Rebetol (Ribavirin)
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Rebetol (Ribavirin)

REBETOL
(ribavirin, USP) Capsules, Oral Solution

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

REBETOL (ribavirin) ® monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication [see WARNINGS AND PRECAUTIONS].

The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with REBETOL (ribavirin) therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].

Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, REBETOL (ribavirin) therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL (ribavirin) therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use in Specific Populations, Nonclinical Toxicology, and PATIENT INFORMATION].

DRUG 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 Figure 1).

Figure 1: Structural Formula

REBETOL (ribavirin) Structural Formula Illustration

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C8H12N4O5 and the molecular weight is 244.21.

REBETOL (ribavirin) 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 (ribavirin) 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.

What are the possible side effects of ribavirin (Copegus, Rebetol, RibaPak, Ribasphere, RibaTab)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using ribavirin and call your doctor at once if you have a serious side effect such as:

  • problems with your vision;
  • fever, chills, body aches, flu symptoms;
  • severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
  • stabbing chest pain, wheezing, feeling short of breath;
  • severe depression,...

Read All Potential Side Effects and See Pictures of Rebetol »

What are the precautions when taking ribavirin (Rebetol)?

Before taking ribavirin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: other types of hepatitis (e.g., autoimmune hepatitis), blood disorders (e.g., sickle cell anemia, low hemoglobin, thalassemia), kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other liver problems, heart disease, high blood pressure, breathing problems, pancreas problems (e.g., pancreatitis),...

Read All Potential Precautions of Rebetol »

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Chronic Hepatitis C (CMC)

REBETOL (ribavirin) in combination with interferon alfa-2b (pegylated and nonpegylated) is indicated for the treatment of Chronic Hepatitis C (CMC) in patients 3 years of age and older with compensated liver disease [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

The following points should be considered when initiating REBETOL (ribavirin) combination therapy with Peglntron or INTRON A:

  • These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
  • Combination therapy with REBETOL (ribavirin) /Peglntron is preferred over REBETOL (ribavirin) /INTRON A as this combination provides substantially better response rates [see Clinical Studies].
  • Patients with the following characteristics are less likely to benefit from retreatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection [see Clinical Studies].
  • No safety and efficacy data are available for treatment of longer than one year.

DOSAGE AND ADMINISTRATION

Under no circumstances should REBETOL (ribavirin) Capsules be opened, crushed, or broken. REBETOL should be taken with food [see CLINICAL PHARMACOLOGY]. REBETOL (ribavirin) should not be used in patients with creatinine clearance < 50 mL/min.

REBETOL (ribavirin) /Peglntron Combination Therapy

Adult Patients

The recommended dose of Peglntron is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg REBETOL (ribavirin) Capsules orally based on patient body weight (see Table 1). The volume of Peglntron to be injected depends on the strength of Peglntron and patient's body weight (see Table 1).

Duration of Treatment- Interferon Alpha-naive Patients

The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 Iog10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks.

Duration of Treatment- Retreatment with Peglntron/REBETOL (ribavirin) of Prior Treatment Failures

The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies].

Table 1: Recommended REBETOL (ribavirin) /Peglntron Combination Therapy Dosing (Adults)

Body weight kg (lbs) PegIntron Redipen® or Vial Strength to Use Amount of PegIntron (mcg) to Administer Volume (mL)* of Peglntron to Administer REBETOL Daily Dose REBETOL Number of Capsules
< 40 ( < 87) 50 mcg per 0.5 mL 50 0.5 800 mg/day 2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M.
40-50 (87-111)   64 0.4 800 mg/day 2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M.
51-60 (112-133) 0.5 mL 80 mcg per 80 0.5 800 mg/day 2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M.
61-65 (134-144) 1 20 mcg per 0.5 mL 96 0.4 800 mg/day 2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M.
66-75 (145-166) 96 0.4 1000 mg/day 2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.
76-80 (167-177) 120 0.5 1000 mg/day 2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.
81-85 (178-187) 1200 mg/day 3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.
86-105 (188-231) 150 mcg per 0.5 mL 150 0.5 1200 mg/day 3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.
> 105 ( > 231) 1400 mg/day 3 x 200 mg capsules A.M.
4 x 200 mg capsules P.M.
* When reconstituted as directed.
For patients weighing > 105 kg ( > 231 pounds), the Peglntron dose of 1.5 mcg/kg/week should be calculated based on the individual patient weight. Two vials of Peglntron may be necessary to provide the dose.

