No

Antiviral Agent; Biological Response Modulator

The combination therapy of oral ribavirin with interferon alfa-2b, recombinant (Intron® A) injection is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed after alpha interferon therapy.

X

Known hypersensitivity to interferon alfa-2b or any component; females of childbearing age

Interferon Alfa-2b: The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution in patients with seizure disorders, brain metastases, compromised CNS, multiple sclerosis, and patients with pre-existing cardiac disease, severe renal or hepatic impairment, or myelosuppression; safety and efficacy in children <18 years of age have not been established. Higher doses in the elderly or in malignancies other than hairy cell leukemia may result in severe obtundation.

Ribavirin: Use with caution in patients requiring assisted ventilation because precipitation of the drug in the respiratory equipment may interfere with safe and effective patient ventilation; monitor carefully in patients with COPD and asthma for deterioration of respiratory function. Ribavirin is potentially mutagenic, tumor-promoting, and gonadotoxic.

Anemia (hemoglobin <10 g/dL) was observed in 10% of treated patients in clinical trials; anemia occurred within 1-2 weeks of initiation of 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

Interferon Alfa-2b

>10%:

Central nervous system: Dizziness, fatigue, malaise, fever (usually within 4-6 hours), chills

Dermatologic: Skin rash

Gastrointestinal: Xerostomia, nausea, vomiting, diarrhea, dizziness, abdominal cramps, weight loss, metallic taste, anorexia

Hematologic: Mildly myelosuppressive and well tolerated if used without adjunct antineoplastic agents; thrombocytosis has been reported, leukopenia (mainly neutropenia), anemia, thrombocytopenia, decreased hemoglobin, hematocrit, platelets

Myelosuppressive:

WBC: Mild

Platelets: Mild

Onset (days): 7-10

Nadir (days): 14

Recovery (days): 21

Neuromuscular & skeletal: Rigors, arthralgia

Miscellaneous: Flu-like syndrome, diaphoresis

1% to 10%:

Central nervous system: Neurotoxicity

Dermatologic: Dry skin, alopecia

Gastrointestinal: Stomatitis

Hepatic: Hepatotoxicity

Neuromuscular & skeletal: Peripheral neuropathy, leg cramps

Ocular: Blurred vision

<1%:

Cardiovascular: Cardiotoxicity, tachycardia, arrhythmias, hypotension, SVT, arrhythmias, chest pain, edema

Central nervous system: EEG abnormalities, confusion, sensory neuropathy, fever, headache, psychiatric effects, delirium, somnolence, chills

Dermatologic: Partial alopecia, rash

Endocrine & metabolic: Increased uric acid level, hypothyroidism

Gastrointestinal: Weight loss, change in taste

Hematologic: Decreased hemoglobin, hematocrit, platelets

Hepatic: Increased hepatic transaminase, increased ALT and AST

Local: Sensitivity to injection

Neuromuscular & skeletal: Myalgia, arthralgia, rigors

Ocular: Visual disturbances, blurred vision

Renal: Proteinuria, increased creatinine, increased BUN

Respiratory: Coughing, dyspnea, nasal congestion

Miscellaneous: Neutralizing antibodies; usually patient can build up a tolerance to side effects

Ribavirin

1% to 10%:

Central nervous system: Fatigue, headache, insomnia

Gastrointestinal: Nausea, anorexia

Hematologic: Anemia

<1%:

Cardiovascular: Hypotension, cardiac arrest, digitalis toxicity

Dermatologic: Rash, skin irritation

Ocular: Conjunctivitis

Respiratory: Mild bronchospasm, worsening of respiratory function, apnea

Interferon Alfa-2b:

Signs and symptoms: CNS depression, obtundation, flu-like symptoms, myelosuppression

Treatment: Supportive

Interferon Alfa-2b:

Increased effect: Cimetidine: May augment the antitumor effects of interferon in melanoma

Increased toxicity:

Theophylline: Clearance has been reported to be decreased in hepatitis patients receiving interferon

Vinblastine: Enhances interferon toxicity in several patients; increased incidence of paresthesia has also been noted

Ribavirin: Decreased effect of zidovudine

Store the Rebetol® capsules plus Intron® A injection combination package refrigerated between 2°C and 8°C (36°F and 46°F)

When separated, the individual carton or vial of Intron® A injection and the Intron® A multidose pen should be stored refrigerated between 2°C and 8°C (36°F and 46°F)

Interferon Alfa-2b: Alpha interferons are a family of proteins, produced by nucleated cells, that have antiviral, antiproliferative, and immune-regulating activity. There are 16 known subtypes of alpha interferons. Interferons interact with cells through high affinity cell surface receptors. Following activation, multiple effects can be detected including induction of gene transcription. Inhibits cellular growth, alters the state of cellular differentiation, interferes with oncogene expression, alters cell surface antigen expression, increases phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells

