Rebetol Description

REBETOL®

REBETOL is Schering Corporation's brand name for ribavirin, a nucleoside analog. The chemical name of ribavirin is 1-?-D-ribofuranosyl-1 H -1,2,4-triazole-3-carboxamide and has the following structural formula:

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C8 H12 N4 O5 and the molecular weight is 244.21.

REBETOL Capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin, sodium lauryl sulfate, silicon dioxide, and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, and FD&C Blue #2 aluminum lake.

REBETOL Oral Solution is a clear, colorless to pale or light yellow bubble gum-flavored liquid. Each milliliter of the solution contains 40 mg of ribavirin and the inactive ingredients sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.

Mechanism Of Action

The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with ribavirin and interferon products has not been established.

Rebetol Indications And Usage

Adult Use

REBETOL (ribavirin, USP) Capsules and Oral Solution are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 18 years of age and older with compensated liver disease previously untreated with alpha interferon and in patients 18 years of age and older who have relapsed following alpha interferon therapy.

REBETOL Capsules are indicated in combination with PEG-INTRON (peginterferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age.

The safety and efficacy of REBETOL Capsules or Oral Solution with interferons other than INTRON A or PEG-INTRON products have not been established.

Pediatric Use

REBETOL (ribavirin, USP) Capsules are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 5 years of age and older with compensated liver disease previously untreated with alpha interferon and in patients who have relapsed following alpha interferon therapy.

REBETOL (ribavirin, USP) Oral Solution is indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease previously untreated with alpha interferon and in patients who have relapsed following alpha interferon therapy.

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 (see PRECAUTIONS Pediatric Use ) for pediatric subjects in the clinical trials.

Description Of Clinical Studies

Rebetol/Intron A Combination Therapy

Adult Patients

Previously Untreated Patients

Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL Capsules 1200 mg/day (1000 mg/day for patients weighing ?75 kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in TABLE 3 .

Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of REBETOL/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV Genotype 1 treated with REBETOL/INTRON A therapy who achieved HCV RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV nongenotype 1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL 1200 mg/day (1000 mg/day for patients weighing ?75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in TABLE 4 .

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

Pediatric Patients

Pediatric patients 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) were treated with REBETOL 15 mg/kg per day plus INTRON A 3 MIU/m2 TIW for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 patients received treatment who were 57% male, 80% Caucasian, and 78% genotype 1. Patients <5 years of age received REBETOL Oral Solution and those ?5 years of age received either REBETOL Oral Solution or Capsules.

Study results are summarized in Table 5.

Patients with viral genotype 1, regardless of viral load, had a lower response rate to INTRON A/REBETOL combination therapy compared to patients with genotype non-1, 36% versus 81%. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).

Rebetol/Peg-intron Combination Therapy

A randomized study compared treatment with two PEG-INTRON/REBETOL regimens [PEG-INTRON 1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PEG-INTRON 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44 weeks/REBETOL 1000/1200 mg PO daily (in divided doses)] with INTRON A [3 MIU SC thrice weekly (TIW)/REBETOL 1000/1200 mg PO daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon naïve patients were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible patients had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV RNA at 24 weeks posttreatment (See Table 6 ).

The response rate to PEG-INTRON 1.5?0.5µg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-INTRON (1.5 µg/kg)/REBETOL combination therapy compared to patients with other viral genotypes. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/REBETOL combination therapy.

Patients with lower body weight tended to have higher adverse event rates (see ADVERSE REACTIONS ) and higher response rates than patients with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PEG-INTRON/REBETOL combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic patients and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 68% of patients. Compared to baseline approximately 2/3 of patients in all treatment groups were observed to have a modest reduction in inflammation.

Rebetol Contraindications

Pregnancy

REBETOL Capsules and Oral Solution may cause birth defects and/or death of the exposed fetus. REBETOL therapy is contraindicated for use in women who are pregnant or in men whose female partners are pregnant. (See WARNINGS, PRECAUTIONS-Information for Patients and Pregnancy Category X ).

REBETOL Capsules and Oral Solution are contraindicated in patients with a history of hypersensitivity to ribavirin or any component of the capsule.

Patients with autoimmune hepatitis must not be treated with combination REBETOL/INTRON A therapy because using these medicines can make the hepatitis worse.

Patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia) should not be treated with REBETOL Capsules or Oral Solution.

Rebetol Side Effects

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 (interferon alfa-2b, recombinant) as a combination therapy or with PEG-INTRON Injection.

There are significant adverse events caused by REBETOL/INTRON A or PEG-INTRON 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. The Intron A and PEG-INTRON package inserts should be reviewed in their entirety prior to initiation of combination treatment for additional safety information.

