCV-negative:
Immunocompromised patients
Organ transplant patients
- --------------------------------------------------------------------
(Table 1): (1) How and whether to treat patients with atypical or complicated
disease? (2) What is the optimal dose and duration of alpha-interferon therapy?
(3) How can one predict which patients are likely to have a beneficial response
to therapy? (4) How can one identify whether a relapse is likely to occur when
therapy is stopped? (5) How can one increase the response rate?
ATYPICAL PATIENTS
Alpha-interferon is recommended largely for patients with
well-compensated chronic hepatitis C who have serologic evidence of disease
ianti-HCV or HCV-RNA, elevations in serum aminotransferase activities, chronic
hepatitis by liver biopsy, and no other serious complicating illness. Not
included in these recommendations are patients with clinically apparent
cirrhosis, children, patients with atypical serologic patterns and patients who
are immunocompromised either because of an immune deficiency or
immunosuppressive therapy (Table 2).
Patients with decompensated cirrhosis due to hepatitis C represent an
important group that warrants some form of therapy short of liver
transplantation. There have been no prospective randomized studies of
alpha-interferon in patients with advanced cirrhosis due to chronic hepatitis
C, but anecdotal reports indicate that a proportion of such patients responds
to treatment with improvements in aminotransferases and liver histology (12).
However, the response rate to alpha-interferon is somewhat lower in patients
with cirrhosis (5) and the improvements induced by therapy are difficult to
sustain. A prospective, controlled trial of alpha-interferon in patients with
early or mildly decompensated liver disease (Child's Class A or B) is needed.
Chronic hepatitis C is rare in childhood. As a result
<PAGE> 19
S131
there have been no controlled trials of alpha-interferon treatment in children.
There is no reason to believe that children will respond differently to
interferon from adults. Indeed, children tolerate interferon very well.
Consequently, interferon therapy is indicated in children with chronic
hepatitis C.
Therapy of patients with suspected chronic hepatitis C and atypical
serologic markers can be problematic. At least 80% of patients with chronic
hepatitis C will have anti-HCV in serum using a first-generation assay and the
remainder will have HCV-RNA in serum (11,13,14). A higher percentage will be
reactive using a second-generation anti-HCV test (15). Unfortunately,
second-generation anti-HCV tests and assays for HCV-RNA are not commercially
available in all areas of the world.
At present, most patients are diagnosed as having chronic hepatitis C based
upon the finding of anti-HCV in serum by a first-generation ELISA along with
elevations in serum aminotransferases and liver histology compatible with
chronic hepatitis. However, this approach is not without shortcomings. Some
patients with chronic hepatitis C will be non-reactive for anti-HCV (false
negatives)(11,13). In addition, some patients with other forms of liver disease
(autoimmune hepatitis or alcoholic liver disease) will test positive for
anti-HCV by ELISA due to a non-specific reaction (false positives) (16,17). The
history of an exposure to blood or blood products (transfusion, drug addiction,
medical care exposure) is helpful in verifying the diagnosis of hepatitis C,
but these features are not always present in the clinical history and are not
always reliable. These difficulties become important because there is evidence
that auto-immune chronic active hepatitis will worsen with alpha-interferon
therapy (18). For this reason, additional efforts should be made to exclude
patients with autoimmune features of disease before using alpha-interferon,
particularly if HCV-RNA testing is not available and if there is no history of
exposure, or if clinical features of the disease are atypical. Autoimmune
hepatitis should be considered in young patients, particularly women, if the
disease is severe or there is no exposure history. In any case,
alpha-interferon should be withdrawn rapidly if there is worsening of serum
aminotransferases with alpha-interferon therapy (18,19). Severe worsening of
disease and even fatalities due to exacerbation of the underlying hepatitis
have been reported during alpha-interferon therapy of hepatitis C.
Another group of problematic patients are those who are immunocompromised,
such as patients who have human immunodeficiency virus (HIV) infection, who
have renal failure, who have received an organ transplant, or who are receiving
immunosuppresive
<PAGE> 20
S132
therapy. There are no reports available concerning treatment of such patients.
Anecdotal results suggest that, in contrast to immunocompromised patients with
chronic hepatitis B, those with chronic hepatitis C may benefit from alpha-
interferon therapy (12). The role of interferon therapy in this group deserves
further evaluation, particularly in view of new information suggesting that
chronic hepatitis C can be severe following organ transplantation (20.21).
A final group of patients in whom studies of therapy are needed are those
with acute hepatitis C. Preliminary, small trials of alpha- and beta-interferon
in acute hepatitis C have indicated that early treatment may prevent chronicity
(22-24). In most opf these studies, interferon was given for 6-12 weeks and
patients were followed for the development of chronic hepatitis C for up to
1 year after treatment. In all 3 studies reported to date, the interferon-
treated patients have demonstrated a more rapid decrease of aminotransferase
levels into the normal range and a lower rate of chronicity at 6 months and
1 year. Overall, however, the decrease in chrnicity with interferon treatment
has been limited. Obviously, larger controlled trials with longer periods of
follow-up evaluation are needed. At present alpha-interferon should not be
used in acute hepatitis C outside of a controlled trial.
DOSE AND DURATION OF THERAPY
The currently recommended regimen of alpha-interferon for chronic hepatitis
C is 3 MU subcutaneously thrice weekly for 6 months. However, this dose may
not be high enough for some patients, and a 6-month course may be suboptimal in
reliably inducing a sustained response. Several ongoing trials are comparing
regimens of 3, 5 and 10 MU and courses of 6 and 12 months. In a randomized,
placebo-controlled trial conducted at the National Institutes of Health,
patients received either alpha-interferon (2 MU) or placebo thrice weekly for
6 months (4). Afterwards patients who received placebo were crossed over to
receive interferon for up to 12 months in doses of 2-5 MU trice weekly
depending upon response in aminotransferase levels and tolerance. While the
overall response rate was similar with both regimens, the sustained response
rate was higher with the 12-month course of treatment (Fig.1).
Thus, at present, the optimal dose and duration of therapy are unclear.
There also may be variation between patients in response to different doses.
Until prospective, randomized controlled trials demonstrate a benefit for
higher doses of alpha-interferon or for longer courses of therapy, one must
recommend a dose of 3 MU and a
<PAGE> 21
J. H. HOOFNAGLE et al.
[GRAPH]
Di Bisceglie et al 1990
Fig. 1. Overall response rate among 41 patients with chronic hepatitis C who
were entered into a randomized, controlled trial of alpha-interferon and who
were given interferon (2 MU) (n = 21) or placebo (n = 20) thrice weekly for 6
months. Eighteen of the placebo recipients were then crossed over to receive
interferon (2-3 MU) thrice weekly for 12 months. The upper bars show the
overall response rate, the lower bars the sustained response rate associated
with each treatment.
6-month course of treatment. The dose should be increased only if the response
is partial.