Pediatric Patients

Dosing for pediatric patients is determined by body surface area for Peglntron and by body weight for REBETOL (ribavirin) . The recommended dose of Peglntron is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of REBETOL (ribavirin) orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving Peglntron/REBETOL (ribavirin) should remain on the pediatric dosing regimen. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

Table 2: Recommended REBETOL (ribavirin) * Dosing in Combination Therapy (Pediatrics)

Body weight kg (Ibs) REBETOL Daily Dose REBETOL Number of Capsules
< 47 ( < 103) 1 5 mg/kg/day Use REBETOL Oral Solution
47-59 (103-131) 800 mg/day 2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M.
60-73 (132-162) 1000 mg/day 2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.
> 73 ( > 162) 1200 mg/day 3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.
* REBETOL (ribavirin) to be used in combination with Peglntron 60 mcg/m2 weekly.
REBETOL (ribavirin) Oral Solution may be used for any patient regardless of body weight.

REBETOL (ribavirin) /INTRON A Combination Therapy

Adults
Duration of Treatment- Interferon Alpha-naive Patients

The recommended dose of INTRON A is 3 million IU three times weekly subcutaneously. The recommended dose of REBETOL (ribavirin) Capsules depends on the patient's body weight (refer to Table 3). 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 [see INDICATIONS, ADVERSE REACTIONS, and Clinical Studies]. 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.

Duration of Treatment- Retreatment with INTRON A/REBETOL (ribavirin) in Relapse Patients

In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

Table 3: Recommended Dosing

Body weight REBETOL Capsules
≤ 75kg 2 x 200 mg capsules AM
3 x 200 mg capsules PM daily orally
> 75kg 3 x 200 mg capsules AM
3 x 200 mg capsules PM daily orally

Pediatrics

The recommended dose of REBETOL (ribavirin) is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of REBETOL (ribavirin) in combination with INTRON A. INTRON A for Injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously. Refer to adult dosing table for > 61 kg body weight.

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.

Laboratory Tests

The following laboratory tests are recommended for all patients treated with REBETOL (ribavirin) , 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 AND PRECAUTIONS], 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 AND PRECAUTIONS].

Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination REBETOL (ribavirin) /INTRON A therapy or REBETOL (ribavirin) /Peglntron therapy, modified, or discontinue the dose until the adverse reaction abates or decreases in severity [see WARNINGS AND PRECAUTIONS]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of Peglntron in adult patients on REBETOL (ribavirin) /Peglntron 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 Peglntron in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 4.

In the adult combination therapy study 2 dose reductions occurred in 42% of subjects receiving Peglntron 1.5 meg/kg plus REBETOL (ribavirin) 800 mg daily including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of Peglntron to 1 meg/kg in combination with REBETOL (ribavirin) , with an additional 4% requiring the second dose reduction of Peglntron to 0.5 meg/kg due to adverse events [see ADVERSE REACTIONS].

