Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/79
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Rebetol (Capsule)
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REBETOL'/INTRON' A Combination Therapy:<br/>Adults: The recommended dose of REBETOL Capsules depends on the patient's body weight. The recommended dose of REBETOL is provided in TABLE 11. The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen . After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population. In patients who relapse following non-pegylated interferon monotherapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.<br/>Pediatrics: The recommended dose of REBETOL is 15 mg/kg per day orally (divided dose AM and PM). For children weighing���25 kg or who cannot swallow capsules, REBETOL Oral Solution is supplied in a concentration of 40 mg/mL. For children weighing>25 kg, either the Oral Solution or 200-mg capsule may be administered. Refer to TABLE 12 for dosing recommendations for the 200-mg capsule to achieve the recommended dose. The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in pediatrics. REBETOL may be administered without regard to food, but should be administered in a consistent manner with respect to food intake . Under no circumstances should REBETOL Capsules be opened, crushed, or broken .<br/>REBETOL/PegIntron Combination Therapy: The recommended dose of REBETOL Capsules is 800 mg/day in 2 divided doses: two capsules (400 mg) in the morning with food and two capsules (400 mg) in the evening with food.<br/>Dose Modifications: If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, REBETOL/INTRON A therapy should be discontinued. REBETOL should not be used in patients with creatinine clearance<50 mL/min. Subjects with impaired renal function and/or those over the age of 50 should be carefully monitored with respect to development of anemia . REBETOL should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped . For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by���2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains<12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination REBETOL/INTRON A therapy. It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL dose reduced to 600 mg daily (1��200-mg capsule AM, 2��200 mg capsules PM) for adults and 7.5 mg/kg per day (divided dose AM and PM) for pediatric patients. A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL therapy .
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REBETOL REBETOL is Schering Corporation's brand name for ribavirin, a nucleoside analog. The chemical name of ribavirin is 1-��-D-ribofuranosyl-1H-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 CHNOand 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.<br/>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.
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Pharmacokinetics:<br/>Ribavirin: Single- and multiple-dose pharmacokinetic properties in adults are summarized in TABLE 1. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUC(AUC from time zero to last measurable concentration) following single doses of 200���1200 mg ribavirin. The relationship between dose and Cwas curvilinear, tending to asymptote above single doses of 400���600 mg. Upon multiple oral dosing, based on AUC12, a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.<br/>Effect of Food on Absorption of Ribavirin: Both AUCand Cincreased by 70% when REBETOL' Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies with REBETOL/INTRON' A were conducted without instructions with respect to food consumption. During clinical studies with REBETOL/PegIntron���, all subjects were instructed to take REBETOL Capsules with food .<br/>Effect of Antacid on Absorption of Ribavirin: Coadministration of REBETOL Capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta) resulted in a 14% decrease in mean ribavirin AUC. The clinical relevance of results from this single-dose study is unknown. Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an e-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins. Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg ofC-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose. Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions. No pharmacokinetic interactions were noted between INTRON A for Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.<br/>Drug Interactions: Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased antiretroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities .<br/>Special Populations:<br/>Renal Dysfunction: The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction. The mean AUCvalue was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance>90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCwas twofold greater when compared to control subjects. The increased AUCappears to be due to reduction of renal and non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values>50 mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance<50 mL/min should not be treated with REBETOL .<br/>Hepatic Dysfunction: The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCvalues were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean Cvalues increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.<br/>Elderly Patients: Pharmacokinetic evaluations in elderly subjects have not been performed.<br/>Gender: There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.<br/>Pediatric Patients: Multiple-dose pharmacokinetic properties for REBETOL Capsules and INTRON A in pediatric patients with chronic hepatitis C between 5 and 16 years of age are summarized in TABLE 2. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric patients. Complete pharmacokinetic characteristics of REBETOL Oral Solution have not been determined in pediatric patients. Ribavirin Cvalues were similar following administration of REBETOL Oral Solution or REBETOL Capsules during 48 weeks of therapy in pediatric patients (3 to 16 years of age). * In this section of the label, numbers in parenthesis indicate % coefficient of variation.