PREDICTORS OF RESPONSE
Only 50% of patients with chronic hepatitis C respond to alpha-interferon
therapy. It would be very helpful if there were clinical or serologic features
that would predict which patients were likely to respond to therapy and which
were not. Unfortunately, retrospective analyses from the controlled trials of
interferon have failed to identify any clinical, serum biochemical, serological
or histological feature of disease that reliably predicted a response to
treatment (3-6.25). Importantly, the presence or titers of anti-HCV or HCV-RNA
in serum did not identify patients who were likely to have a response to
interferon (11). These findings were in contrast to hepatitis B, where the
height of serum aminotransferases and level of HBV-DNA are helpful in
identifying patients who are likely to benefit from treatment (26). In some
studies, patients who lacked anti-HCV and who had cirrhosis histologically were
less likely to benefit from therapy (5). However, these correlations have been
weak and cannot be used to decide on whether to use interferon or not.
<PAGE> 22
ANTIVIRAL THERAPY OF HEPATITIS C
PREDICTORS OF RELAPSE
The optimal duration of therapy is not currently known. Different patients
may require different lengths of treatment. What is needed is a means of
monitoring treatment that would correctly identify when HCV has been cleared
and a sustained clinical response could be expected. In this way, the duration
of therapy would be based upon attainment of a complete response. This is the
case in chronic hepatitis B. in which serological markers can identify when a
sustained response is attained: the loss of HBV-DNA and HBeAg from serum
indicates clearance of HBV replication 1261.
Several clinical, serum biochemical, serological and histological features
have been analyzed as possible means of monitoring therapy in chronic hepatitis
C. (Table 3). Obviously, serum aminotransferase levels and liver histology,
while correlating with a response to therapy, do not predict a sustained
response. More recently, specific serologic markers have been analyzed for a
possible role in monitoring treatment and identifying when a complete and
lasting response in chronic hepatitis C. has occurred.
Most patients with chronic hepatitis C. have anti-HCV in serum in titers
ranging from 10 degrees to 10(5). Retrospective analyses have shown that titers
of anti-HCV as assessed by first-generation ELISA did not change in a
consistent manner during alpha-interferon therapy (11.27). A preliminary report
has suggested that IgM anti-HCV, which is frequently detectable in patients
with chronic hepatitis C. decreases and often disappears during treatment in
patients who have a sustained response but not in those without a response or
with a transient response ???. If these findings are confirmed, lgM anti-HCV
testing might play an important role in monitoring patients and deciding how
long to continue treatment.
The technique of polymerase chain reaction (PCR) is a very sensitive means of
detecting specific nucleic acid sequences and has been used to detect and
quantify HCV-RNA in serum (11.13.14). Most patients with chronic hepatitis C.
have HCV-RNA in serum in titers ranging from 10 degrees to 10(5). Testing of
stored serum from
TABLE 3
Alpha-interferon therapy in chronic hepatitis C. potential means for monitoring
therapy.
- -----------------------------------------------------------------------------
Serum aminotransferase levels
Liver histology
Antibody to HCV
lgM antibody to HCV
HCV-RNA in serum
HCV-RNA in liver
HCV antigens in liver
- -----------------------------------------------------------------------------
<PAGE> 23
5133
patients treated with alpha-interferon has shown that levels of this viral
marker decrease on treatment and HCV-RNA becomes undetectable in most patients
with a beneficial response to treatment (Fig. 2). Levels decrease only slightly
or not at all in patients with no or only a partial response. However, HCV-RNA
reappears in patients with a relapse after therapy is stopped and loss of
HCV-RNA, while correlating well with a
[HCV-RNA CHART]
Responders Non-responders Placebo
Fig. 2. Serum levels of HCV-RNA in 39 patients who entered a randomized placebo
controlled trial of alpha-interferon in chronic hepatitis C. HCV-RNA fell to
undetectable levels in most patients who responded to treatment but in only
rare patients without a response and in no patients who received placebo.
[Serum ALT CHART]
Fig. 3. Course of a patient with chronic hepatitis C treated with
alpha-interferon. Serum ALT levels fell into the normal range and serum HCV-RNA
became undetectable and remained undetectable even when therapy was stopped.
[INTERFERON NORMS CHART]
Fig. 4. Course of a patient with chronic hepatitis C treated with
alpha-interferon. Serum ALT levels fell into the normal range and serum HCV-RNA
became undetectable. However, a relapse of disease and reappearance of serum
HCV-RNA occurred when treatment was stopped.
<PAGE> 24
response to alpha-interferon treatment, does not predict a sustained response
(Figs. 3 and 4). Nevertheless, these findings provide a virologic basis for
assessing the efficacy of alpha-interieron in chronic hepatitis C. The major
effect of interferon appears to be inhibition of viral replication, and thus
long-term responses occur when there has been sustained clearance of virus.
Obviously, better markers are needed to assess and monitor therapy and to
provide guidance in when to initiate and when to stop therapy. Further
assessments of serum antibody responses and evaluation of HCV-RNA and HCV
antigens in liver tissue (28) may yet provide the serologic tools to place
therapy of hepatitis C on a more rational basis.
HOW TO INCREASE THE RESPONSE RATE
While alpha-interferon has provided the first effective treatnent for
chronic hepatitis C, this treatment is effective in only 50% of patients and a
long-term response occurs in only 10-25% of patients. Furthermore, interferon
is difficult to administer, is quite expensive, and has multiple side effects
which can be dose-limiting. Better tolerated and more effective therapies are
needed. Use of repeated courses of alpha-interferon in patients with partial or
temporary responses has been only partially beneficial.
Characterization of the genome of HCV suggests that it is a flavi- or
pesti-like virus. A tissue culture or simple animal model of hepatitis C would
be extremely helpful in further characterizing this virus and to screen for
anitviral agents of potential use. Until there is such an in vitro or in vivo
method for monitoring HCV replication, however, antiviral studies will have to
be done in human patients with this disease. For this reason, the majority of
agents that have been used in chronic hepatitis C are those that have been
previously evaluated for other conditions in man (Table 4). The agent that
currently demonstrates the most promise is ribavirin.
Ribavirin (1-B-d-riboiuranosyl 1.2.4-triazole-3-carbox-amiac) is a
guanosine analogue that has been evaluated extensively as therapy of
respiratory syncytial virus and HIV injection in man (29). Ribavirin is
especially attractive as it is absorbed orally and is well tolerated, its only
significant side effect being a dose-related hemolysis that is generally mild,
subclinical, and rapidly reversible when therapy is stopped. Ribavirin was
initially tried in chronic hepatitis C based upon its safe clinical profile and
its known activity against many RNA viruses including some flaviviruses.
Wetland and co-workers from Sweden treated 10
<PAGE> 25
J.H. HOOFNAGLE et al.
TABLE 4
Therapy of chronic hepatitis C; potential agents
- --------------------------------------------------------------------
Antivirals
Ribavirin, acyciovir, adenine arabinoside,
foscarnet, dideoxynucleosides, azathymidine,
gangiciovir, suramin
Biologic response modifiers
Alpha-, beta- and gamma-interferon, interleukins
2, 4 and 6, colony-stimulating factors, tumor
necrosis factor
Immunomodulators
Prednisone, thymosin, levamisole
- --------------------------------------------------------------------
patients with chronic hepatitis C with ribavirin for 12 weeks in doses of
1000-1200 mg per day (30). Serum aminotransferases decreased by 60% during
therapy but rose to pre-treatment values soon after ribavirin was stopped.
