RIBAVIRIN Drug Interactions: What You Need to Know

INTERACTIONS Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between PEGASYS ® (peginterferon alfa-2a) and ribavirin. Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, ribavirin or both with worsening toxicities (7.1) Azathioprine: Concomitant use of azathioprine with ribavirin has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity (7.3)

7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HCV/HIV coinfected patients.

In

Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.3) ] . Patients receiving PEGASYS ® /ribavirin and NRTIs should be closely monitored for treatment-associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS ® , ribavirin or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see Warnings and Precautions (5.3) and Dosage and Administration (2.3) ] .

Didanosine

Coadministration of ribavirin and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4) ] .

Zidovudine In

Study NR15961, patients who were administered zidovudine in combination with PEGASYS ® /ribavirin developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.

7.2 Drugs Metabolized by Cytochrome P450 In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

7.3 Azathioprine The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span> .

Ribavirin capsules combination therapy is contraindicated in: pregnancy. Ribavirin capsules may cause fetal harm when administered to a pregnant woman. Ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant. If a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1, 8.3) ]. men whose female partners are pregnant [see Use in Specific Populations (8.3) ] patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product patients with autoimmune hepatitis patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) patients with creatinine clearance less than 50 mL/min [see Clinical Pharmacology (12.3) ] when coadministered with didanosine because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in patients receiving didanosine in combination with ribavirin [see Drug Interactions (7.1) ]. Pregnancy and men whose female partners are pregnant ( 4 , 5.1 , 8.1 , 8.3 ) Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product ( 4 ) Autoimmune hepatitis ( 4 ) Hemoglobinopathies ( 4 ) Creatinine clearance less than 50 mL/min ( 4 , 12.3 ) Coadministration with didanosine ( 4 , 7.1 )

AND PRECAUTIONS Significant adverse reactions associated with ribavirin/PEGASYS ® combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes. The PEGASYS ® Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment. Birth defects and fetal death with ribavirin: Do not use in pregnancy and for 6 months after treatment. Patients must have a negative pregnancy test prior to therapy, use at least 2 forms of contraception and undergo monthly pregnancy tests (4 , 5.1 , 8.1) PEGASYS ® /Ribavirin: Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: Hemolytic anemia may occur with a significant initial drop in hemoglobin. This may result in worsening cardiac disease leading to fatal or nonfatal myocardial infarctions (5.2 , 6.1) Risk of hepatic failure and death: Monitor hepatic function during treatment and discontinue treatment for hepatic decompensation (5.3) Severe hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, and anaphylaxis, and serious skin reactions such as Stevens-Johnson syndrome (5.4) Pulmonary disorders, including pulmonary function impairment and pneumonitis, including fatal cases of pneumonia (5.5) Severe depression and suicidal ideation, autoimmune and infectious disorders, suppression of bone marrow function, pancreatitis, and diabetes (5) Bone marrow suppression with azathioprine coadministration (5.6) Growth impairment with combination therapy in pediatric patients (5.8)

5.1 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 <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications (4) , Use in Specific Populations (8.1) , and Patient Counseling Information (17) ]</span>.

5.2 Anemia The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/PEGASYS ® -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) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . 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 pre-existing 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin <span class="opacity-50 text-xs">[see Boxed Warning and Dosage and Administration (2.3) ]</span> .

5.3 Hepatic Failure Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS ® . 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 [see Clinical Studies (14.3) ], 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 PEGASYS ® /ribavirin should be discontinued immediately in patients with hepatic decompensation [see Contraindications (4) ].

5.4 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 PEGASYS ® 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 PEGASYS ® with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.5 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/PEGASYS ® treatment should be discontinued.

5.6 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. PEGASYS ® , ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> .

5.7 Pancreatitis Ribavirin and PEGASYS ® therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

5.8 Impact on Growth in Pediatric Patients During combination therapy for up to 48 weeks with PEGASYS ® plus ribavirin, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed.

At

2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve. The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients [see Clinical Studies Experience (6.1) ].

5.9 Laboratory Tests Before beginning PEGASYS ® /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 pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with PEGASYS ® /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 adult 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. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. 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 PEGASYS ® may be considered as a guideline to acceptable baseline values for initiation of treatment: Platelet count greater than or equal to 90,000 cells/mm 3 (as low as 75,000 cells/mm 3 in HCV patients with cirrhosis or 70,000 cells/mm 3 in patients with CHC and HIV) Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm 3 TSH and T 4 within normal limits or adequately controlled thyroid function CD4+ cell count greater than or equal to 200 cells/mm 3 or CD4+ cell count greater than or equal to 100 cells/mm 3 but less than 200 cells/mm 3 and HIV-1 RNA less than 5,000 copies/mL in patients coinfected with HIV Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected patients Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV