Rebetol Information
Rebetol () Dosage And Administration
Under no circumstances should Rebetol () Capsules be opened, crushed, or broken. Rebetol () should be taken with food []. Rebetol () should not be used in patients with creatinine clearance If severe adverse reactions or laboratory abnormalities develop during combination Rebetol () /INTRON A therapy or Rebetol () /PegIntron therapy, modified, or discontinue the dose until the adverse reaction abates or decreases in severity [see ]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of PegIntron in adult patients on Rebetol () /PegIntron combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Dose reduction of PegIntron in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in
In the adult combination therapy study 2 dose reductions occurred in 42% of subjects receiving PegIntron 1.5 mcg/kg plus Rebetol () 800 mg daily including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with Rebetol () , with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events [].
Dose reduction in pediatric patients is accomplished by modifying the recommended PegIntron dose in a two-step process from the original starting dose of 60 mcg/m/week, to 40 mcg/m/week, then to 20 mcg/m/week, if needed (see )In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving PegIntron 60 mcg/m weekly plus Rebetol () 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended Rebetol () dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed ( ).
Rebetol () should not be used in patients with creatinine clearance
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 [see ].
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
It is that a patient whose hemoglobin level falls below 10 g/dL have his/her Rebetol () dose modified or discontinued per [see ].
Refer to the INTRON A Package Insert or PegIntron Powder for Injection Package Insert for additional information about how to reduce an INTRON A or PegIntron dose.
Rebetol () Dosage Form And Strengths
Rebetol () 200 mg Capsules
Rebetol () Oral Solution 40 mg per mL
Rebetol () Contraindications
Rebetol () combination therapy is contraindicated in:
Rebetol () Warnings And Precautions
Rebetol () Capsules and Oral Solution may cause birth defects and death of the unborn child. 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 use at least two forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped.
The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of Rebetol () /INTRON A-treated subjects in clinical trials. The anemia associated with Rebetol () capsules occurs within 1 to 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 [see ].
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 ]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use Rebetol () .
PegIntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.
Patients on PegIntron/Rebetol () combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult 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. In pediatric subjects the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see ].
Pancytopenia (marked decreases in red blood cells, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PegIntron, Rebetol () and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see ].
Data on the effects of PegIntron plus Rebetol () on growth come from an open-label study in subjects 3 through 17 years of age, and weight and height changes are compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron plus Rebetol () lags behind that predicted by normative population data for the entire length of treatment. After about 6 months posttreatment (Follow-Up Week 24), subjects had weight gain rebounds and regained their weight to 53 percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57 percentile). After about 6 months posttreatment, height gain stabilized and subjects treated with PegIntron plus Rebetol () had an average height percentile of 44 percentile, which was less than the average of the normative population and less than their average baseline height (51 percentile). Severely inhibited growth velocity (
Among the boys studied, the age groups of 3–11 years old and 12–17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months posttreatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3–11 years old and treated for 48 weeks had the largest average drop in height and weight percentiles (13 percentiles and 7 percentiles, respectively), whereas girls 12–17 years old continued along their average baseline height and weight percentiles after 6 months posttreatment.
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 or PegIntron (not other interferons) as a combination therapy.
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.
There are significant adverse reactions caused by Rebetol () /INTRON A or PegIntron 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 PegIntron package inserts should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.
Rebetol () Adverse Reactions
Clinical trials with Rebetol () in combination with PegIntron or INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [].
Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving PegIntron or INTRON A in combination with Rebetol () were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving Rebetol () in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.
The Adverse Reactions section references the following clinical studies:
Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without Rebetol () [see ]. The most common serious events occurring in subjects treated with PegIntron and Rebetol () were depression and suicidal ideation each occurring at a frequency of less than 1%. 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 ]. The most common fatal reaction occurring in subjects treated with PegIntron and Rebetol () was cardiac arrest, suicide ideation, and suicide attempt [see ], all occurring in less than 1% of subjects.
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rated in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Rebetol () Drug Interactions
Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Adding treatment with alpha interferons alone or in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment- associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate . Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6).
Ribavirin may antagonize the antiviral activity of stavudine and zidovudine against HIV. Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine and zidovudine, which could lead to decreased antiretroviral activity. However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen to HIV/HCV co-infected subjects. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution.
Results of 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.
Rebetol () Use In Specific Populations
Safety and effectiveness of Rebetol () in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with Rebetol () /INTRON A, 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.
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
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 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 ].
Rebetol () Overdosage
There is limited experience with overdosage. Acute ingestion of up to 20 g 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 reactions 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 these agents.
Rebetol () Description
Rebetol () is Schering Corporation's brand name for ribavirin, a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula (see ).
Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is CHNO 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.
Rebetol () Clinical Pharmacology
Single- and multiple-dose pharmacokinetic properties in adults are summarized in . 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 to 1200 mg ribavirin. The relationship between dose and C was curvilinear, tending to asymptote above single doses of 400 to 600 mg.
Upon multiple oral dosing, based on AUC12, a 6 fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.
Rebetol () Nonclinical Toxicology
Long-term studies in the mouse and rat [18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively {estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times 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 Days 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.
Rebetol () Clinical Studies
Clinical Study 1 evaluated PegIntron monotherapy. See PegIntron Powder for Injection Package Insert for information about this study.
Rebetol () How Supplied/storage And Handling
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 56 capsules (NDC 0085-1351-05), 70 capsules (NDC 0085-1385-07), and 84 capsules (NDC 0085-1194-03).
Rebetol () Oral Solution 40 mg per 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).
Rebetol () Patient Counseling Information
[See ]
Patients must be informed that Rebetol () Capsules and Oral Solution may cause birth defects and 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 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 post therapy. 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 post therapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy [see and ].
If pregnancy does occur during treatment or during 6 months post therapy, 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 . 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.
Patients should be informed about what to do in the event they miss a dose of Rebetol () ; the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to contact their healthcare provider if they have questions.
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