Changes in liver histology and levels of HCV-RNA or anti-HCV were not reported.
At the National Institutes of Health, we have completed a pilot study of oral
ribavirin therapy in 13 patients with chronic hepatitis C (31). Ribavirin was
administered in gradually escalating doses for 6 months. Serum
aminotransferases levels fell in all 13 patients and became normal in 4 (28%).
The average decrease in aminotransferases was 67%. However, even after 6 months
of treatment, liver biopsies demonstrated no consistent improvement in degree
of inflammation or hepatocellular necrosis. When ribavirin was stopped, serum
aminotransferases rose to pre-treatment levels in most, but not all patients.
On the other hand, ribavirin was well-tolerated even at the highest doses (1200
mg.d) and the only side effect noted was a mild, clinically silent, hemolytic
anemia.
Interesting differences were noted between the clinical and serologic
responses in patients treated with ribavirin versus those treated with
alpha-interferon. The serum aminotransferases fell much more slowly with
ribavirin than with interferon therapy. However, the ultimate level of
improvement in aminotransferases was the same with both drugs: with both there
was a 60-70% decrease from pre-treatment levels (3.31). Another difference was
that aminotransferase levels decreased in all patients treated with ribavirin
but in only 50-70% of those treated with interferon. This fact underscores the
peculiar variability in response to alpha-interferon therapy. Finally, serum
levels of HCV-RNA decreased markedly in all patients who responded to
alpha-interferon therapy (11); in contrast, HCV-RNA levels decreased only
slightly during ribavirin therapy (31).
The encouraging preliminary observations on the effects of ribavirin therapy
in chronic hepatitis C have
<PAGE> 26
ANTIVIRAL THERAPY OF HEPATITIS C
led to a prospective, randomized, double-blind controlled trial of ribavirin
(1200 mg/d) versus placebo for 12 months that is being carried out at the
National Institutes of Health (Fig. 5). This trial began in November 1991 and
will include 50-60 patients entered over a 6-month period. Meanwhile, more
studies are needed on the potential combination of ribavirin with
alpha-interferon as well as dose-finding studies based upon response of
aminotransferases to ribavirin therapy.
THE FUTURE OF THERAPY OF HEPATITIS C
Future research into therapy for hepatitis C will focus on more agents
than alpha-interferon and ribavirin (Table 4) and on a broader spectrum of this
disease. It is possible that multiple antiviral agents with activity against
HCV will be identified. Indeed, initial results suggest that this virus is
quite sensitive to inhibition and that lowering the level of virus leads to
amelioration of disease. In addition to a search for more agents to treat this
disease, further studies of alpha-interferon and riba-
REFERENCES
1. Hoofnagle JH. Mullen KD. Jones DB. et al. Treatment of chronic non-A,
non-B hepatitis with recombinant human alpha interferon: a
preliminary report. N Engl J Mod 1987: 315: 1575-8.
2. Jacyna MR. Brooks MG. Loke RHT. Main J. Murray-Lyon IM. Thomas HC.
Randomized controlled trial of interferon alfa (lympnoblastoid interferon)
in chronic non-A, non-B hepatitis. Br Med J 1989: 298: 80-L.
3. Davis GL. Balart LA. Schiff ER. et al. Treatment of chronic hepatitis C
with recombinant interferon alfa: a multicenter randomized, controlled
trial, N Engl J Med 1989: 321: 1501-6.
4. Di Bisceglie AM. Martin P. Kassianides C. et al. Recombinant interferon
alfa therapy for chronic hepatitis C: a randomized, double-blind,
placebo-controlled trial. N Engl J Med 1989: 321: 1506-10.
5. Marcellin P. Boyer N. Giostra E. et al. Recombinant human alpha-interferon
in patients with chronic non-A, non-B hepatitis: a multicenter randomized
controlled trial from France. Hepatology 1991: 13: 393-7.
6. Saracco G. Rosina F. Torrani Cerenzia MR. et al. A randomized
controlled trial of interferon alfa-2b as therapy for chronic non-A, non-B
hepatitis. J Hepatol 1990: 11: S43-9.
7. Ferenci P. Vogel W. Pristautz H. et al. One-year treatment of chronic
non-A, non-B hepatitis with interferon alfa-2b. J Hepatol 1990: 11:
S50-6.
8. Weiland O. Schvarcz R. Wejstal R. Norkrans G. Fryden A. Therapy of
chronic post-transfusion non-A, non-B hepatitis with interferon
alfa-2b: Swedish experience, J Hepatol 1990: 11: S57-62.
9. Gomez-Rubio M. Porres JC. Castillo I. Quiroga JA. Moreno A. Carreno
V. Prolonged treatment (18 months) of chronic hepatitis C with recombinant
alpha-interferon in comparison with a control group. J Hepatol 1990: 11:
S63-.
10. Realdi G. Diodata G. Bonetti P. Scaccabarozzi S. Alberti A.
<PAGE> 27
[GRAPH]
Fig. 5. Design of randomized controlled trial of ribavirin in chronic
hepatitis C.
virin therapy are needed. Particularly important are studies in patients with
clinically apparent cirrhosis, in children, in patients with unusual forms of
the disease and immunocompromised patients.
Thus, the future of antiviral therapy in chronic hepatitis C will help to
fill in the gaps in knowledge about the correct use of alpha-interferon but
will also focus on newer antiviral agents that alone or in combination with
interferon promise to provide a relatively safe but highly effective therapy
for all patients with liver disease due to hepatitis C.
Ruol A. Recombinant human interferon alfa-2a in community-acquired non-A,
non-B chronic active hepatitis; preliminary results of a randomized,
controlled trial. J Hepatol 1990: 11: S68-71.
11. Shindo M, Di Bisceglie AM, Cheung L, Shih W-K, Cristiano K, Feinstone SM,
Hoofnagle JH. Decrease in serum hepatitis C viral RNA during
alpha-interferon therapy for chronic hepatitis C. Ann Intern
Med 1991: 115: 700-4.
12. Martin P, Di Bisceglie AM, Kassianides C. Lisker-Melman M. Hoofnagle JH.
Rapidly progressive non-A, non-B hepatitis in patients with human
immunodeficiency virus infection. Gastroenterology 1989: 97: 1559-61.
13. Weiner AJ. Kuo G, Bradley DW, et al. Detection of hepatitis C viral
sequences in non-A, non-B hepatitis. Lancet 1990: 335: 1-3.
14. Farci P. Alter HJ. Wong D. Miller RH. Shih JW. Gett B. Purcell RH. A
long-term study of hepatitis C virus replication in non-A, non-B
hepatitis. N Engl J Med 1991: 325: 98-104.
15. Van der Poel CL. Cuypers HTM. Reesink HW. et al. Confirmation
of hepatitis C virus infection by new four-antigen recombinant
immunoblot assay. Lancet 1991: 337: 317-9.
16. McFarlane IG. Smith HM. Johnson PJ. Bray GP. Vergani D, Williams R.
Hepatitis C virus antibodies in chronic active hepatitis:
pathogenic factor or false-positive result? Lancet 1990: 335: 754-7.
