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Pegintron and Rebetol

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PegIntron and Rebetol Combo Pack

WARNINGS

Pregnancy

REBETOL® Capsules may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL® 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. 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 be instructed to use at least two forms of effective contraception during treatment and during the 6 month period after treatment has been stopped based on multiple-dose half-life of ribavirin of 12 days. Pregnancy testing should occur monthly during REBETOL® therapy and for 6 months after therapy has stopped (See BOXED WARNING, CONTRAINDICATIONS and PRECAUTIONS: Pregnancy Category X and PATIENT INFORMATION).

Anemia

Ribavirin caused hemolytic anemia in 10% of Peglntron™/REBETOL®-treated patients within 1-4 weeks of initiation of therapy. Complete blood counts 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.

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 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: Guidelines for Dose Modification.) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use Peglntron™/REBETOL® Combo Pack (See ADVERSE REACTIONS).

Neuropsychiatric events

Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior sometimes directed towards others have occurred in patients with and without a previous psychiatric disorder during Peglntron™ treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with alpha interferons. Peglntron™/REBETOL® Combo Pack should be used with extreme caution in patients with a history of psychiatric disorders. Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with Peglntron™/REBETOL® Combo Pack be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, Peglntron™/REBETOL® Combo Pack therapy should be stopped immediately and psychiatric intervention instituted (see DOSAGE AND ADMINISTRATION: Dose Reduction). Cases of encephalopathy have been observed in some patients, usually elderly, treated with higher doses of Peglntron™.

Bone marrow toxicity

Peglntron™ suppresses bone marrow function, sometimes resulting in severe cytopenias. Peglntron™/REBETOL® Combo Pack therapy should be discontinued in patients who develop severe decreases in neutrophil or platelet counts (see DOSAGE AND ADMINISTRATION: Dose Reduction). Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia.

Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including Peglntron™. Cirrhotic CHC patients co-infected with HIV receiving highly active antiretroviral therapy (HAART) and alpha interferons with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients' clinical status and hepatic function should be closely monitored, and Peglntron™/REBETOL® Combo Pack treatment should be immediately discontinued if decompensation (Child-Pugh score > 6) is observed (see CONTRAINDICATIONS).

Endocrine disorders

Peglntron™ causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with Peglntron™. Diabetes mellitus has been observed in patients treated with alpha interferons. Patients with these conditions who cannot be effectively treated by medication should not begin Peglntron™/REBETOL® Combo Pack therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue Peglntron™/REBETOL® Combo Pack therapy.

Cardiovascular events

Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with Peglntron™. Peglntron™/REBETOL® Combo Pack therapy should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require Peglntron™/REBETOL® Combo Pack_therapy should be closely monitored (see Laboratory Tests). Patients with a history of significant or unstable cardiac disease should not be treated with Peglntron™/REBETOL® Combo Pack.

Cerebrovascular disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients with interferon alpha-based therapies, including Peglntron™. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alpha-based therapies and these events is difficult to establish.

Pulmonary disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by Peglntron™ or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. Peglntron™/REBETOL® Combo Pack treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.

Colitis

Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. Peglntron™/REBETOL® Combo Pack treatment should be discontinued immediately in patients who develop these symptoms and signs. The colitis usually resolves within 1-3 weeks of discontinuation of alpha interferons.

Pancreatitis

Fatal and nonfatal pancreatitis have been observed in patients treated with alpha interferon. Peglntron™/REBETOL® Combo Pack therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.

Autoimmune disorders

Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis) have been observed in patients receiving Peglntron™. Peglntron™/REBETOL® Combo Pack therapy should be used with caution in patients with autoimmune disorders.

Ophthalmologic disorders

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Peglntron™/REBETOL® Combo Pack treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Hypersensitivity

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) and cutaneous eruptions (Stevens Johnson syndrome, toxic epidermal necrolysis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with Peglntron™/REBETOL® Combo Pack, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

PRECAUTIONS

  • Peglntron™ in combination with REBETOL® has not been studied in patients who have failed other alpha interferon treatments.
  • The safety and efficacy of Peglntron™ in combination with REBETOL® for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. 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.
  • The safety and efficacy of Peglntron™/REBETOL® for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

Triglycerides

Elevated triglyceride levels have been observed in patients treated with interferon alpha including Peglntron™ therapy. Hypertriglyceridemia may result in pancreatitis (See WARNINGS: Pancreatitis). Elevated triglyceride levels should be managed as clinically appropriate. Discontinuation of Peglntron™/REBETOL® Combo Pack therapy should be considered for patients with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting and persistently elevated triglycerides (e.g., triglycerides > 1000 mg/dL).

Patients with renal insufficiency

Increases in serum creatinine levels have been observed in patients with renal insufficiency receiving interferon alpha products, including Peglntron™. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and Peglntron™ dosing should be adjusted accordingly or discontinued (See CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION: Dose Reduction). Peglntron Patients with renal ™/REBETOL® Combo Pack therapy must not be used in patients with creatinine clearance < 50 mL/min (See CLINICAL PHARMACOLOGY, Special populations).

Information for Patients

Patients receiving Peglntron™/REBETOL® Combo Pack therapy should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the MEDICATION GUIDE.

Patients must be informed that REBETOL® may cause birth defects and/or 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 during treatment with Peglntron™/REBETOL® Combo Pack therapy and for 6 months posttherapy. Peglntron™/REBETOL® Combo Pack 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. 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 treatment 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 and WARNINGS).

If pregnancy does occur during treatment or during 6 months posttherapy, 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. Physicians should report such cases by calling 1-800- 593-2214.

The most common adverse experience occurring with REBETOL® Capsules is anemia, which may be severe. (See ADVERSE REACTIONS.) Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter (See Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment. “Flu-like” symptoms associated with administration of Peglntron™ may be minimized by bedtime administration of Peglntron™ or by use of antipyretics.

Patients should be advised to use a puncture-resistant container for disposal of the used REDIPEN®. The full container should be disposed of in accordance with state and local laws. Patients should be thoroughly instructed in the importance of proper disposal. Patients should also be cautioned against reusing or sharing the REDIPEN®

Dental and periodontal disorders

Dental and periodontal disorders have been reported in patients receiving Peglntron™/REBETOL® 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 Peglntron™. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, patients should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests

Pregnancy testing should occur monthly during therapy and for 6 months after therapy has stopped in women of childbearing potential.

Peglntron™/REBETOL® Combo Pack therapy may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g.,TSH), and hepatic abnormalities. Transient elevations in ALT (2- to 5-fold above baseline) were observed in 10% of patients treated with Peglntron™, and was not associated with deterioration of other liver function. Triglyceride levels are frequently elevated in patients receiving alpha interferon therapy including Peglntron™ and should be periodically monitored.

Patients on Peglntron™/REBETOL® Combo Pack therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the clinical trial CBC (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. TSH levels were measured every 12 weeks during the treatment period. HCV RNA should be measured at 6 months of treatment. Peglntron™/REBETOL® Combo Pack therapy should be discontinued in patients with persistent high viral levels.

Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Peglntron™/REBETOL® Combo Pack.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis and Mutagenesis

Peglntron™ has not been tested for its carcinogenic potential. Neither Peglntron™, nor its components interferon or methoxypolyethylene glycol caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.

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 non-carcinogenic 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). However, this dose was less than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin.

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 X 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.

Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.

Impairment of Fertility

No reproductive toxicology studies have been performed using peginterferon alfa-2b, recombinant in combination with ribavirin. However, evidence for peginterferon alfa-2b and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effect produced by either agent alone will also be caused by the combination of the two agents.

Peglntron™ may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 mcg/m² Peglntron™ alone every other day for one month (approximately 345 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of Peglntron™ treatment. Every other day dosing with 262 mcg/m² (approximately 21 times the weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of Peglntron™ on male fertility have not been studied.

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 women and partners of fertile women should not receive Peglntron™/REBETOL® Combo Pack therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose halflife (t½) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (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 150mg/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 X 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.

Pregnancy Category X

(see CONTRAINDICATIONS)

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 X 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 X 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 X 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 Peglntron™/REBETOL® Combo Pack 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 (t½) of ribavirin of 12 days.

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

Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six 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 components of Peglntron™ and/or REBETOL® are excreted in human milk. Studies in mice have shown that mouse interferons are excreted in breast milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue Peglntron™/REBETOL® Combo Pack treatment, taking into account the importance of the therapy to the mother.

Pediatric

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric

In general, younger patients tend to respond better than older patients to interferon-based therapies. Clinical studies of Peglntron™ in combination with REBETOL® did not include sufficient numbers of subjects aged 65 and over, however, to determine whether they respond differently than younger subjects. Treatment with alpha interferons, including Peglntron™, is associated with neuropsychiatric, cardiac, pulmonary, Gl, and systemic (flu-like) adverse effects. Because these adverse reactions may be more severe in the elderly, caution should be exercised in the use of Peglntron™ in this population. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in patients with impaired renal function (See CLINICAL PHARMACOLOGY: Special Populations: Renal Dysfunction). Peglntron™/REBETOL® Combo Pack therapy should not be used in patients with creatinine clearance < 50 mL/min.

Last reviewed on RxList: 6/24/2013
This monograph has been modified to include the generic and brand name in many instances.

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