Ribavirin is a synthetic
guanosine analogue that pos-sesses broad antiviral inhibitory activity against
many viruses, including influenza A and B, parainfluenza, RSV, HCV, HIV-1, and
various herpesviruses, arenaviruses, and paramyxoviruses. Its exact mechanism
of action has not been fully elucidated; however, it appears to inhibit the
synthesis of viral mRNA through an effect on nu-cleotide pools. Following
absorption, host cell enzymes convert ribavirin to its monophosphate,
diphosphate, and triphosphate forms. Ribavirin monophosphate inhibits the
guanosine triphosphate (GTP) synthesis pathway and subsequently inhibits many
GTP-depend-ent processes. Ribavirin triphosphate inhibits the 5 cap-ping of
viral mRNA with GTP and specifically inhibits influenza virus RNA polymerase.
Ribavirin may also act by increasing the mutation rate of RNA viruses, lead-ing
to the production of nonviable progeny virions. Ribavirin resistance has not
been documented in clinical isolates.
Ribavirin can be administered
as an aerosol using a small-particle aerosol generator. When administered by
this route, the drug has only minimal systemic ab-sorption, with drug
concentrations in respiratory tract secretions approximately 100 times as high
as those found in plasma. Oral absorption is rapid, and first-pass metabolism
is extensive; ribavirin’s oral bioavailability is 64% and can be increased by
administration with a high-fat meal. Steady-state levels are reached after 4
Ribavirin is reversibly
phosphorylated by all nucle-ated cells. It is also metabolized in the liver to
a triazole carboxylic acid metabolite that is eliminated in the urine along
with the parent compound. The plasma half-life of ribavirin is 9.5 hours when
it is administered by aerosol (2.5 hours/day for 3 days), whereas its half-life
is around 12.5 days at steady state. The drug accumulates in erythrocytes, with
a half-life of 40 days.
Ribavirin aerosol (Virazole) is indicated in the treat-ment
of high-risk infants and young children with se-vere bronchiolitis or pneumonia
due to RSV infection. Treatment is most effective if begun within 3 days of the
onset of symptoms.
monotherapy is ineffective against HCV, oral ribavirin in combination with
inter-feron- (Rebatron) is approved
for this indication and is effective in patients resistant to interferon
therapy alone. Intravenous ribavirin may be useful in the ther-apy of Hantaan
virus infection, Crimean or Congo virus hemorrhagic fever, Lassa fever, and
severe adenovirus infection.
Most adverse effects associated
with aerosol ribavirin are local. Pulmonary function may decline if aerosol
rib-avirin is used in adults with chronic obstructive lung dis-ease or asthma.
Deterioration of pulmonary and cardio-vascular function has also been seen in
severely ill infants given this preparation. Rash, conjunctivitis, and rare
cases of anemia have been reported. Health care workers exposed to aerosol
ribavirin during its administration have reported adverse effects including
head-ache, conjunctivitis, rash, and rarely, bronchospasm.
Oral and intravenous
ribavirin are associated with additional adverse effects. When given via these
routes, ribavirin can produce hemolytic anemia that is re-versible following
dosage reduction or cessation of ther-apy. When given in combination with interferon-
, rib-avirin increases the incidence of many of its side effects, such as
fatigue, nausea, insomnia, depression, and ane-mia, and may cause fatal or
nonfatal pancreatitis. Ribavirin is mutagenic, teratogenic, and embryotoxic in
animals at doses below the therapeutic level in humans. It is contraindicated in pregnant women and in the male partners of
pregnant women. Women of childbearing
potential and male partners of these women must use two effective forms of
contraception during ribavirin treatment and for 6 months post therapy.
Pregnant women should not directly care for patients receiving ribavirin.
Ribavirin is contraindicated
in patients with sickle cell anemia and other hemoglobinopathies because of its
propensity to cause anemia. Similarly, persons with coronary disease should not
use ribavirin, because anemia may cause deterioration of cardiac function. Oral
ribavirin should not be given to individuals with severe renal impairment; no
dosage adjustment is nec-essary for the inhaled formulation. However, patients
with hepatic impairment may require dosage adjust-ment.
Little information on the
drug interactions of rib-avirin is available. In vitro, ribavirin inhibits the
phos-phorylation reactions that are required for activation of zidovudine and