Pregnancy

REBETOL Capsules and Oral Solution 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 six 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 six months after therapy has stopped (see CONTRAINDICATIONS and PRECAUTIONS: Information for Patients and Pregnancy Category X).

Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of REBETOL/INTRON A-treated patients in clinical trials (See adverse reactions laboratory values - hemoglobin). The anemia associated with REBETOL capsules occurs within 1 ? 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.

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: 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 REBETOL. (See ADVERSE REACTIONS.)

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

REBETOL should not be used in patients with creatinine clearance <50 mL/min. ( See Clinical Pharmacology, Special populations. )

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.

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 interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition, some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Rebetol Precautions

The safety and efficacy of REBETOL/INTRON A and PEG-INTRON 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 a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

The safety and efficacy of REBETOL/INTRON A therapy has not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C infection, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.

Information For Patients

Patients must be informed that REBETOL Capsules and Oral Solution may cause birth defects and/or death of the exposed fetus. 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 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 REBETOL 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.

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.

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 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 treated with REBETOL Capsules, prior to beginning treatment and then periodically thereafter.

• 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.
• Blood chemistries - liver function tests and TSH.
• Pregnancy - including monthly monitoring for women of childbearing potential.
• ECG (See Warnings )

Carcinogenesis and Mutagenesis

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 × 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/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 REBETOL 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).

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 ? 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 )

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.

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 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 REBETOL and for the 6-month posttherapy period (eg, 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 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.

Geriatric Use

Clinical studies of REBETOL/INTRON A or PEG-INTRON 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 <50 mL/min. (See WARNINGS. )

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/or cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%). (See WARNINGS. )

Pediatric Use

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 (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 9%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 13%). A general reversal of these trends was noted during the 24-week post-treatment period.

Drug Interactions

Didanosine

Co-administration of REBETOL Capsules or Oral Solution and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions ).

Stavudine and Zidovudine

Ribavirin may antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution (see CLINICAL PHARMACOLOGY: Drug Interactions ).

Rebetol Overdosage

There is limited experience with overdosage. Acute ingestion of up to 20 grams of REBETOL Capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse events related to the therapeutic use of INTRON A and REBETOL. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

There is no specific antidote for INTRON A or REBETOL, and hemodialysis and peritoneal dialysis are not effective treatment of overdose of either agent.

Rebetol Description Of Clinical Studies

Rebetol/Intron A Combination Therapy

Adult Patients

Previously Untreated Patients

Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL Capsules 1200 mg/day (1000 mg/day for patients weighing ?75 kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in TABLE 3 .

Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of REBETOL/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV Genotype 1 treated with REBETOL/INTRON A therapy who achieved HCV RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV nongenotype 1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL 1200 mg/day (1000 mg/day for patients weighing ?75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in TABLE 4 .

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

Pediatric Patients

Pediatric patients 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) were treated with REBETOL 15 mg/kg per day plus INTRON A 3 MIU/m2 TIW for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 patients received treatment who were 57% male, 80% Caucasian, and 78% genotype 1. Patients <5 years of age received REBETOL Oral Solution and those ?5 years of age received either REBETOL Oral Solution or Capsules.

Study results are summarized in Table 5.

Patients with viral genotype 1, regardless of viral load, had a lower response rate to INTRON A/REBETOL combination therapy compared to patients with genotype non-1, 36% versus 81%. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).

Rebetol/Peg-intron Combination Therapy

A randomized study compared treatment with two PEG-INTRON/REBETOL regimens [PEG-INTRON 1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PEG-INTRON 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44 weeks/REBETOL 1000/1200 mg PO daily (in divided doses)] with INTRON A [3 MIU SC thrice weekly (TIW)/REBETOL 1000/1200 mg PO daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon naïve patients were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible patients had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV RNA at 24 weeks posttreatment (See Table 6 ).

The response rate to PEG-INTRON 1.5?0.5µg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-INTRON (1.5 µg/kg)/REBETOL combination therapy compared to patients with other viral genotypes. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/REBETOL combination therapy.

Patients with lower body weight tended to have higher adverse event rates (see ADVERSE REACTIONS ) and higher response rates than patients with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PEG-INTRON/REBETOL combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic patients and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 68% of patients. Compared to baseline approximately 2/3 of patients in all treatment groups were observed to have a modest reduction in inflammation.

Rebetol Information For Patients

Patients must be informed that REBETOL Capsules and Oral Solution may cause birth defects and/or death of the exposed fetus. 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 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 REBETOL 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.

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.

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 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.