Moderiba (ribavirin)

Administer ribavirin with caution to patients with pre-existing cardiac disease. Evaluate patients before commencement of therapy and monitor patients appropriately during therapy. If there is any deterioration of cardiovascular status, discontinue therapy.

If severe adverse effects or laboratory changes occur when ribavirin capsules are used in combination with interferon alfa-2b (Intron(R) A) or peginterferon alfa-2b (PegIntron(R)), dosage should be modified or the agent(s) should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dosage adjustment, discontinue combination therapy. Refer to Table 6 for recommendations for dosage modification or treatment discontinuation based on laboratory parameters.

In pediatric patients, dosage reduction is accomplished by modifying the recommended ribavirin capsules dose from the original starting dosage of 15 mg/kg daily in a 2-step process to 12 mg/kg daily, then to 8 mg/kg daily, if needed (see Table 6).

In patients with a history of stable cardiovascular disease, permanently reduce dosage if the hemoglobin decreases by >=2 g/dL during any 4-week period. If hemoglobin remains <12 g/dL after 4 weeks on a reduced dosage, discontinue combination therapy.

Modify or discontinue ribavirin capsules dosing in any patient whose hemoglobin level falls below 10 g/dL.

Table 6. Dosage Modification Recommendations for Ribavirin Capsule Combination Therapy in Adults and Pediatric Patients

Laboratory Parameters Recommendation WBC Discontinue combination therapy if <1000/mm3 Neutrophils Discontinue combination therapy if <500/mm3 Platelets Discontinue combination therapy if <25,000/mm3 (adults) or <50,000/mm3 (pediatrics) Creatinine Discontinue combination therapy if >2 mg/dL (pediatrics) Hemoglobin in patients without Reduce ribavirin capsule daily history of cardiac disease dosage if 8.5 to <10 g/dL; Discontinue combination therapy if <8.5 g/dL Hemoglobin in patients with history Reduce ribavirin capsule daily of stable cardiac disease dosage by 200 mg/day if >=2 g/dL decrease in hemoglobin during any 4-week period during treatment Discontinue combination therapy <8.5 g/dL or <12 g/dL after 4 weeks of dosage reduction

Refer to labeling for interferon alfa-2b (Intron(R) A) or peginterferon alfa-2b (PegIntron(R)) for information on how and when to reduce dosage of these agents for specific laboratory parameters.

In adults, 1st dosage reduction of ribavirin is by 200 mg/day (except in patients receiving 1400 mg, for whom dosage reduction should be by 400 mg/day). If needed, 2nd dosage reduction of ribavirin is by an additional 200 mg/day. Patients whose dosage of ribavirin is reduced to 600 mg daily receive 200 mg in the morning and 400 mg in the evening. In pediatric patients, 1st dosage reduction of ribavirin is to 12 mg/kg daily, and 2nd dosage reduction of ribavirin is to 8 mg/kg daily.

Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease >=2 g/dL during any 4-week period during therapy should undergo weekly evaluations and hematology testing.

Patients with a history of significant or unstable cardiac disease should not be treated with peginterferon alfa-2b/ribavirin capsules combination therapy.

If serious adverse effects or laboratory changes occur when ribavirin tablets are used in conjunction with peginterferon alfa-2a (Pegasys(R)), dosage should be modified or the agent(s) should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dosage adjustment, discontinue combination therapy. Refer to Table 7 for recommendations for dosage modifications and treatment discontinuation based on the patient's hemoglobin concentration and cardiac status.

In adults, once ribavirin tablets have been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at 600 mg daily and further increase the dosage to 800 mg daily. However, do not increase the dosage to the original assigned dosage (1-1.2 g).

In pediatric patients, upon resolution of a laboratory abnormality or clinical adverse reaction, an attempt may be made (based on physician judgment) to increase the ribavirin tablet dosage to the original dosage. If ribavirin tablets have been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at one-half the full dosage.

