WARNINGS
PREGNANCY
Category X, may cause birth defects. See boxed CONTRAINDICATIONS AND WARNINGS. See CONTRAINDICATIONS.
ANEMIA
HEMOLYTIC ANEMIA (HEMOGLOBIN <10 G/DL) WAS OBSERVED IN APPROXIMATELY 10% OF REBETOL/INTRON A-TREATED PATIENTS IN CLINICAL TRIALS (SEE ADVERSE REACTIONS LABORATORY VALUES - HEMOGLOBIN). ANEMIA OCCURRED WITHIN 1-2 WEEKS OF INITIATION OF RIBAVIRIN THERAPY. BECAUSE OF THIS INITIAL ACUTE DROP IN HEMOGLOBIN, IT IS ADVISED THAT COMPLETE BLOOD COUNTS (CBC) SHOULD 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.
The anemia associated with REBETOL/INTRON A therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease. Patients should be assessed before initiation of therapy 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 combination REBETOL/INTRON A therapy. (See ADVERSE REACTIONS.)
Similarly, patients with hemoglobinopathies (eg, thalassemia, sickle-cell anemia) should not be treated with combination REBETOL/INTRON A therapy.
PSYCHIATRIC
Severe psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicides), and rare instances of homicidal ideation have occurred during combination REBETOL/INTRON A therapy, both in patients with and without a previous psychiatric disorder. REBETOL/INTRON A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders, and all patients should be carefully monitored for evidence of depression and other psychiatric symptoms. Suspension of REBETOL/INTRON A therapy should be considered if psychiatric intervention and/or dose reduction is unsuccessful in controlling psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention sought. (See ADVERSE REACTIONS.)
BONE MARROW TOXICITY
INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy (see PRECAUTIONS: Laboratory Tests). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 × 109/L) or platelet counts (<25 × 109/L) (See DOSAGE AND ADMINISTRATION: Guidelines for Dose Modifications).
PULMONARY
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, have been reported during therapy with REBETOL/INTRON A; 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 REBETOL/INTRON A treatment should be discontinued.
OTHER
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REBETOL Capsule monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication.
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Fatal and nonfatal pancreatitis has been observed in patients treated with REBETOL/INTRON A therapy. REBETOL/INTRON A therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.
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Combination REBETOL/INTRON A therapy should not be used in patients with creatinine clearance <50 mL/min.
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Diabetes mellitus and hyperglycemia have been observed in patients treated with INTRON A.
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Ophthalmologic disorders have been reported with treatment with alpha interferons (including INTRON A therapy). Investigators using alpha interferons have reported the occurrence of retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction in rare instances. Any patient complaining of loss of visual acuity or visual field should have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual exam prior to initiation of combination REBETOL/INTRON A therapy is recommended in patients with diabetes mellitus or hypertension.
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Acute serious hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed in INTRON A-treated patients; if such an acute reaction develops, combination REBETOL/INTRON A therapy should be discontinued immediately and appropriate medical therapy instituted.
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Combination REBETOL/INTRON A therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be controlled by medication.
PRECAUTIONS
Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). REBETOL/INTRON A therapy should be used with caution in patients with other autoimmune disorders.
There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant) exacerbating pre-existing psoriasis; therefore, combination REBETOL/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.
The safety and efficacy of REBETOL/INTRON A therapy has not been established in liver or other organ transplant patients, decompensated hepatitis C patients, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.
The safety and efficacy of REBETOL Capsule monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and REBETOL Capsules should not be used for these indications.
There is no information regarding the use of REBETOL Capsules with other interferons. Triglycerides Elevated triglyceride levels have been observed in patients treated with interferon including REBETOL/INTRON A therapy. Elevated triglyceride levels should be managed as clinically appropriate. Severe hypertriglyceridemia (triglycerides >1000 mg/dL) may result in pancreatitis. Discontinuation of REBETOL/INTRON A therapy should be considered for patients with persistently elevated triglycerides (triglycerides >1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting (see WARNINGS - Other).
Drug Interactions Nucleoside Analogues: Administration of nucleoside analogues has resulted in fatal and nonfatal lactic acidosis. Coadministration of ribavirin and nucleoside analogues should be undertaken with caution and only if the potential benefit outweighs the potential risks. Information for Patients Combination REBETOL/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination REBETOL/INTRON A therapy. Combination REBETOL/INTRON A therapy 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 posttherapy. Females 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 combination REBETOL/INTRON A therapy and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS.)
If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the significant 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. Physicians are encouraged to report such cases by calling (800) 727-7064.
Patients receiving combination REBETOL/INTRON A treatment should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the patient MEDICATION GUIDE. There are no data evaluating whether REBETOL/INTRON A therapy will prevent transmission of infection to others. Also, it is not known if treatment with REBETOL/INTRON A therapy will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.