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REBETOL' 200-mg Capsules are white, opaque capsules with REBETOL, 200 mg, and the Schering Corporation logo imprinted on the capsule shell; the capsules are packaged in a bottle containing 42 capsules (NDC 0085-1327-04), 56 capsules (NDC 0085-1351-05), 70 capsules (NDC 0085-1385-07), and 84 capsules (NDC 0085-1194-03). REBETOL Oral Solution 40 mg/mL is a clear, colorless to pale or light yellow bubble gum-flavored liquid and it is packaged in 4-oz amber glass bottles (100 mL/bottle) with child-resistant closures (NDC 0085-1318-01).<br/>Storage Conditions: The bottle of REBETOL Capsules should be stored at 25��C (77��F); excursions permitted to 15�����30��C (59�����86��F) [see USP Controlled Room Temperature]. REBETOL Oral Solution should be stored between 2�����8��C (36�����46��F) or at 25��C (77��F); excursions permitted to 15�����30��C (59�����86��F) [see USP Controlled Room Temperature].
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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 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 non-responders to interferon therapy, or patients coinfected with HBV or HIV.<br/>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 for6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy . 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 . Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter . It is advised that patients be well hydrated, especially during the initial stages of treatment.<br/>Laboratory Tests: The following laboratory tests are recommended for all patients treated with REBETOL Capsules, prior to beginning treatment and then periodically thereafter.<br/>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 wasless 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.<br/>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 (t) 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 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.<br/>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. In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25 and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study days 13 and 48. Rat pups dosed from postnatal day 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.<br/>Pregnancy Category X: 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).<br/>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 (t) 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 (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.<br/>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.<br/>Geriatric Use: Clinical studies 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<50 mL/min . 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%) .<br/>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 . As in adult patients, pediatric patients experienced other psychiatric adverse events (e.g., depression, emotional lability, somnolence), anemia, and neutropenia . 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 posttreatment period.<br/>Drug Interactions:<br/>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 .<br/>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 .
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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 overdose, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of either agent.
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Ribavirin
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Rebetol (Capsule)
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The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1���2 weeks of oral therapy . Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients .<br/>REBETOL'/INTRON' A Combination Therapy: In clinical trials, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-emergent adverse events that occurred in the US studies with���5% incidence are provided in TABLE 7 by treatment group. In general, the selected treatment-emergent adverse events were reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.<br/>Pediatric Patients: In clinical trials of 118 pediatric patients 3 to 16 years of age, 6% discontinued therapy due to adverse events. Dose modifications were required in 30% of patients, most commonly for anemia and neutropenia. In general, the adverse event profile in the pediatric population was similar to that observed in adults. 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. Selected treatment-emergent adverse events that occurred with���5% incidence among all pediatric patients who received the recommended dose of REBETOL/INTRON A combination therapy are provided in TABLE 7. In addition, the following spontaneous adverse events have been reported during the marketing surveillance of REBETOL/INTRON A therapy: hearing disorder and vertigo.<br/>REBETOL/PegIntron Combination Therapy: Overall, in clinical trials, 14% of patients receiving REBETOL in combination with PegIntron���, discontinued therapy compared with 13% treated with REBETOL in combination with INTRON A. The most common reasons for discontinuation of therapy were related to psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse events. Adverse events that occurred in clinical trial at>5% incidence are provided in TABLE 8 by treatment group. Safety and effectiveness of REBETOL in combination with PegIntron has not been established in pediatric patients.<br/>Laboratory Values:<br/>REBETOL/INTRON A Combination Therapy: Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see TABLE 9).<br/>REBETOL/PegIntron Combination Therapy: Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see TABLE 10).<br/>Postmarketing Experiences: The following adverse reactions have been identified during post-approval use of REBETOL in combination with INTRON A or PegIntron therapy: hearing disorder, vertigo, aplastic anemia, pure red cell aplasia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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Adult Use: REBETOL' (ribavirin, USP) Capsules and Oral Solution are indicated in combination with INTRON' A (interferon alfa-2b, recombinant) for 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 PegIntron���(peginterferon alfa-2b) Powder for 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 PegIntron products have not been established.<br/>Pediatric Use: REBETOL (ribavirin, USP) Capsules are indicated in combination with INTRON A for 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 for 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 for pediatric subjects in the clinical trials.<br/>Description of Clinical Studies:<br/>REBETOL/INTRON A Combination Therapy:<br/>REBETOL/PegIntron Combination Therapy: A randomized study compared treatment with two PegIntron/REBETOL regimens [PegIntron 1.5��g/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PegIntron 1.5��g/kg SC QW for 4 weeks then 0.5��g/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-na��ve 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 PegIntron 1.5���0.5��g/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 PegIntron (1.5��g/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 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 PegIntron/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.
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Rebetol
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