17. Mendenhall CL. Seen L. Diehl AM. et al. Antibodies to hepatitis B virus
and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence
and clinical relevance. Hepatology 1991: 14: 581-9.
18. Papo T. Marcellin P. Bernuau J. Durand F. Poynard T. Benhamou J-P.
Autoimmune chronic hepatitis exacerbated by alpha-interferon.
Ann Intern Med 1992: 116: 51-3.
19. Shindo M. Di Bisceglie AM. Hoofnagle JH. Acute exacerbation of
liver disease during alpha interferon therapy for chronic hepatitis C.
Gastroenterology 1992: 102: in press.
20. Martin P. Munoz SJ. Di Bisceglie AM. et al. Recurrence of hepatitis C
infection following orthotopic liver transplantation. Hepatology 1991:
13: 719-21.
<PAGE> 28
21. Pereira BJG, Milford EL. Kirkman RL. Levey AS. Transmission of hepatitis C
virus by organ transplantation. N Engl J Med 1991: 325: 454-60.
22. Omata M. Yokosuka O. Takano S. et al. Resolution of acute hepatitis C
after therapy with natural beta interferon. Lancet 1991: 338: 914-5.
23. Alberti A. Chemello L. Benvegnu L. Belussi F. Tagger A. Ruol A. Pilot
study of interferon alpha-2a therapy in preventing chronic evoluation of
acute hepatitis C. In: Hollinger FB. Lemon SM. Margolis H. Eds. Viral
Hepatitis and Liver Disease, Baltimore: Williams and Wilkins. 1991: 656-8.
24. Viladomiu L. Gonzalez A. Lopez-Talavera JC. et al. a randomized controlled
trial of alpha-interferon in acute posttransfusion C hepatitis (Abstract)
J. Hepatol 1990: 11: S64.
25. Lindsay K.L. Davis GL. Bodenheimer HC. et al. Predictors of relapse and
response to re-treatment in patients with an initial response to
recombinant alpha interferon (rIFN) therapy for chronic hepatitis C
(Abstract). Hepatology 1990: 12: 847.
<PAGE> 29
26. Perrillo RP. Schiff E.R. Davis GL. et al. A randomized controlled trial of
interferon alfa-2b alone and after prednizone withdrawal for the treatment
of chronic hepatitis B. N Engl J Med 1990: 323: 295-301.
27. Brillianti S. Masci C. Ricci P. Paganelli GM. Miglioli M. Barbara L. Serum
IgM antibody to HCV: a reliable marker of active hepatitis C (Abstract).
Gastroenterology 1991: 100: A723.
28. Krawczynski K. Beach MJ. Bradley DW. et al. Hepatitis C virus antigen in
hepatocytes: immunomorphologic detection and identification.
Gastroenterology 1992: 102: in press.
29. Gilbert BE. Knight V. Biochemistry and clinical applications of ribavirin.
Antimicrob Agents Chemother 1986: 30: 200-5.
30. Reichard O. Andersson J. Schvarcz R. Weiland O. Ribavirin treatment for
chronic hepatitis C. Lancet 1991: 337: 1058-61.
31. Di Bisceglie AM. Fong T-L. Fried MW. Swain MG. Bergasa NV. Shindo M.
Hoofnagle JH. Ribavirin therapy for 6 months in patients with chronic
hepatitis C (Abstract). Gastronenterology 1991: 100: A734.
Consent of publication has not been received from the Journal of Hepatology as
of the date of this filing.
<PAGE> 30
VIRAZOLE(R)
(ribavirin for inhalation solution)
PRESCRIBING INFORMATION
- -----------------------------------------------------------------------------
WARNINGS:
USE OF AEROSOLIZED VIRAZOLE IN PATIENTS REQUIRING MECHANICAL VENTILATOR
ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR
WITH THE SPECIFIC VENTILATOR BEING USED AND THIS MODE OF ADMINISTRATION OF THE
DRUG. STRICT ATTENTION MUST BE PAID TO PROCEDURES THAT HAVE BEEN SHOWN TO
MINIMIZE THE ACCUMULATION OF DRUG PRECIPITATE, WHICH CAN RESULT IN MECHANICAL
VENTILATOR DYSFUNCTION AND ASSOCIATED INCREASED PULMONARY PRESSURES (SEE
WARNINGS).
SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH
INITIATION OF AEROSOLIZED VIRAZOLE USE IN INFANTS. RESPIRATORY FUNCTION SHOULD
BE CAREFULLY MONITORED DURING TREATMENT. IF INITIATION OF AEROSOLIZED VIRAZOLE
TREATMENT APPEARS TO PRODUCE SUDDEN DETERIORATION OF RESPIRATORY FUNCTION,
TREATMENT SHOULD BE STOPPED AND REINSTITUTED ONLY WITH EXTREME CAUTION,
CONTINUOUS MONITORING AND CONSIDERATION OF CONCOMITANT ADMINISTRATION OF
BRONCHODILATORS (SEE WARNINGS).
VIRAZOLE IS NOT INDICATED FOR USE IN ADULTS. PHYSICIANS AND PATIENTS SHOULD BE
AWARE THAT RIBAVIRIN HAS BEEN SHOWN TO PRODUCE TESTICULAR LESIONS IN RODENTS
AND TO BE TERATOGENIC IN ALL ANIMAL SPECIES IN WHICH ADEQUATE STUDIES HAVE BEEN
CONDUCTED (RODENTS AND RABBITS); (SEE CONTRAINDICATIONS).
- ------------------------------------------------------------------------------
DESCRIPTION
VIRAZOLE(R) is a brand name for ribavirin, a synthetic nucleoside with
antiviral activity. VIRAZOLE for inhalation solution is a sterile, lyophilized
powder to be reconstituted for aerosol administration. Each 100 ml glass vial
contains 6 grams of ribavirin, and when reconstituted to the recommended volume
of 900 ml with sterile water for injection or sterile water for inhalation (no
preservatives added), will contain 20 mg of ribavirin per ml, pH approximately
5.5. Aerosolization is to be carried out in a Small Particle Aerosol Generator
(SPAG-2) nebulizer only.
Ribavirin is 1-beta-D-ribofuranosyl-1H-1, 2, 4-triazole-3-carboxamide, with
the following structural formula:
[FORMULA] Ribavirin is a stable, white crystalline compound with a maximum
solubility in water of 142 mg/ml at 25 degrees C and with only
a slight solubility in ethanol. The empirical formula is
C8H12N4O5 and the molecular weight is 244.21.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
In cell cultures the inhibitory activity of ribavirin for respiratory syncytial
virus (RSV) is selective. The mechanism of action is unknown. Reversal of the
in vitro antiviral activity by guanosine or xanthosine suggests ribavirin may
act as an analogue of these cellular metabolites.
MICROBIOLOGY
Ribavirin has demonstrated antiviral activity against RSV in vitro(1) and in
experimentally infected cotton rats.(2) Several clinical isolates of RSV were
evaluated for ribavirin susceptibility by plaque reduction in tissue culture.
