Ribavirin Brand Name: Virazole, Rebetol, Copegus

Ribavirin Brand Name: Virazole, Rebetol, Copegus Drug Description alfa and are at least 18 years of age who have relapsed after interferon alfa therapy.[6] Ribavirin is a synthetic nucleoside agent that has a broad spectrum of antiviral activity against both Ribavirin inhalation solution is indicated as a DNA and RNA viruses. [1] Ribavirin is primary agent in the treatment of lower respiratory structurally related to pyrazofurin (pyrazomycin), tract disease (including bronchiolitis and guanosine, and xanthosine. [2] pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and young children HIV/AIDS-Related Uses who are at high risk for severe or complicated RSV infection. This category includes premature infants HIV infected patients are commonly coinfected and infants with structural or physiologic with hepatitis C virus (HCV). Interferon alfa-2b, cardiopulmonary disorders, bronchopulmonary peginterferon alfa-2a, or peginterferon alfa-2b in dysplasia, immunodeficiency or imminent conjunction with oral ribavirin are regimens often respiratory failure. Ribavirin is also indicated in the prescribed for the treatment of chronic HCV treatment of RSV infections in infants requiring infection with compensated liver disease in patients mechanical ventilator assistance.[7] Ribavirin is who have not previously received interferon used via nasal or oral inhalation in the treatment of therapy. Although therapy with oral ribavirin alone these severe lower respiratory tract infections.[8] is not effective for the treatment of chronic HCV infection, use of the drug in conjunction with an Orally ingested ribavirin has been used with some interferon alfa preparation has been shown to success for the treatment of various strains of increase the rate of sustained response by two- to influenza A virus and influenza B virus. Inhalation three-fold and decrease the rate of relapse therapy with ribavirin is currently being studied for following discontinuance of therapy. The highest the treatment of these viruses.[9] rates of sustained virologic response and the lowest rates of relapse have been achieved with Ribavirin has been used for the treatment of a concomitant use of peginterferon alfa and oral variety of viral hemorrhagic fevers, including Lassa ribavirin. Interferon monotherapy generally is fever, Hantavirus infections, and Crimean-Congo reserved for use in patients in whom ribavirin is hemorrhagic fever. Viral hemorrhagic fevers are a contraindicated or not tolerated.[3] diverse group of infections caused by RNA viruses from several viral families. Ribavirin is the only Oral ribavirin monotherapy has been investigated antiviral agent identified to date that exhibits for use in the management of HIV infection; potential efficacy for the management of some viral however, the results of several limited studies in hemorrhagic fevers.[10] patients with HIV infection have failed to show evidence of beneficial effects.[4] Pharmacology Ribavirin is being studied in combination with The mechanism of action of ribavirin's antiviral peginterferon alfa-2a and adefovir dipivoxil in activity has not been fully elucidated, but the drug patients triple-infected with HIV, HCV, and appears to interfere with RNA and DNA synthesis hepatitis B virus (HBV).[5] and subsequently inhibit protein synthesis and viral replication. The drug's antiviral activity results Non-HIV/AIDS-Related Uses principally in an intracellular virustatic effect in cells infected with ribavirin-sensitive RNA or DNA Ribavirin is indicated in combination with viruses; however, its specific mechanisms of action interferon alfa-2a or -2b or peginterferon alfa-2a or may vary depending on the virus. The antiviral -2b for the treatment of chronic HCV infection in activity of ribavirin appears to depend principally patients who have compensated liver disease and on intracellular conversion of the drug to have not been previously treated with interferon ribavirin-5'-triphosphate (RTP) and http://aidsinfo.nih.gov • 1-800-448-0440 • March 4, 2004 Ribavirin Pharmacology (cont.) are sequestered in RBCs, reaching a plateau in approximately 4 days and remaining sequestered -monophosphate. Ribavirin is phosphorylated to for weeks after administration. Time to peak ribavirin-5'-monophosphate, -diphosphate, and plasma concentration (Cmax) for IV doses is -triphosphate. Phosphorylation of ribavirin occurs reached at the end of infusion; for oral doses, it is 1 principally in virus-infected cells but also occurs in to 1.5 hours. Therapeutically effective uninfected cells. Formulation of concentrations depend primarily on the duration of ribavirin-5'-monophosphate appears to be the exposure and patient minute volume. rate-limiting step in the formation of Concentrations in respiratory tract secretions are ribavirin-5'-triphosphate. RTP competes with much higher than corresponding plasma adenosine-5'-triphosphate and concentrations.