Ribavirin: Inhibits replication of RNA and DNA viruses; inhibits influenza virus RNA polymerase activity and inhibits the initiation and elongation of RNA fragments resulting in inhibition of viral protein synthesis

Absorption: Filtered and absorbed at the renal tubule

Distribution: The V_d of interferon is 31 L; but has been noted to be much greater (370-720 L) in leukemia patients receiving continuous infusion IFN; IFN does not penetrate the CSF

Metabolism: Majority of dose thought to be metabolized in the kidney

Bioavailability:

I.M.: 83%

S.C.: 90%

Half-life: Elimination:

I.M., I.V.: 2 hours

S.C.: 3 hours

Time to peak serum concentration: I.M., S.C.: ~6-8 hours

The recommended dosage of combination therapy is 3 million int. units of Intron® A injected subcutaneously 3 times/week and 1000-1200 mg of Rebetol® capsules administered orally in a divided daily (morning and evening) dose for 24 weeks; patients weighing 75 kg (165 pounds) or less should receive 1000 mg of Rebetol® daily (2 x 200 mg capsules in the morning and 3 x 200 mg capsules in the evening); while patients weighing more than 75 kg should receive 1200 mg of Rebetol® daily (3 x 200 mg capsules in the morning and 3 x 200 mg capsules in the evening)

Baseline chest x-ray, EKG, CBC with differential, liver function tests, electrolytes, platelets, weight; patients with pre-existing cardiac abnormalities, or in advanced stages of cancer should have EKGs taken before and during treatment; reticulocyte count, I & O

Peak serum level after I.V. infusion of 10 million units: 546 units/mL

None noted

None noted

No information available to require special precautions

>10% of patients experience dry mouth and metallic taste

Do not operate heavy machinery while on therapy since changes in mental status may occur; report to physician any persistent or severe sore throat, fever, fatigue, unusual bleeding, or bruising; may cause photosensitivity; patient should be well hydrated

Use acetaminophen to prevent or partially alleviate headache and fever; do not use 3, 5, and 25 million unit strengths intralesionally, solutions are hypertonic; 50 million unit strength is not for use in condylomata

Combination package:

Each Rebetron™ combination package consists of:

A box containing 6 vials of Intron® A (3 million int. units in 0.5 mL per vial) and 6 syringes and alcohol swabs; two boxes containing 35 Rebetol® 200 mg capsules each for a total of 70 capsules (5 capsules per blister card)

One 18 million int. units multidose vial of Intron® A injection (22.8 million int. units per 3.8 mL; 3 million int. units/0.5 mL) and 6 syringes and alcohol swabs; two boxes containing 35 Rebetol® 200 mg capsules each for a total of 70 capsules (5 capsules per blister card)

One 18 million int. units Intron® A injection multidose pen (22.5 million int. units per 1.5 mL; 3 million int. units/0.2 mL) and 6 disposable needles and alcohol swabs; two boxes containing 35 Rebetol® 200 mg capsules each for a total of 70 capsules (5 capsules per blister card)

For patients >75 kg:

A box containing 6 vials of Intron® A injection (3 million int. units in 0.5 mL per vial) and 6 syringes and alcohol swabs; two boxes containing 42 Rebetol® 200 mg capsules each for a total of 84 capsules (6 capsules per blister card)

One 18 million int. units multidose vial of Intron® A injection (22.5 million int. units per 3.8 mL; 3 million int. units/0.5 mL) and 6 syringes and alcohol swabs; two boxes containing 42 Rebetol® 200 mg capsules each for a total of 84 capsules (6 capsules per blister card)

One 18 million int. units Intron® A injection multidose pen (22.5 million int. units per 1.5 mL; 3 million int. units/0.2 mL) and 6 disposable needles and alcohol swabs; two boxes containing 42 Rebetol® 200 mg capsules each for a total of 84 capsules (6 capsules per blister card)

For Rebetol® dose reduction:

A box containing 6 vials of Intron® A injection (3 million int. units in 0.5 mL per vial) and 6 syringes and alcohol swabs; one box containing 42 Rebetol® 200 mg capsules (6 capsules per blister card)

One 18 million int. units multidose vial of Intron® A injection (22.8 million int. units per 3.8 mL; 3 million int. units/0.5 mL) and 6 syringes and alcohol swabs; one box containing 42 Rebetol® 200 mg capsules (6 capsules per blister card)

One 18 million int. units Introl® A injection multidose pen (22.5 million int. units per 1.5 mL; 3 million int. units/0.2 mL) and 6 disposable needles and alcohol swabs; one box containing 42 Rebetol® 200 mg capsules (6 capsules per blister card)