TABLE 4. Two-Step Dose Reduction of Peglntron in Combination Therapy in Adults

First Dose Reduction to Peglntron 1 mcg/kg Second Dose Reduction to Peglntron 0.5 mcg/kg
Body weight kg (Ibs) Peglntron REDIPEN/Vial Strength to Use Amount of Peglntron (meg) to Administer Volume (mL) f of Peglntron to Administer Body weight kg (Ibs) Peglntron REDIPEN/Vial Strength to Use Amount of Peglntron (meg) to Administer Volume (mL) of Peglntron to Administer
< 40 ( < 88) 50 mcg per 0.5 mL 35 0.35 < 40 ( < 88) 50 mcg per 0.5 mL* 20 0.2
40-50 (88-111) 45 0.45 40-50 (88-111) 25 0.25
51 -60 (112 - 133) 50 0.5 51-60 (112-133) 50 mcg per 0.5 mL 30 0.3
61 - 75 (134 - 166) 80 mcg per 0.5 mL 64 0.4 61-75 (134-166) 35 0.35
76 - 85 (167 - 187)
80 0.5 76-85 (167-187) 45 0.45
86-104 (188-230) 120 mcg per 0.5 mL 96 0.4 86-104 (188-230) 50 0.5
105-125 (231 - 275) 108 0.45 105-125 (231-275) 80 mcg per 0.5 mL 64 0.4
> 125 ( > 275) 150 mcg per 0.5 mL 135 0.45 > 125 ( > 275) 72 0.45
* Must use vial. Minimum delivery for REDIPEN 0.3 mL
When reconstituted as directed

Dose reduction in pediatric patients is accomplished by modifying the recommended Peglntron dose in a two-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Table 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving Peglntron 60 mcg/m2 weekly plus REBETOL (ribavirin) 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended REBETOL (ribavirin) dose from the original starting does of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 5).

REBETOL (ribavirin) should not be used in patients with creatinine clearance < 50 mL/min. Subjects with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see WARNINGS AND PRECAUTIONS, Use in Specific Populations, and CLINICAL PHARMACOLOGY].

REBETOL (ribavirin) 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 WARNINGS AND PRECAUTIONS].

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 therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL (ribavirin) dose modified or discontinued per Table 5 [see WARNINGS AND PRECAUTIONS].

Table 5: Guidelines for Dose Modification and Discontinuation of Peglntron, INTRON A or Peglntron/REBETOL (ribavirin) Based on Laboratory Parameters in Adults and Pediatrics

Laboratory Values Adults Pediatrics Adults Pediatrics
Hgb < 10g/dL Peglntron/INTRON A Peglntron INTRON A REBETOL
For patients with cardiac disease, reduce by 50%* See footnote* See footnote* Adjust Dose 1st reduction to 12 mg/kg/day
2nd reduction to 8 mg/kg/day
WBC < 1.5 x 109/L
Neutrophils < 0.75 x 109/L
Platelets < 50 x109/L (Adults)
< 70 x109/L (Pediatrics)
Adjust Dose 1st reduction to 40 mcg/m2/week
2nd reduction to 20 mcg/m2/week
Reduce by 50% No Dose Change No Dose Change
Hgb < 8.5g/dL
WBC < 1 x 109/L
Neutrophils < 0.5 x 109/L
Creatinine > 2 mg/dL (Pediatrics)
Platelets < 25 x 109L (Adults)
< 50 x 109/L (Pediatrics)
Permanently Discontinue Permanently Discontinue Permanently Discontinue Permanently Discontinue Permanently Discontinue
* For adult patients with a history of stable cardiac disease receiving Peglntron or INTRON A in combination with ribavirin, the Peglntron or INTRON A dose should be reduced by half and the REBETOL (ribavirin) dose by 200 mg/day if a > 2 g/dL decrease in hemoglobin is observed during any 4-week period. Both Peglntron and REBETOL (ribavirin) or INTRON A and REBETOL (ribavirin) should be permanently discontinued if patients have hemoglobin levels < 12 g/dL after this REBETOL (ribavirin) dose reduction. Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease ≥ 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing.
1 dose reduction of REBETOL (ribavirin) is by 200 mg/day, except in patients receiving the 1400 mg dose it is by 400 mg/day; 2nd dose reduction of REBETOL (ribavirin) (if needed) is by an additional 200 mg/day.
For patients on REBETOL (ribavirin) /Peglntron combination therapy: 1st dose reduction of Peglntron is to 1 mcg/kg/week, 2nd dose reduction (if needed) of Peglntron is to 0.5 mcg/kg/week. For patients on REBETOL (ribavirin) /INTRON A combination therapy, reduce INTRON A dose by 50%.