If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see MEDICATION GUIDE). To avoid possible transmission of disease, do not share your multidose pen with anyone; it is for you and you alone.
The most common adverse experiences occurring with combination REBETOL/INTRON A therapy are "flu-like" symptoms, such as headache, fatigue, myalgia, and fever (see ADVERSE REACTIONS) and appear to decrease in severity as treatment continues. Some of these "flu-like" symptoms may be minimized by bedtime administration of INTRON A therapy. Antipyretics should be considered to prevent or partially alleviate the fever and headache. Another common adverse experience associated with INTRON A therapy is thinning of the hair.
Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.
Laboratory Tests The following laboratory tests are recommended for all patients on combination REBETOL/INTRON A therapy, prior to beginning treatment and then periodically thereafter.
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Standard hematologic tests - including hemoglobin (pretreatment, week 2 and week 4 of therapy, and as clinically appropriate [see WARNINGS ]), complete and differential white blood cell counts, and platelet count.
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Blood chemistries - liver function tests and TSH.
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Pregnancy - including monthly monitoring for females of childbearing potential.
Carcinogenesis and Mutagenesis Carcinogenicity studies with interferon alfa-2b, recombinant have not been performed because neutralizing activity appears in the serum after multiple dosing in all of the animal species tested.
Adequate studies to assess the carcinogenic potential of ribavirin in animals have not been conducted. However, ribavirin is a nucleoside analog that has produced positive findings in multiple in vitro and animal in vivo genotoxicity assays, and should be considered a potential carcinogen. Further studies to assess the carcinogenic potential of ribavirin in animals are ongoing.
Mutagenicity studies have demonstrated that interferon alfa-2b, recombinant is not mutagenic. 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 20-200 mg/kg (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1-1 × 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 No reproductive toxicology studies have been performed using interferon alfa-2b, recombinant in combination with ribavirin. However, evidence provided below for interferon alfa-2b, recombinant and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effects produced by either agent alone will also be caused by the combination of the two agents. Interferons may impair human fertility. In studies of interferon alfa-2b, recombinant administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in females treated with human leukocyte interferon. In addition, ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.
Fertile females and partners of fertile females should not receive combination REBETOL/INTRON A therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (eg, 15 half-lives of clearance for ribavirin).
Combination REBETOL/INTRON A therapy should be used with caution in fertile males. 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 1.25-12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1-0.8 × 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. Animal Toxicology Long-term studies in the mouse and rat (18-24 months; doses of 20-75 and 10-40 mg/kg/day, respectively [estimated human equivalent doses of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1-0.4 × the maximum human 24-hour dose of ribavirin]) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats. Pregnancy Category X (see CONTRAINDICATIONS) Interferon alfa-2b, recombinant has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). There are no adequate and well-controlled studies in pregnant females.
Ribavirin produced significant embryocidal and/or teratogenic effects 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 × 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 × the maximum recommended human 24-hour dose of ribavirin).
Treatment and Posttreatment: 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 7.14-28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 × 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.
Females of childbearing potential should not receive combination REBETOL/INTRON A therapy unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple dose half-life (t1/2) of ribavirin of 12 days.
Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with combination REBETOL/INTRON A therapy and for the 6-month posttherapy period (eg, 15 half-lives for ribavirin clearance from the body).
If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, physicians are encouraged to report such cases by calling (800) 727-7064. Nursing Mothers It is not known whether REBETOL and INTRON A are excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drugs in nursing infants, a decision should be made whether to discontinue nursing or to discontinue combination REBETOL/INTRON A therapy, taking into account the importance of the therapy to the mother.
Pediatric Use One hundred twenty-five pediatric patients between three and sixteen years of age with chronic hepatitis C virus infection (median duration 10.7 years) received REBETOL Capsules with INTRON A for up to 48 weeks. The overall sustained response rate cannot be calculated since all patients have not yet completed 24-weeks of off-therapy follow-up. Suicidal ideation or attempts occurred more frequently among pediatric patients compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up (see WARNINGS). As in adult patients, pediatric patients experienced other psychiatric adverse events (eg, depression, emotional lability, somnolence), anemia, and neutropenia (see WARNINGS). During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24-week posttreatment period.
Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric patients compared to adult patients. Conversely, pediatric patients experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult patients. Geriatric Use Clinical studies of REBETRON Combination Therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (see WARNINGS).
In general, REBETOL (ribavirin) should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased renal, hepatic and/or cardiac function, and of concomitant disease or other drug therapy.
REBETOL (ribavirin) is known to be substantially excreted by the kidney, and the risk of adverse reactions to ribavirin 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 of ribavirin should be made accordingly (see DOSAGE AND ADMINISTRATION: Guidelines for Dose Modifications). REBETOL should not be used in elderly patients with creatinine clearance <50mL/min (see WARNINGS).
REBETRON Combination Therapy should be used very cautiously in elderly patients with a history of psychiatric disorders (see WARNINGS).
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