Plaques were reduced 85-98% by 16 ug/ml; however, results may vary with the
test system. The development of resistance has not been evaluated in vitro or
in clinical trials.
In addition to the above, ribavirin has been shown to have in vitro activity
against influenza A and B viruses and herpes simplex virus, but the clinical
significance of these data is unknown.
IMMUNOLOGIC EFFECTS
Neutralizing antibody responses to RSV were decreased in aerosolized VIRAZOLE
treated infants compared to placebo treated infants.(3) One study also showed
that RSV-specific lgE antibody in bronchial secretions was decreased in
patients treated with aerosolized VIRAZOLE. In rats, ribavirin administration
resulted in lymphoid atrophy of the thymus, spleen, and lymph nodes. Humoral
immunity was reduced in guinea pigs and ferrets. Cellular immunity was also
mildly depressed in animal studies. The clinical significance of these
observations is unknown.
PHARMACOKINETICS
Assay for VIRAZOLE in human materials is by a radioimmunoassay which detects
ribavirin and at least one metabolite.
VIRAZOLE brand of ribavirin, when administered by aerosol, is absorbed
systemically. Four pediatric patients inhaling VIRAZOLE aerosol
<PAGE> 31
administered by face mask for 2.5 hours each day for 3 days had plasma
concentrations ranging from 0.44 to 1.55 uM, with a mean concentration of 0.76
uM. The plasma half-life was reported to be 9.5 hours. Three pediatric patients
inhaling aerosolized VIRAZOLE administered by face mask or mist tent for 20
hours each day for 5 days had plasma concentrations ranging from 1.5 to 14.3
uM, with a mean concentration of 6.8 uM.
The bioavailability of aerosolized VIRAZOLE is unknown and may depend on the
mode of aerosol delivery. After aerosol treatment, peak plasma concentrations
of ribavirin are 85% to 98% less than the concentration that reduced RSV plaque
formation in tissue culture. After aerosol treatment, respiratory tract
secretions are likely to contain ribavirin in concentrations many fold higher
than those required to reduce plaque formation. However, RSV is an
intracellular virus and it is unknown whether plasma concentrations or
respiratory secretion concentrations of the drug better reflect intracellular
concentrations in the respiratory tract.
In man, rats, and rhesus monkeys, accumulation of ribavirin and/or
metabolites in the red blood cells has been noted, plateauing in red cells in
man in about 4 days and gradually declining with an apparent half-life of 40
days (the half-life of erythrocytes). The extent of accumulation of ribavirin
following inhalation therapy is not well defined.
ANIMAL TOXICOLOGY
Ribavirin, when administered orally or as an aerosol, produced cardiac lesions
in mice, rats, and monkeys, when given at doses of 30, 36 and 120 mg/kg or
greater for 4 weeks or more (estimated human equivalent doses of 4.8, 12.3 and
111.4 mg/kg for a 5 kg child, or 2.5, 5.1 and 40 mg/kg for a 60 kg adult, based
on body surface area adjustment). Aerosolized ribavirin administered to
developing ferrets at 60 mg/kg for 10 or 30 days resulted in inflammatory and
possibly emphysematous changes in the lungs. Proliferative changes were seen in
the lungs following exposure at 131 mg/kg for 30 days. The significance of
these findings to human administration is unknown.
INDICATIONS AND USAGE
VIRAZOLE is indicated for the treatment of hospitalized infants and young
children with severe lower respiratory tract infections due to respiratory
synctial virus. Treatment early in the course of severe lower respiratory tract
infection may be necessary to achieve efficacy.
Only severe RSV lower respiratory tract infection should be treated with
VIRAZOLE. The vast majority of infants and children with RSV infection have
disease that is mild, self-limited, and does not require hospitalization or
antiviral treatment. Many children with mild lower respiratory tract
involvement will require shorter hospitalization than would be required for a
full course of VIRAZOLE aerosol (3 to 7 days) and should not be treated with
the drug. Thus the decision to treat with VIRAZOLE should be based on the
severity of the RSV infection. The presence of an underlying condition such as
prematurity, immunosuppression or cardiopulmonary disease may increase the
severity of clinical manifestations and complications of RSV infection.
Use of aerosolized VIRAZOLE in patients requiring mechanical ventilator
assistance should be undertaken only by physicians and support staff familiar
with this mode of administration and the specific ventilator being used (see
Warnings, and Dosage and Administration).
DIAGNOSIS
RSV infection should be documented by a rapid diagnostic method such as
demonstration of viral antigen in respiratory tract secretions by
immunofluorescence(3,4) or ELISA(5) before or during the first 24 hours of
treatment. Treatment may be initiated while awaiting rapid diagnostic test
results. However, treatment should not be continued without documentation of
RSV infection. Non-culture antigen detection techniques may have false positive
or false negative results. Assessment of the clinical situation, the time of
year and other parameters may warrant reevaluation of the laboratory diagnosis.
DESCRIPTION OF STUDIES
NON-MECHANICALLY-VENTILATED INFANTS: In two placebo controlled trials in
infants hospitalized with RSV lower respiratory tract infection, aerosolized
VIRAZOLE treatment had a therapeutic effect, as judged by the reduction in
severity of clinical manifestations of disease by treatment day 3.(3,4)
Treatment was most effective when instituted within the first 3 days of
clinical illness. Virus titers in respiratory secretions were also
significantly reduced with VIRAZOLE in one of these original studies.(4)
Additional controlled studies conducted since these initial trials of
aerosolized VIRAZOLE in the treatment of RSV infection have supported these
data.
MECHANICALLY-VENTILATED INFANTS: A randomized, double-blind placebo controlled
evaluation of aerosolized VIRAZOLE at the recommended dose was conducted in 28
infants requiring mechanical ventilation for respiratory failure caused by
documented RSV infection.(6) Mean age was 1.4 months (SD, 1.7 months). Seven
patients had underlying diseases predisposing them to severe infection and 21
were previously normal. Aerosolized VIRAZOLE treatment significantly decreased
the duration of mechanical ventilation required (4.9 vs 9.9 days, p=0.01).
Intensive patient management and monitoring techniques were employed in this
study. These included endotracheal tube suctioning every 1 to 2 hours;
recording of proximal airway pressure, ventilatory rate, and F(1)O(2) every
hour; and arterial blood gas monitoring every 2 to 6 hours. To reduce the risk
of VIRAZOLE precipitation and ventilator malfunction, heated wire tubing, two
bacterial filters connected in series in the expiratory limb of the ventilator
(with filter changes every 4 hours), and water column pressure release valves
to monitor internal ventilator pressures were used in connecting ventilator
circuits to the SPAG-2.
Employing these techniques, no technical difficulties with VIRAZOLE
administration were encountered during the study. Adverse events consisted of
bacterial pneumonia in one case, staphyloccus bacteremia in one case and two
cases of post-extubation stridor. None were felt to be related to VIRAZOLE
administration.
CONTRAINDICATIONS
VIRAZOLE is contraindicated in individuals who have shown hypersensitivity to
the drug or its components, and in women who are or may become pregnant.