Refer to the INTRON A Package Insert or Peglntron Powder for Injection Package Insert for additional information about how to reduce an INTRON A or Peglntron dose.

Discontinuation of Dosing

Adults

It is recommended that HCV genotype 1 interferon-alfa-na'i've patients receiving Peglntron in combination with ribavirin, be discontinued from therapy if there is not at least a 2 Iog10 drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable ( > 10-20 lU/mL) after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Pediatrics (3-17 years of age)

It is recommended that patients receiving Peglntron/REBETOL (ribavirin) combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped < 2 Iog10 compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA ( > 10-20 lU/mL) at treatment Week 24.

HOW SUPPLIED

Dosage Forms And Strengths

REBETOL (ribavirin) 200 mg Capsules REBETOL (ribavirin) Oral Solution 40 mg per mL

REBETOL (ribavirin) 200 mg Capsules are white, opaque capsules with REBETOL (ribavirin) , 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 (ribavirin) 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).

The bottle of REBETOL (ribavirin) Capsules should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

REBETOL (ribavirin) Oral Solution should be stored between 2° to 8°C (36° to 46°F) or at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Manufactured by Schering Corporation, a subsidiary of Schering-Plough Corporation, Kenilworth, NJ 07033 USA.

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Clinical trials with REBETOL (ribavirin) in combination with Peglntron 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 [see WARNINGS AND PRECAUTIONS].

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 Peglntron or INTRON A in combination with REBETOL (ribavirin) 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 (ribavirin) in combination with Peglntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The Adverse Reactions section references the following clinical studies:

  • REBETOL (ribavirin) /Peglntron Combination therapy studies:
    • Clinical Study 1 - evaluated Peglntron monotherapy (not further described in this label; see Peglntron Powder for Injection Package Insert for information about this study).
    • Study 2 - evaluated REBETOL (ribavirin) 800 mg/day flat dose in combination with 1.5 mcg/kg/week Peglntron or with INTRON A.
    • Study 3 - evaluated Peglntron/weight-based REBETOL (ribavirin) in combination with Peglntron/flat dose REBETOL (ribavirin) regimen.
    • Study 4- compared two Peglntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL (ribavirin) and a third treatment group receiving Pegasys® (180 mcg/week)/Copegus (1000-1200 mg/day).
    • Study 5 - evaluated Peglntron (1.5 mcg/kg/week) in combination with weight-based REBETOL (ribavirin) in prior treatment failure subjects.
  • Peglntron/REBETOL (ribavirin) Combination Therapy in Pediatric Patients
  • REBETOL (ribavirin) /INTRON A Combination Therapy studies for adults and pediatrics

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with Peglntron with or without REBETOL [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. The most common serious events occurring in subjects treated with Peglntron and REBETOL (ribavirin) were depression and suicidal ideation [see WARNINGS AND PRECAUTIONS], 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 WARNINGS AND PRECAUTIONS]. The most common fatal reaction occurring in subjects treated with Peglntron and REBETOL (ribavirin) was cardiac arrest, suicide ideation, and suicide attempt [see WARNINGS AND PRECAUTIONS], 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.

Clinical Studies Experience - REBETOL (ribavirin) /Peglntron Combination Therapy

Adult Subjects

Adverse reactions that occurred in the clinical trial at > 5% incidence are provided by treatment group from the REBETOL (ribavirin) /Peglntron Combination Therapy (Study 2) in Table 6.

Table 6: Adverse Reactions Occurring in > 5% of Adult Subjects

Adverse reactions Percentage of Subjects Reporting Adverse Reactions* Adverse Reactions Percentage of Subjects Reporting Adverse Reactions*
Peglntron
1.5 mcg/kg/ REBETOL (ribavirin)
(N=511)
INTRON A/ REBETOL
(N=505)
Peglntron
1 .5 mcg/kg/ REBETOL (ribavirin)
(N=511)
INTRON A/ REBETOL
(N=505)
Application Site Musculoskeletal
  Injection Site Inflammation 25 18   Myalgia 56 50
  Injection Site Reaction 58 36   Arthralgia 34 28
Autonomic Nervous System   Musculoskeletal Pain 21 19
  Dry Mouth 12 8 Psychiatric
  Increased Sweating 11 7   Insomnia 40 41
  Flushing 4 3   Depression 31 34
Body as a Whole   Anxiety/Emotional Lability/Irritability 47 47
  Fatigue/Asthenia 66 63   Concentration Impaired 17 21
  Headache 62 58   Agitation 8 5
  Rigors 48 41   Nervousness 6 6
  Fever 46 33 Reproductive, Female
  Weight Loss 29 20   Menstrual Disorder 7 6
  Right Upper Quadrant Pain 12 6 Resistance Mechanism
  Chest Pain 8 7   Viral Infection 12 12
  Malaise 4 6   Fungal Infection 6 1
Central/Peripheral Nervous System Respiratory System
  Dizziness 21 17   Dyspnea 26 24
  Endocrine   Coughing 23 16
  Hypothyroidism 5 4   Pharyngitis 12 13
Gastrointestinal   Rhinitis 8 6
  Nausea 43 33   Sinusitis 6 5
  Anorexia 32 27 Skin and Appendages
  Diarrhea 22 17   Alopecia 36 32
  Vomiting 14 12   Pruritus 29 28
  Abdominal Pain 13 13   Rash 24 23
  Dyspepsia 9 8   Skin Dry 24 23
  Constipation 5 5 Special Senses, Other
Hematologic Disorders   Taste Perversion 9 4
  Neutropenia 26 14 Vision Disorders
  Anemia 12 17   Vision Blurred 5 6
  Leukopenia 6 5   Conjunctivitis 4 5
  Thrombocytopenia 5 2  
Liver and Biliary System  
  Hepatomegaly 4 4  
* A subject may have reported more than one adverse reaction within a body system/organ class category.

Table 7 summarizes the treatment related adverse reactions in Study 4 that occurred at a 510% incidence.

Table 7: Summary of Treatment-Related Adverse Reactions (210% Incidence) By Descending Frequency

Adverse Reactions Study 4 Percentage of Patients Reporting Treatment-Related Adverse Reactions
Peglntron 1 .5 mcg/kg with REBETOL
(n=1019)
Peglntron 1 mcg/kg with REBETOL
(n=1016)
Pegasys 180 mcg with Copegus
(n=1035)
Fatigue 67 68 64
Headache 50 47 41
Nausea 40 35 34
Chills 39 36 23
Insomnia 38 37 41
Anemia 35 30 34
Pyrexia 35 32 21
Injection Site Reactions 34 35 23
Anorexia 29 25 21
Rash 29 25 34
Myalgia 27 26 22
Neutropenia 26 19 31
Irritability 25 25 25
Depression 25 19 20
Alopecia 23 20 17
Dyspnea 21 20 22
Arthralgia 21 22 22
Pruritus 18 15 19
Influenza-like Illness 16 15 15
Dizziness 16 14 13
Diarrhea 15 16 14
Cough 15 16 17
Weight Decreased 13 10 10
Vomiting 12 10 9
Unspecified Pain 12 13 9
Dry Skin 11 11 12
Anxiety 11 11 10
Abdominal Pain 10 10 10
Leukopenia 9 7 10

The incidence of serious adverse reactions was comparable in all studies. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL (ribavirin) group (12%) and with the flat-dose REBETOL (ribavirin) regimen. In Study 2, the incidence of serious adverse reactions was 17% in the Peglntron/REBETOL (ribavirin) groups compared to 14% in the INTRON A/REBETOL (ribavirin) group.

In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the Incidence of ongoing adverse reactions by body class In the Peglntron 1.5/REBETOL (ribavirin) group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for Gl). In approximately 10 to 15% of subjects'weight loss, fatigue, and headache had not resolved.

There have been 31 subject deaths which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving Peglntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving Peglntron/REBETOL (ribavirin) combination therapy; and 1 subject death in the INTRON A/REBETOL (ribavirin) group (motor vehicle accident). There have been 31 subject deaths which occurred during treatment or during follow-up in the three clinical trials. In Study 3, there were 14 deaths, 2 of which were probable suicides and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received Peglntron/REBETOL (ribavirin) combination therapy, 5 in the Peglntron 1.5 mcg/REBETOL (ribavirin) arm (N=1019) and 1 in the Peglntron 1 mcg/REBETOL (ribavirin) arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides which occurred during the off treatment follow-up period in subjects who received Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) combination therapy.

In studies 1 and 2,10 to 14% of subjects receiving Peglntron, alone or in combination with REBETOL (ribavirin) , discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL (ribavirin) . Similarly in Study 3,15% of subjects receiving Peglntron in combination with weight-based REBETOL (ribavirin) and 14% of subjects receiving Peglntron and flat dose REBETOL (ribavirin) discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In study 4,13% of subjects in the Peglntron 1.5 mcg/REBETOL (ribavirin) arm, 10% in the Peglntron 1 mcg/REBETOL (ribavirin) arm and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) and in 34% of those receiving INTRON A/REBETOL (ribavirin) . The majority of subjects (57%) weighing 60 kg or less receiving Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) required dose reduction. Reduction of interferon was dose related (Peglntron 1.5 meg/kg > Peglntron 0.5 meg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL (ribavirin) was similar across all three groups, 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with WBD compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of Peglntron to 1 meg/kg in combination with REBETOL (ribavirin) , with an additional 4% requiring the second dose reduction of Peglntron to 0.5 meg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 meg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 meg/week with Pegasys.

In the Peglntron/REBETOL (ribavirin) combination trials the most common adverse reactions were psychiatric which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see WARNINGS AND PRECAUTIONS]. In study 4 psychiatric adverse reactions occurred in 58 % of subjects in the Peglntron 1.5 mcg/REBETOL (ribavirin) arm, 55% of subjects in the Peglntron 1 mcg/REBETOL (ribavirin) arm, 57% of subjects in the Pegasys 180 mcg/Copegus arm.

Peglntron induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with Peglntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection site pain was infrequent (2 to 3%) in all groups. In Study 3 there was a 23 to 24% incidence overall for injection site reactions or inflammation.

Subjects receiving REBETOL (ribavirin) /Peglntron as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naTve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment, 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations.

Dose modifications of Peglntron and/or ribavirin were required in 25% of subjects due to treatment-related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction.

Adverse reactions that occurred with ≥ 5 10% incidence in the pediatric trial subjects are provided in Table 8.

Table 8: Percentage (%) of Pediatric Subjects With Treatment-Related Adverse Reactions (in at Least 10% of All Subjects)

System Organ Class/ Preferred Term All subjects
(N=107)
Blood and Lymphatic System Disorders
  Neutropenia 33%
  Anemia 11%
  Leukopenia 10%
Gastrointestinal Disorders
  Abdominal Pain 21%
  Abdominal Pain Upper 12%
  Vomiting 27%
  Nausea 18%
General Disorders and Administration Site Conditions
  Pyrexia 80%
  Fatigue 30%
  Injection-Site Erythema 29%
  Chills 21%
  Asthenia 15%
  Irritability 14%
Investigations
  Weight Loss 19%
Metabolism and Nutrition Disorders
  Anorexia 29%
  Decreased Appetite 22%
Musculoskeletal and Connective Tissue Disorders
  Arthralgia 17%
  Myalgia 17%
Nervous System Disorders
  Headache 62%
  Dizziness 14%
Skin and Subcutaneous Tissue Disorders
  Alopecia 17%

Laboratory Values

Adult and Pediatric Subjects

The adverse reaction profile in Study 3, which compared Peglntron/weight-based REBETOL (ribavirin) combination to a Peglntron/flat dose REBETOL (ribavirin) regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions.

Changes in selected laboratory values during treatment in combination with REBETOL (ribavirin) treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see DOSAGE AND ADMINISTRATION]. Changes in selected laboratory values during therapy are described in Table 9. Most of the changes in laboratory values in the Peglntron/REBETOL (ribavirin) study with pediatric were mild or moderate.