Table 7. Ribavirin Tablet Dosage Modification Recommendations in Adults and Pediatric Patients

Recommendations Recommendations Regarding Ribavirin Regarding Ribavirin Therapy Therapy Laboratory Values Hemoglobin <10 g/dL in Hemoglobin <8.5 g/dL in patients with no cardiac patients with no cardiac disease, or Decrease in disease, or Hemoglobin hemoglobin of >=2 g/dL <12 g/dL despite 4 weeks during any 4-week period at reduced dose in in patients with history patients with history of of stable cardiac stable cardiac disease disease Adults (any weight) Reduce ribavirin dosage Discontinue ribavirin to 200 mg in the morning and 400 mg in the evening Pediatric patients 5-18 years of age 23-33 kg Reduce ribavirin dosage Discontinue ribavirin to 200 mg in the morning 34-46 kg Reduce ribavirin dosage Discontinue ribavirin to 200 mg in the morning and 200 mg in the evening 47-59 kg Reduce ribavirin dosage Discontinue ribavirin to 200 mg in the morning and 200 mg in the evening 60-74 kg Reduce ribavirin dosage Discontinue ribavirin to 200 mg in the morning and 400 mg in the evening >=75 kg Reduce ribavirin dosage Discontinue ribavirin to 200 mg in the morning and 400 mg in the evening

The recommendations in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Ribavirin is administered orally. Ribavirin has also been administered IV+.

When ribavirin is used in conjunction with peginterferon or interferon, the cautions, precautions, and contraindications associated with both ribavirin and the interferon should be considered. Refer to the full prescribing information for warnings and precautions of peginterferon alfa-2a (Pegasys(R)), peginterferon alfa-2b (PegIntron(R)), or interferon alfa-2b (Intron(R) A).

No dosing information is available for this tab.

No dosing information is available for this tab.

The following drug interactions are based on studies using oral ribavirin. When ribavirin is used in combination with peginterferon alfa-2a, peginterferon alfa-2b (no longer available in the US), or interferon alfa-2b (no longer available in the US), consider the interactions associated with the interferon; refer to the full prescribing information for the interferon drug interactions.

In vitro studies indicate that ribavirin does not inhibit cytochrome P-450 (CYP) isoenzymes 2C9, 2C19, 2D6, or 3A4, and is not a substrate of CYP enzymes.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Ribavirin

*Known hypersensitivity (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) to ribavirin or any ingredient in the formulation (capsules).

*Women who are or may become pregnant.

*Male partners of pregnant women.

*Hemoglobinopathies (e.g., thalassemia major, sickle cell anemia).

*Creatinine clearance <50 mL/minute (capsules).

*Autoimmune hepatitis (ribavirin capsules; ribavirin tablets and peginterferon alfa-2a combination therapy).

*Use of ribavirin tablets and peginterferon alfa-2a combination therapy in cirrhotic patients with chronic hepatitis C virus (HCV) monoinfection (without coexisting human immunodeficiency virus (HIV) infection) who have hepatic decompensation (Child-Pugh score >6; class B and C) prior to treatment.

*Use of ribavirin tablets and peginterferon alfa-2a combination therapy in cirrhotic patients with chronic HCV infection who are coinfected with HIV and have hepatic decompensation (Child-Pugh score >=6) prior to treatment.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse effects in adults (>=40%) receiving ribavirin capsule plus peginterferon alfa-2b (PegIntron(R)) or interferon alfa-2b (Intron(R) A) combination therapy were injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. Hemolytic anemia occurred in >10% of adults receiving ribavirin capsule plus peginterferon alfa-2b or interferon alfa-2b combination therapy. The most common adverse effects (greater than 25%) in pediatric patients receiving ribavirin capsule plus peginterferon alfa-2b or interferon alfa-2b combination therapy were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The most common adverse effects (frequency >40%) in adults receiving ribavirin tablet plus peginterferon alfa-2a (Pegasys(R)) combination therapy were fatigue/asthenia, pyrexia, myalgia, and headache. The most common adverse effects in pediatric patients were similar to those seen in adults.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of ribavirin tablets have not been established for treatment of chronic HCV infection in children younger than 5 years of age. Pharmacokinetic evaluations in pediatric patients have not been performed.

Safety and efficacy of ribavirin capsules in conjunction with peginterferon alfa-2b (PegIntron(R)) have not been established for treatment of chronic HCV infection in children younger than 3 years of age. When deciding whether to use ribavirin capsules in conjunction with interferon alfa-2b (Intron(R) A) in HCV-infected children, evidence of disease progression (e.g., hepatic inflammation, fibrosis), prognostic factors for response, HCV genotype, and viral load should be considered. The benefits of such treatment should be weighed against adverse effects reported in pediatric patients.

Suicidal ideation or attempts occurred more frequently in pediatric patients (2.4%) than in adults (1%) during or after therapy; most of these children were adolescents. Like adults, other adverse psychiatric effects (e.g., depression, emotional lability, somnolence), anemia, and neutropenia were also reported in pediatric patients.

Ribavirin may cause fetal toxicity and/or death based on findings from animal studies. The drug has been shown to be teratogenic and/or embryocidal in almost all animal species tested to date at dosages well below the recommended human dosage. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and GI tract have been reported in animal studies. The incidence and severity of teratogenic effects increase with increasing dosage. Survival of fetuses and offspring was reduced.

Data from the ribavirin pregnancy registry are insufficient to identify a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes in humans.

Ribavirin is contraindicated in women who are or may become pregnant and also is contraindicated in male partners of such women. Extreme care should be exercised to avoid pregnancy in female patients receiving ribavirin and in female partners of male patients receiving ribavirin. Based on a multiple-dose ribavirin half-life of 12 days, the drug may persist in nonplasma compartments for as long as 6 months (e.g., 15 half-lives of clearance for ribavirin). If ribavirin is inadvertently administered during pregnancy or pregnancy occurs, inform the patient of the potential hazard to the fetus.

Ribavirin should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiating therapy. Perform periodic pregnancy testing during treatment with ribavirin capsules and during the 9-month period after treatment discontinuation. Perform pregnancy testing monthly during therapy with ribavirin tablets and for 6 months after treatment discontinuation.

Advise female patients of reproductive potential to use effective contraception during treatment with ribavirin capsules and for 9 months after treatment discontinuation. Advise male patients and their female partners of reproductive potential to use effective contraception during treatment with ribavirin capsules and for 6 months after treatment discontinuation.

Advise female patients of reproductive potential and male patients and their female partners of reproductive potential to use >=2 forms of effective contraception during treatment with ribavirin tablets and for 6 months after treatment discontinuation.

It is not known whether ribavirin is distributed into human milk following administration. There are no data on the effects of ribavirin on the breast-fed infant or on milk production.

Because of the potential for serious adverse reactions to ribavirin in nursing infants, a decision should be made whether to discontinue nursing or discontinue ribavirin therapy, taking into account the importance of the drug to the woman. The benefits of breast-feeding should be considered along with the mother's clinical need for ribavirin and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

The manufacturers makes no specific dosage recommendations for geriatric patients.

Since ribavirin is substantially excreted by the kidney and geriatric patients frequently have decreased renal function, renal function should be monitored closely and dosage adjusted accordingly.

Ribavirin capsules should be used with caution in geriatric patients, usually initiating therapy at the lower end of the usual dosage range to reflect the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in this population.

Clinical studies of ribavirin used in conjunction with interferon therapy did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. In clinical trials, geriatric patients had a higher frequency of anemia (67%) than did younger patients (28%). Pharmacokinetic evaluations for ribavirin in geriatric patients have not been performed.

Because ribavirin is known to be substantially excreted by the kidney, patients with renal impairment are at increased risk of ribavirin-induced toxicity; geriatric patients frequently have decreased renal function, and renal function should be monitored closely and dosage adjusted accordingly.

Ribavirin capsules should be used with caution in geriatric patients, usually initiating therapy at the lower end of the usual dosage range to reflect the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in this population.