<PAGE> 32
during exposure to the drug, Ribavirin has demonstrated significant teratogenic
and/or embryocidal potential in all animal species in which adequate studies
have been conducted (rodents and rabbits). Therefore, although clinical studies
have not been performed, it should be assumed that VIRAZOLE may cause fetal
harm in humans. Studies in which the drug has been administered systemically
demonstrate that ribavirin is concentrated in the red blood cells and persists
for the life of the erythrocyte.
WARNINGS
SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH
INITIATION OF AEROSOLIZED VIRAZOLE USE IN INFANTS. Respiratory function should
be carefully monitored during treatment. If initiation of aerosolized VIRAZOLE
treatment appears to produce sudden deterioration of respiratory function,
treatment should be stopped and reinstituted only with extreme caution,
continuous monitoring, and consideration of concomitant administration of
bronchodilators.
USE WITH MECHANICAL VENTILATORS
USE OF AEROSOLIZED VIRAZOLE IN PATIENTS REQUIRING MECHANCIAL VENTILATOR
ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR
WITH THIS MODE OF ADMINISTRATION AND THE SPECIFIC VENTILATOR BEING USED. Strict
attention must be paid to procedures that have been shown to minimize the
accumulation of drug precipitate, which can result in mechanical ventilator
dysfunction and associated increased pulmonary pressures. These procedures
include the use of bacteria filters in series in the expiratory limb of the
ventilator circuit with frequent changes (every 4 hours), water column pressure
release valves to indicate elevated ventilator pressures, frequent monitoring
of these devices and verification that ribavirin crystals have not accumulated
within the ventilator circuitry, and frequent suctioning and monitoring of the
patient (see Clinical Studies).
Those administering aerosolized VIRAZOLE in conjunction with mechanical
ventilator use should be thoroughly familiar with detailed descriptions of
these procedures as outlined in the SPAG-2 manual.
PRECAUTIONS
GENERAL
Patients with severe lower respiratory tract infection due to respiratory
syncytial virus require optimum monitoring and attention to respiratory and
fluid status (see SPAG-2 manual).
DRUG INTERACTIONS
Clinical studies of interactions of VIRAZOLE with other drugs commonly used to
treat infants with RSV infections, such as digoxin, bronchodilators, other
antiviral agents, antibiotics or anti-metabolites, have not been conducted.
Interference by VIRAZOLE with laboratory tests has not been evaluated.
CARCINOGENESIS AND MUTAGENESIS
Ribavirin increased the incidence of cell transformations and mutations in
mouse Balb/c 3T3 (fibroblasts) and L5178Y (lymphoma) cells at concentrations of
0.015 and 0.03-5 mg/ml, respectively (without metabolic activation. Modest
increases in mutation rates (3-4x) were observed at concentrations between
3.75-10.0 mg/ml in L5178Y cells in vitro with the addition of a metabolic
activation fraction. In the mouse micronucleus assay, ribavirin was clastogenic
at intravenous doses of 20-200 mg/kg, (estimated human equivalent of 1.67-16.7
mg/kg, based on body surface area adjustment for a 60 kg adult). Ribavirin was
not mutagenic in a dominant lethal assay in rats at intraperitoneal doses
between 50-200 mg/kg when administered for 5 days (estimated human equivalent
of 7.14-28.6 mg/kg, based on body surface area adjustment; see
Pharmacokinetics).
In vivo carcinogenicity studies with ribavirin are incomplete. However,
results of a chronic feeding study with ribavirin in rats, at doses of 16-100
mg/kg/day (estimated human equivalent of 2.3-14.3 mg/kg/day, based on body
surface area adjustment for the adult), suggest that ribavirin may induce
benign mammary, pancreatic, pituitary and adrenal tumors. Preliminary results
of 2 oral gavage oncogenicity studies in the mouse and rat (18-24 months; doses
of 20-75 and 10-40 mg/kg/day, respectively (estimated human equivalent of
1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area
adjustment for the adult)) are inconclusive as to the carcinogenic potential of
ribavirin (see Pharmacokinetics). However, these studies have demonstrated a
relationship between chronic ribavirin exposure and increased incidences of
vascular lesions (microscopic hemorrhages in mice) and retinal degeneration
(in rats).
IMPAIRMENT OF FERTILITY
The fertility of ribavirin-treated animals (male or female) has not been fully
investigated. However, in the mouse, administration of ribavirin at doses
between 35-150 mg/kg/day (estimated human equivalent of 2.92-12.5 mg/kg/day,
based on body surface area adjustment for the adult) resulted in significant
seminiferous tubule atrophy, decreased sperm concentratons, and increased
numbers of sperm with abnormal morphology. Partial recovery of sperm production
was apparent 3-6 months following dose cessation. In several additional
toxicology studies, ribavirin has been shown to cause testicular lesions
(tubular atrophy) in adult rats at oral dose levels as low as 16 mg/kg/day
(estimated human equivalent of 2.29 mg/kg/day, based on body surface area
adjustment; see Pharmacokinetics). Lower doses were not tested. The
reproductive capacity of treated male animals has not been studied.
PREGNANCY: CATEGORY X
Ribavirin has demonstrated significatnt teratogenic and/or embryocidal
potential in all animal species in which adequate studies have been conducted.
Teratogenic effects were evident after single oral doses of 2.5 mg/kg or
greater in the hamster, and after daily oral doses of 0.3 and 1.0 mg/kg in the
rabbit and rat, respectively (estimated human equivalent doses of 0.2 and
0.14 mg/kg based on body surface area adjustment for the
<PAGE> 33
adult). Malformations of the skull, palate, eye, jaw, limbs, skeleton, and
gastrointestinal tract were noted. The incidence and severity of teratogenic
effects increased with escalation of the drug dose. Survival of fetuses and
offspring was reduced. Ribavirin caused embryolethality in the rabbit at daily
oral dose levels as low as 1 mg/kg. No tetratogenic effects were evident in the
rabbit and rat administered daily doses of 0.1 and 0.3 mg/kg, respectively with
estimated human equivalent doses of 0.01 and 0.04 mg/kg, based on body surface
area adjustment (see Pharmacokinetics). These doses are considered to define
the "No Observable Teratogenic Effects Level" (NOTEL) for ribavirin in the
rabbit and rat.
Following oral administration of ribavirin in the pregnant rat (1.0
mg/kg) and rabbit (0.3 mg/kg), mean plasma levels of drug ranged from 0.10-0.20
uM [0.024-0.049 ug/ml] at 1 hour after dosing, to undetectable levels at 24
hours. At 1 hour following the administration of 0.3 or 0.1 mg/kg in the rat
and rabbit (NOTEL), respectively, mean plasma levels of drug in both species
were near or below the limit of detection (0.05 uM; see Pharmacokinetics).
Although clinical studies have not been performed, VIRAZOLE may cause
fetal harm in humans. As noted previously, ribavirin is concentrated in red
blood cells and persists for the life of the cell. Thus the terminal half-life
for the systemic elimination of ribavirin is essentially that of the half-life
of circulating erythrocytes. The minimum interval following exposure to
VIRAZOLE before pregnancy may be safely initiated is unknown (see
Contraindications, Warnings, and Information for Health Care Personnel).
NURSING MOTHERS
VIRAZOLE has been shown to be toxic to lactating animals and their
offspring. It is not known if VIRAZOLE is excreted in human milk.
INFORMATION FOR HEALTH CARE PERSONNEL
Health care workers directly providing care to patients receiving
aerosolized VIRAZOLE should be aware that ribavirin has been shown to be
teratogenic in all animal species in which adequate studies have been conducted
(rodents and rabbits). Although no reports of teratogenesis in offspring of
mothers who were exposed to aerosolized VIRASOLE during pregnancy have been
confirmed, no controlled studies have been conducted in pregnant women. Studies
of environmental exposure in treatment settings have shown that the drug can
disperse into the immediate bedside area during routine patient care activities
with highest ambient levels closest to the patient and extremely low levels
outside of the immediate bedside area. Adverse reactions resulting from actual
occupational exposure in adults are described below (see Adverse Events in
Health Care Workers). Some studies have documented ambient drug concentrations
at the bedside that could potentially lead to systemic exposures above those
considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the
most sensitive animal species).(7,8,9)
A 1992 study conducted by the National Institute of Occupational Safety
and Health (NIOSH) demonstrated measurable urine levels of ribavirin in health
care workers exposed to aerosol in the course of direct patient care.(7) Levels
were lowest in workers caring for infants receiving aerosolized VIRAZOLE with
mechanical ventilation and highest in those caring for patients being
administered the drug via an oxygen tent or hood. This study employed a more
sensitive assay to evaluate ribavirin levels in urine than was available for
several previous studies of environmental exposure that failed to detect
measurable ribavirin levels in exposed workers. Creatinine adjusted urine
levels in the NIOSH study ranged from less than 0.001 to 0.140 uM of ribavirin
per gram of creatinine in exposed workers. However, the relationship between
urinary ribavirin levels in exposed workers, plasma levels in animal studies,
and the specific risk of teratogenesis in exposed pregnant women is unknown.
It is good practice to avoid unnecessary occupational exposure to
chemicals wherever possible. Hospitals are encouraged to conduct training
programs to minimize potential occupational exposure to VIRAZOLE. Health care
workers who are pregnant should consider avoiding direct care of patients
receiving aerosolized VIRAZOLE. If close patient contact cannot be avoided,
precautions to limit exposure should be taken. These include administration of
VIRAZOLE in negative pressure rooms; adequate room ventilation (at least six
air exchanges per hour); the use of VIRAZOLE aerosol scavenging devices;
turning off the SPAG-2 device for 5 to 10 minutes prior to prolonged patient
contact; and wearing appropriately fitted respirator masks. Surgical masks do
not provide adequate filtration of VIRAZOLE particles. Further information is
available from NIOSH's Hazard Evaluation and Technical Assistance Branch and
additional recommendations have been published in an Aerosol Consensus
Statement by the American Respiratory Care Foundation and the American
Association for Respiratory Care.(10)
ADVERSE REACTIONS
The description of adverse reactions is based on events from clinical
studies (approximately 200 patients) conducted prior to 1986, and the
controlled trial of aerosolized VIRAZOLE conducted in 1989-1990. Additional
data from spontaneous post-marketing reports of adverse events in individual
patients have been available since 1986.
DEATHS
Deaths during or shortly after treatment with aerosolized VIRAZOLE have
been reported in 20 cases of patients treated with VIRAZOLE (12 of these
patients were being treated for RSV infections). Several cases have been
characterized as "possibly related" to VIRAZOLE by the treating physician;
these were in infants who experienced worsening respiratory status related to
bronchospasm while being treated with the drug. Several other cases have been
attributed to mechanical ventilator malfunction in which VIRAZOLE precipitation
within the ventilator apparatus led to excessively high pulmonary pressures and
diminished oxygenation. In these cases the monitoring procedures described in
the current package insert were not
<PAGE> 34
employed (see Description of Studies, Warnings, and Dosage and Administration).
PULMONARY AND CARDIOVASCULAR
Pulmonary function significantly deteriorated during aerosolized VIRAZOLE
treatment in six of six adults with chronic obstructive lung disease and in
four of six asthmatic adults. Dyspnea and chest soreness were also reported in
the latter group. Minor abnormalities in pulmonary function were also seen in
healthy adult volunteers.
In the original study population of approximately 200 infants who
received aerosolized VIRAZOLE, several serious adverse events occurred in
severely ill infants with life-threatening underlying diseases, many of whom
required assisted ventilation. The role of VIRAZOLE in these events is
indeterminate. Since the drug's approval in 1986, additional reports of similar
serious, though non-fatal, events have been filed infrequently. Events
associated with aerosolized VIRAZOLE use have included the following:
Pulmonary: Worsening of respiratory status, bronchospasm, pulmonary
edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia,
pneumothorax, apnea, atelectasis and ventilator dependence.
Cardiovascular: Cardiac arrest, hypotension, bradycardia and digitalis
toxicity. Bigeminy, bradycardia and tachycardia have been described in
patients with underlying congenital heart disease.
Some subjects requiring assisted ventilation experienced serious
difficulties, due to inadequate ventilation and gas exchange. Precipitation of
drug within the ventilatory apparatus, including the endotracheal tube, has
resulted in increased positive and expiratory pressure and increased positive
inspiratory pressure. Accumulation of fluid in tubing ("rain out") has also
been noted. Measures to avoid these complications should be followed carefully
(see Dosage and Administration).
HEMATOLOGIC
Although anemia was not reported with use of aerosolized VIRAZOLE in controlled
clinical trials, most infants treated with the aerosol have not been evaluated
1 to 2 weeks post-treatment when anemia is likely to occur. Anemia has been
shown to occur frequently with experimental oral and intravenous VIRAZOLE in
humans. Also, cases of anemia (type unspecified), reticulocytosis and hemolytic
anemia associated with aerosolized VIRAZOLE use have been reported through
post-marketing reporting systems. All have been reversible with discontinuation
of the drug.
OTHER
Rash and conjunctivitis have been associated with the use of aerosolized
VIRAZOLE. These usually resolve within hours of discontinuing therapy. Seizures
and asthenia associated with experimental intravenous VIRAZOLE therapy have
also been reported.
ADVERSE EVENTS IN HEALTH CARE WORKERS
Studies of environmental exposure to aerosolized VIRAZOLE in health care
workers administering care to patients receiving the drug have not detected
adverse signs or symptoms related to exposure. However, 152 health care workers
have reported experiencing adverse events through post-marketing surveillance.
Nearly all were in individuals providing direct care to infants receiving
aerosolized VIRAZOLE. Of 358 events from these 152 individual health care
worker reports, the most common signs and symptoms were headache (51% of
reports), conjunctivitis (32%), and rhinitis, nausea, rash, dizziness,
pharyngitis, or lacrimation (10-20% each). Several cases of bronchospasm and/or
chest pain were also reported, usually in individuals with known underlying
reactive airway disease. Several case reports of damage to contact lenses after
prolonged close exposure to aerosolized VIRAZOLE have also been reported. Most
signs and symptoms reported as having occurred in exposed health care workers
resolved within minutes to hours of discontinuing close exposure to aerosolized
VIRAZOLE (also see Information for Health Care Personnel).
