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Rebetol

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Rebetol

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Pregnancy

REBETOL capsules and oral solution may cause birth defects and death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at leasttwo forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL has demonstrated significant teratogenic and 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. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy [see BOXED WARNING, CONTRAINDICATIONS, Use in Specific Populations, and PATIENT INFORMATION].

Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of REBETOL/INTRON A-treated subjects in clinical trials. The anemia associated with REBETOL capsules 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 before the start of treatment and at Week 2 and Week 4 of therapy, or more frequently if clinically indicated. Patients should then be followed as clinically appropriate [see DOSAGE AND ADMINISTRATION].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by REBETOL. 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 [see DOSAGE AND ADMINISTRATION]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use REBETOL.

Pancreatitis

REBETOL and INTRON A or PegIntron therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.

Pulmonary Disorders

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during therapy with REBETOL with alpha interferon combination therapy; 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, the patient should be closely monitored, and if appropriate, combination therapy should be discontinued.

Ophthalmologic Disorders

Ribavirin is used in combination therapy with alpha interferons. Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by treatment with alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferon treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Laboratory Tests

PegIntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.

Patients on PegIntron/REBETOL combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood counts (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at Weeks 2, 4, 8, 12, and then at 6-week intervals, or more frequently if abnormalities developed. In pediatric subjects, the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment Week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see DOSAGE AND ADMINISTRATION].

Dental And Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of REBETOL and pegylated or nonpegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Concomitant Administration Of Azathioprine

Pancytopenia (marked decreases in red blood cells, 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. PegIntron, REBETOL, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be reintroduced with concomitant azathioprine [see DRUG INTERACTIONS].

Impact On Growth -Pediatric Use

Data on the effects of PegIntron and REBETOL on growth come from an open-label study in subjects 3 through 17 years of age, in which weight and height changes are compared to US normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron and REBETOL lags behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with REBETOL may induce a growth inhibition that results in reduced adult height in some patients [see ADVERSE REACTIONS].

Similarly, an impact on growth was seen in subjects after treatment with REBETOL and INTRON A combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects, combination therapy resulted in reduced final adult height in some subjects [see ADVERSE REACTIONS].

Usage Safeguards

Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, REBETOL capsules or oral solution must not be used alone. The safety and efficacy of REBETOL capsules and oral solution have only been established when used together with INTRON A or PegIntron (not other interferons) as combination therapy.

The safety and efficacy of REBETOL/INTRON A and PegIntron therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. REBETOL capsules should not be used for these indications. Ribavirin for inhalation has separate labeling, which should be consulted if ribavirin inhalation therapy is being considered.

There are significant adverse reactions caused by REBETOL/INTRON A or PegIntron therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. Labeling for INTRON A and PegIntron should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

Patient Counseling Information

Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide).

Anemia

The most common adverse experience occurring with REBETOL capsules is anemia, which may be severe [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see DOSAGE AND ADMINISTRATION]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Pregnancy

Patients must be informed that REBETOL capsules and oral solution may cause birth defects and death of the unborn child. REBETOL must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking REBETOL. REBETOL should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months post therapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during REBETOL and for 6 months post therapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

If pregnancy does occur during treatment or during 6 months post therapy, the patient must be advised of the teratogenic risk of REBETOL therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Prescribers should report such cases by calling 1-800-593-2214.

Risks Versus Benefits

Patients receiving REBETOL capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient MEDICATION GUIDE. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

Patients should be informed about what to do in the event they miss a dose of REBETOL; the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to contact their healthcare provider if they have questions.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was noncarcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult).

Mutagenesis

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Impairment Of Fertility

Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin) [see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].

Fertile women and partners of fertile women should not receive REBETOL unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple-dose half-life (t½) of ribavirin of 12 days, effective contraception must be utilized for 6 months post-therapy (e.g., 15 half-lives of clearance for ribavirin).

REBETOL should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60kg adult; 0.1-0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

Use In Specific Populations

Pregnancy

Pregnancy Category X

[See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Nonclinical Toxicology].

Treatment And Post-treatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Women of childbearing potential should not receive REBETOL unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months post-therapy based on a multiple-dose half-life (t½) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with REBETOL and for the 6month post-therapy period (e.g., 15 half-lives for ribavirin clearance from the body).

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and femalepartners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Nursing Mothers

It is not known whether the REBETOL product is excreted in human milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue REBETOL.

Pediatric Use

Safety and effectiveness of REBETOL in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with REBETOL/INTRON A, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the safety findings observed.

Long-term follow-up data in pediatric subjects indicates that REBETOL in combination with PegIntron or with INTRON A may induce a growth inhibition that results in reduced height in some patients [see ADVERSE REACTIONS].

Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see WARNINGS AND PRECAUTIONS]. As in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see WARNINGS AND PRECAUTIONS].

Geriatric Use

Clinical trials of REBETOL/INTRON A or PegIntron therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

REBETOL is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments should be made accordingly. REBETOL should not be used in patients with creatinine clearance less than 50 mL/min [see CONTRAINDICATIONS].

In general, REBETOL capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than younger patients (28%) [see WARNINGS AND PRECAUTIONS].

Organ Transplant Recipients

The safety and efficacy of INTRON A and PegIntron alone or in combination with REBETOL for the treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center's previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.

HIV Or HBV Co-infection

The safety and efficacy of PegIntron/REBETOL and INTRON A/REBETOL for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

Last reviewed on RxList: 12/9/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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