[17] Following oral administration guanosine-5'-triphosphate for viral RNA of a single 3 mg/kg dose, RBC concentrations of polymerase.[11] RTP is a potent competitive ribavirin have been reported to peak within inhibitor of inosine monophosphate dehydrogenase, approximately 4 days, exceeding concurrent plasma influenza virus RNA polymerase, and messenger concentrations at 4 days by about 100-fold, then RNA (mRNA) guanylyltransferase, the latter declining with a half-life of about 40 days (the resulting in inhibition of the capping of mRNA. half-life of RBCs). During the initial 1 to 2 hours These diverse effects markedly reduce intracellular following oral administration, RBC concentrations guanosine triphosphate pools and inhibit viral RNA increase at a rate similar to plasma concentrations; and protein synthesis.[12] thereafter, RBC concentrations continue to increase When administered orally, ribavirin is rapidly for about 4 days as plasma drug concentrations absorbed from the gastrointestinal (GI) tract, with decline. Significant concentrations (greater than bioavailibility approximately 45%.[13] A small 67%) may be found in the cerebrospinal fluid amount of ribavirin is absorbed systemically from (CSF) after prolonged administration. Ribavirin the respiratory tract following nasal and oral appears to distribute slowly into CSF. Following inhalation. The bioavailability of inhaled ribavirin chronic (4 to 7 weeks) oral administration of may depend on the method of drug delivery during ribavirin in patients with AIDS or AIDS-related nebulization. At a contact flow rate, the amount of complex, CSF concentrations of the drug were drug delivered to the respiratory tract theoretically approximately 70% of concurrent plasma is directly related to the concentration of nebulized concentrations.[18] drug solution and the duration of inhalation Ribavirin is in FDA Pregnancy Category X. No therapy. Peak plasma ribavirin concentrations studies have been done in pregnant women; generally occur at the end of the inhalation period, however, ribavirin is contraindicated during when the drug is inhaled orally and nasally using a pregnancy. Studies in primates (e.g., baboons) have small-particle aerosol generator, and increase with not shown that ribavirin causes adverse effects on longer duration of the inhalation period.[14] the fetus; however, results from studies in other Ribavirin is readily absorbed across the cellular animals have shown that it is teratogenic and/or plasma membrane, probably via a nucleoside embryocidal in nearly all species tested, with transport mechanism. Ribavirin has two pathways effects including reduced survival of fetuses and of metabolism: 1) a reversible phosphorylation offspring and malformation of the skull, palate, eye, pathway in nucleated cells; and 2) a degradative jaw, skeleton, and GI tract. Health care workers and pathway involving deribosylation and amide visitors who spend time at the patient's bedside may hydrolysis to yield a triazole carboxylic acid become environmentally exposed to ribavirin. metabolite.[15] Female health care workers and visitors who are pregnant, or may become pregnant, should be Ribavirin distributes to plasma, respiratory tract advised of the potential risks of exposure. It is not secretions, and erythrocytes (RBCs); following known if ribavirin is excreted into human breast nasal and oral inhalation, the highest ribavirin milk. It does distribute into the breast milk of other concentrations are found in the respiratory tract and species and has been shown to harm lactating RBCs.[16] Large amounts of ribavirin triphosphate animals and their offspring.[19] http://aidsinfo.nih.gov • 1-800-448-0440 • March 4, 2004 2 Ribavirin Pharmacology (cont.) ribavirin and interferon alfa-2b.[25] [26] The anemia associated with ribavirin occurs within the Plasma protein binding of ribavirin is insignificant. first 1 to 2 weeks of oral therapy. Because the The elimination half-life of an IV or oral dose is initial drop in hemoglobin may be significant, it is approximately 0.5 to 2 hours; for inhaled ribavirin, advised that hemoglobin or hematocrit be obtained the elimination half-life is 9.5 hours. The terminal pretreatment and at weeks 2 and 4 of therapy or half-life of a single dose of IV or oral ribavirin is more frequently if clinically indicated. Patients 27 to 36 hours, reaching steady state at should then be followed as clinically approximately 151 hours. Ribavirin is excreted appropriate.[27] [28] principally in urine. For ribavirin administered for inhalation, renal elimination is approximately 30% Fatal

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