The symptoms of RSV in adults can include headache, conjunctivitis,
sore throat and/or cough, fever, hoarseness, nasal congestion and wheezing,
although RSV infections in adults are typically mild and transient. Such
infections represent a potential hazard to uninfected hospital patients. It is
unknown whether certain symptoms cited in reports from health care workers were
due to exposure to the drug or infection with RSV. Hospitals should implement
appropriate infection control procedures.
OVERDOSAGE
No overdosage with VIRAZOLE by aerosol administration has been reported in
humans. The LD50 in mice is 2 gm orally and is associated with hypoactivity and
gastrointestinal symptoms (estimated human equivalent dose of 0.17gm/kg, based
on body surface area conversion). The mean plasma half-life after
administration of aerosolized VIRAZOLE for pediatric patients is 9.5 hours.
VIRAZOLE is concentrated and persists in red blood cells for the life of the
erythrocyte (see Pharmacokinetics).
DOSAGE AND ADMINISTRATION
BEFORE USE, READ THOROUGHLY THE VIRATEK SMALL PARTICLE AEROSOL GENERATOR (SPAG)
MODEL SPAG-2 OPERATOR'S MANUAL FOR SMALL PARTICLE AEROSOL GENERATOR OPERATING
INSTRUCTIONS. AEROSOLIZED VIRAZOLE SHOULD NOT BE ADMINISTERED WITH ANY OTHER
AEROSOL GENERATING DEVICE.
The recommended treatment regimen is 20 mg/ml VIRAZOLE as the starting
solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol
administration for 12-18 hours per day for 3 to 7 days. Using the recommended
drug concentration of 20 mg/ml the average aerosol concentration for a 12 hour
delivery period would be 190 micrograms/liter of air. Aerosolized VIRAZOLE
should not be administered in a mixture for combined aerosolization or
simultaneously with other aerosolized medications.
NON-MECHANICALLY VENTILATED INFANTS
VIRAZOLE should be delivered to an infant oxygen hood from the SPAG-2 aerosol
generator. Administration by face mask or oxygen tent may be necessary if a
hood cannot be employed (see SPAG-2 manual). However, the volume and
<PAGE> 35
condensation area are larger in a tent and this may alter delivery dynamics of
the drug.
MECHANICALLY VENTILATED INFANTS
The recommended dose and administration schedule for infants who require
mechanical ventilation is the same as for those who do not. Either a pressure
or volume cycle ventilator may be used in conjunction with the SPAG-2. In
either case, patients should have their endotracheal tubes suctioned every 1-2
hours, and their pulmonary pressures monitored frequently (every 2-4 hours).
For both pressure and volume ventilators, heated wire connective tubing and
bacteria filters in series in the expiratory limb of the system (which must be
changed frequently, i.e., every 4 hours) must be used to minimize the risk of
VIRAZOLE precipitation in the system and the subsequent risk of ventilator
dysfunction. Water column pressure release valves should be used in the
ventilator circuit for pressure cycled ventilators, and may be utilized with
volume cycled ventilators (SEE SPAG-2 MANUAL FOR DETAILED INSTRUCTIONS).
METHOD OF PREPARATION
VIRAZOLE brand of ribavirin is supplied as 6 grams of lyophilized powder per
100 ml vial for aerosol administration only. By sterile technique, solubilize
drug with Sterile Water for Injection, USP, or Inhalation in the 100 ml vial.
Transfer to the clean, sterilized 500 ml SPAG-2 reservoir and further dilute to
a final volume of 300 ml with Sterile Water for Injection, USP, or Inhalation.
The final concentration should be 20 mg/ml. IMPORTANT: This water should NOT
have had any antimicrobial agent or other substance added. The solution should
be inspected visually for particulate matter and discoloration prior to
administration. Solutions that have been placed in the SPAG-2 unit should be
discarded at least every 24 hours and when the liquid level is low before
adding newly reconstituted solution.
HOW SUPPLIED:
VIRAZOLE (ribavirin for inhalation solution) is supplied in 100 ml glass vials
with 6 grams of sterile, lyophilized drug which is to be reconstituted with 300
ml Sterile Water for Injection or Sterile Water for Inhalation (no
preservatives added) and administered only by a small particle aerosol
generator (SPAG-2). Vials containing the lyophilized drug powder should be
stored in a dry place at 15-25 degrees C (59-78 degrees F). Reconstituted
solutions may be stored, under sterile conditions, at room temperature (20-30
degrees C, 68-86 degrees F) for 24 hours. Solutions which have been placed in
the SPAG-2 unit should be discarded at least every 24 hours.
REFERENCES:
1. Hruska JF, Bernstein JM, Douglas Jr., RG, and Hall CB. Effects of Virazole
on respiratory syncytial virus in vitro. Antimicrob Agents Chemother
17:770-775, 1 1980.
2. Hruska JF, Morrow PE, Suffin SC, and Douglas Jr., RG. In vivo inhibition of
respiratory syncytial virus by Virazole, Antimicrob Agents Chemother
21:125-130, 1982.
3. Taber LH, Knight V, Gilbert BE, McClung HW et al. Virazole aerosol treatment
of bronchiolitis associated with respiratory tract infection in infants.
Pediatrics 72:613-618, 1983.
4. Hall CB, McBride JT, Walsh EE, Bell DM et al. Aerosolized Virazole treatment
of infants with respiratory syncytial viral infection. N Engl J Med 308:1443-7,
1983.
5. Hendry RM, McIntosh K, Fahnestock ML, and Pierik LT. Enzyme-linked
immunosorbent assay for detection of respiratory syncytial virus infection. J
Clin Microbiol 16:329-33, 1982.
6. Smith, David W., Frankel, Lorry R., Mather, Larry H., Tang, Allen T.S.,
Ariagno, Ronald L., Prober, Charles G. A Controlled Trial of Aerosolized
Ribavirin in Infants Receiving Mechanical Ventilation for Severe Respiratory
Syncytial Virus Infection. The New England Journal of Medicine 1991; 325:24-29.
7. Decker, John, Shultz, Ruth A., Health Hazard Evaluation Report: Florida
Hospital, Orlando, Florida. Cincinnati OH: U.S. Department of Health and Human
Services, Public Health Service, Centers for NIOSH Report No. HETA
91-104-2229.*
8. Barnes, D.J. and Doursew, M. Reference dose: Description and use in health
risk assessments. Regul Tox. and Pharm. Vol. 8; p. 471-486, 1988.
9. Federal Register Vol. 53 No. 126 Thurs. June 30, 1988 p. 24834-24847.
10. American Association for Respiratory Care [1991]. Aerosol Consensus
Statement-1991. Respiratory Care 36(9):916-921.
*Copies of the Report may be purchased from National Technical Information
Service, 5285 Port Royal Road, Springfield, VA 22161; Ask for Publication PB
93119-345.
1957-03
Rev. 2-93
[LOGO]
ICN Pharmaceuticals, Inc.
ICN Plaza
3300 Hyland Avenue
Costa Mesa, California 92626
714-545-0100