Table 9: Selected Laboratory Values During Treatment With REBETOL (ribavirin) Plus Peglntron or REBETOL (ribavirin) Plus INTRON A in Previously Untreated Subjects

Laboratory Parameters* Percent of Subjects
Adults (Study 2) Pediatrics
Peglntron plus REBETOL
(N=511)
INTRON A plus REBETOL
(N=505)
Peglntron plus REBETOL
(N=107)*
Hemoglobin (g/dL)
  9.5- < 11.0 26 27 30
  8.0-O.5 3 3 2
  6.5-7.9 0.2 0.2 -
Leukocytes (x 109/L)
  2.0-2.9 46 41 39
  1.5- < 2.0 24 8 3
  1.0-1.4 5 1 -
Neutrophils (x 109/L)
  1.0-1.5 33 37 35
  0.75- < 1.0 25 13 26
  0.5-O.75 18 7 13
   < 0.5 4 2 3
Platelets (x 109/L)
  70-100 15 5 1
  50- < 70 3 0.8 -
  30-49 0.2 0.2 -
  25- < 50 - - 1
Total Bilirubin (mg/dL) (µmole/L)
  1.5-3.0 10 13 -
  1.26-2.59 x N - - 7
  3.1-6.0 0.6 0.2 -
  2.6-5 x N - - -
  6.1-12.0 0 0.2 -
ALT (U/L)
  2 x Baseline 0.6 0.2 1
  2.1-5 x Baseline 3 1 5
  5.1-10 x Baseline 0 0 3
* The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included.
N=Upper limit of normal.

Hemoglobin. Hemoglobin levels decreased to < 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL (ribavirin) and 33% on flat dose REBETOL (ribavirin) had decreases in hemoglobin levels < 11 g/dl. Reductions in hemoglobin to < 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the Peglntron/REBETOL (ribavirin) and INTRON A/REBETOL (ribavirin) groups. In Study 4, patients receiving Peglntron (1.5 meg/kg)/REBETOL (ribavirin) had decreases in hemoglobin levels to between 8.5 to < 10 g/dL (28%) and to < 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects respectively. Hemoglobin levels become stable by treatment Weeks 4-6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the Peglntron monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see DOSAGE AND ADMINISTRATION].

Neutrophils. Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with REBETOL (ribavirin) in Study 2 (85%) and INTRON A/REBETOL (ribavirin) (60%). Severe potentially life-threatening neutropenia ( < 0.5 x 109/L) occurred in 2% of subjects treated with INTRON A/REBETOL (ribavirin) and in approximately 4% of subjects treated with Peglntron/REBETOL (ribavirin) in Study 2. Eighteen percent of subjects receiving Peglntron/REBETOL (ribavirin) in Study 2 required modification of interferon dosage. Few subjects ( < 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy [see DOSAGE AND ADMINISTRATION].

Platelets. Platelet counts decreased to < 100,000/mm3 in approximately 20% of subjects treated with Peglntron alone or with REBETOL (ribavirin) and in 6% of adult subjects treated with INTRON A/REBETOL (ribavirin) . Severe decreases in platelet counts ( < 50,000/mm3) occur in < 4% of adult subjects. Subjects may require discontinuation or dose modification as a result of platelet decreases [see DOSAGE AND ADMINISTRATION]. In Study 2,1 % or 3% of subjects required dose modification of INTRON A or Peglntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or Peglntron (with or without REBETOL (ribavirin) ) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still had abnormal TSH values.

Bilirubin and uric acid. In Study 2,10 to 14% of subjects developed hyperbilirubinemia and 33 to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.

Clinical Studies Experience - REBETOL (ribavirin) /INTRON A Combination Therapy

Adult Subjects

In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-related adverse reactions that occurred in the US studies with ≥ 5% incidence are provided by treatment group (see Table 10). In general, the selected treatment-related adverse reactions 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.

