Ribavirin

Ribavirin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

Disclaimer

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Black Box Warning

RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS See full prescribing information for complete Boxed Warning. Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, ribavirin, including ribavirin tablets, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6 month post treatment follow-up period:

Overview

Ribavirin is a nucleoside analogue that is FDA approved for the treatment of chronic hepatitis C (CHC) virus infection in combination with peginterferon alfa-2a in adults with compensated liver disease not previously treated with interferon alpha, and in CHC patients coinfected with HIV (1). There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reaction, pruritus, weight decrease, diarrhea, gastrointestinal symptoms, loss of appetite, nausea, vomiting, neutropenia, asthenia, dizziness, excluding vertigo, headache, insomnia, fatigue and influenza-like illness..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Chronic Hepatitis C Monoinfection

• Dosage: 800-1200 mg/day, administered in two divided doses, for 24-48 week. Administer with food. Exact dose depends on the genotype of the Hepatitis C Virus (HCV) and weight of the patient (see table).

Chronic Hepatitis C with HIV Coinfection=

• Dosage: peg-interferon alfa-2a 180 mcg subcutaneous once weekly and ribavirin tablets, 800 mg PO daily for a total duration of 48 weeks, regardless of HCV genotype. Ribavirin tablets should be taken with food.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ribavirin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ribavirin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Ribavirin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ribavirin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ribavirin in pediatric patients.

Contraindications

Ribavirin tablets are contraindicated in:

• Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. *Ribavirin tablets are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• Men whose female partners are pregnant.
• Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
• In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.

Ribavirin tablets and peginterferon alfa-2a combination therapy is contraindicated in patients with:

• Autoimmune hepatitis.
• Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment
• Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment

Warnings

RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS See full prescribing information for complete Boxed Warning. Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, ribavirin, including ribavirin tablets, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6 month post treatment follow-up period:

Pregnancy

• Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin.
• Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during ribavirin therapy and for 6 months after therapy has stopped.

Anemia

• The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding)

• Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with preexisting cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin

Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with ribavirin/peginterferon alfa-2a should be discontinued immediately in patients with hepatic decompensation.

Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy.

Renal Impairment

Ribavirin should not be used in patients with creatinine clearance < 50 mL/min.

Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, patients should be closely monitored and, if appropriate, combination ribavirin/peginterferon alfa-2a treatment should be discontinued.

Bone Marrow Suppression

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n = 8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Peginterferon alfa-2a, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.

Pancreatitis

Ribavirin and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

Laboratory Tests

Before beginning peginterferon alfa-2a/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have preexisting cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

• Platelet count ≥ 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
• Absolute neutrophil count (ANC) ≥ 1500 cells/mm3
• TSH and T4 within normal limits or adequately controlled thyroid function
• CD4+ cell count ≥ 200 cells/μL or CD4+ cell count ≥ 100 cells/μL but < 200 cells/μL and HIV-1 RNA < 5000 copies/mL in patients coinfected with HIV
• Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected patients
• Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in patients with CHC and HIV

Adverse Reactions

Clinical Trials Experience

Application Site Disorder

• Injection Site Reaction

Endocrine Disorders

• Hypothyroidism

Flu-Like Symptoms

• Fatigue/Asthenia
• Pyrexia
• Rigors
• Pain

Gastrointestinal Effects

• Nausea/Vomiting
• Diarrhea
• Abdominal pain
• Dry Mouth
• Dyspepsia

Hematologic Effects

• Lymphopenia
• Anemia
• Neutropenia
• Thrombocytopenia

Metabolic and Nutritional

• Anorexia
• Weight decrease

Musculoeskeletal, Connective Tissue and Bone

• Myalgia
• Arthralgia
• Back pain

Neurological Effects

• Headache
• Dizziness (excluding vertigo)
• Memory impairment

Psychiatric Effects

• Irritability/Anxiety/Nervousness
• Insomnia
• Depression
• Concentration impairment
• Mood alteration

Respiratory, Thoracic and Mediastinal

• Dyspnea
• Cough
• Dyspnea exertional

Skin and Subcutaneous Tissue

• Alopecia
• Pruritus
• Dermatitis
• Dry Skin
• Rash
• Sweating increased
• Eczema

Visual Disorders

• Vision Blurred

Postmarketing Experience

Blood and Lymphatic System disorders

• Pure red cell aplasia

Ear and Labyrinth disorders

• Hearing impairment
• Hearing loss

Eye disorders

• Serous retinal detachment

Immune disorders

• Renal graft rejection
• Liver graft rejection

Metabolism and Nutrition disorders

• Dehydration

Skin and Subcutaneous Tissue disorders

• Stevens-Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)

Drug Interactions

There is limited information regarding Ribavirin Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Ribavirin in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ribavirin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Ribavirin during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Ribavirin in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Ribavirin in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Ribavirin in geriatric settings.

Gender

There is no FDA guidance on the use of Ribavirin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ribavirin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Ribavirin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Ribavirin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Ribavirin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Ribavirin in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Ribavirin Administration in the drug label.

Monitoring

There is limited information regarding Ribavirin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Ribavirin and IV administrations.

Overdosage

There is limited information regarding Ribavirin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Ribavirin Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Ribavirin Mechanism of Action in the drug label.

Structure

There is limited information regarding Ribavirin Structure in the drug label.

Pharmacodynamics

There is limited information regarding Ribavirin Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Ribavirin Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Ribavirin Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Ribavirin Clinical Studies in the drug label.

How Supplied

There is limited information regarding Ribavirin How Supplied in the drug label.

Storage

There is limited information regarding Ribavirin Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Ribavirin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Ribavirin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Ribavirin Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Ribavirin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Ribavirin
REBETOL® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

Ribavirin (Copegus^®; Rebetol^®; Ribasphere^®; Vilona^®,Virazole^®, also generics from Sandoz, Teva, Warrick) is an anti-viral drug which is active against a number of DNA and RNA viruses. It is a member of the nucleosideantimetabolite drugs that interfere with duplication of viral genetic material. Though not effective against all viruses, ribavirin is remarkable as a small molecule for its wide range of activity, including important activities against influenzas, flaviviruses and agents of many viral hemorrhagic fevers.

Category

Antiviral

US Brand Names

Copegus^®, Pegetron^®, Rebetol^®, Rebetron^®, Ribasphere^®, Virazole^®

FDA Package Insert

Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages

Mechanism of Action

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.