Pediatric Subjects

In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. In general, the adverse-reaction 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 subjects compared to adult subjects. Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with ≥ 5% incidence among all pediatric subjects who received the recommended dose of REBETOL (ribavirin) /INTRON A combination therapy are provided in Table 10.

Table 10: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects

Patients Reporting Adverse reactions Percentage of Subjects
US Previously Untreated Study US Relapse Study Pediatric Subjects
24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment
INTRON A plus REBETOL
(N=228)
INTRON A plus Placebo
(N=231)
INTRON A plus REBETOL
(N=228)
INTRON A plus Placebo
(N=225)
INTRON A plus REBETOL
(N=77)
INTRON A plus Placebo
(N=76)
INTRON A Plus REBETOL
(N=118)
Application Site Disorders
  Injection Site Inflammation 13 10 12 14 6 8 14
  Injection Site Reaction 7 9 8 9 5 3 19
Body as a Whole - General Disorders
  Headache 63 63 66 67 66 68 69
  Fatigue 68 62 70 72 60 53 58
  Rigors 40 32 42 39 43 37 25
  Fever 37 35 41 40 32 36 61
  Influenza-like Symptoms 14 18 18 20 13 13 31
  Asthenia 9 4 9 9 10 4 5
  Chest Pain 5 4 9 8 6 7 5
Central & Peripheral Nervous System Disorders
  Dizziness 17 15 23 19 26 21 20
Gastrointestinal System Disorders
  Nausea 38 35 46 33 47 33 33
  Anorexia 27 16 25 19 21 14 51
  Dyspepsia 14 6 16 9 16 9 < 1
  Vomiting 11 10 9 13 12 8 42
Musculoskeletal System Disorders
  Myalgia 61 57 64 63 61 58 32
  Arthralgia 30 27 33 36 29 29 15
  Musculoskeletal Pain 20 26 28 32 22 28 21
Psychiatric Disorders
  Insomnia 39 27 39 30 26 25 14
  Irritability 23 19 32 27 25 20 10
  Depression 32 25 36 37 23 14 13
  Emotional Lability 7 6 11 8 12 8 16
  Concentration Impaired 11 14 14 14 10 12 5
  Nervousness 4 2 4 4 5 4 3
Respiratory System Disorders
  Dyspnea 19 9 18 10 17 12 5
  Sinusitis 9 7 10 14 12 7 < 1
Skin and Appendages Disorders
  Alopecia 28 27 32 28 27 26 23
  Rash 20 9 28 8 21 5 17
  Pruritus 21 9 19 8 13 4 12
Special Senses, Other Disorders
  Taste Perversion 7 4 8 4 6 5 1

Subjects reporting one or more adverse reactions. A patient may have reported more than one adverse reaction within a body system/organ class category.

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 11).

Hemoglobin. Hemoglobin decreases among subjects receiving REBETOL (ribavirin) therapy began at Week 1, with stabilization by Week 4. In previously untreated subjects treated for 48 weeks, the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse subjects the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most subjects.

Bilirubin and Uric Acid. Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in subjects with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 11: Selected Hematologic Abnormalities During Treatment With REBETOL (ribavirin) Plus INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects

  Percentage of Subjects
US Previously Untreated Study US Relapse Study Pediatric Subjects
24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment
INTRON A plus REBETOL
(N=228)
INTRON A plus Placebo
(N=231)
INTRON A plus REBETOL
(N=228)
INTRON A plus Placebo
(N=225)
INTRON A plus REBETOL
(N=77)
INTRON A plus Placebo
(N=76)
INTRON A plus REBETOL
(N=118)
Hemoglobin (g/dL)
  9.5 to 10.9 24 1 32 1 21 3 24
  8.0 to 9.4 5 0 4 0 4 0 3
  6.5 to 7.9 0 0 0 0.4 0 0 0
   < 6.5 0 0 0 0 0 0 0
Leukocytes (x109/L)
  2.0 to 2.9 40 20 38 23 45 26 35
  1.5 to 1.9 4 1 9 2 5 3 8
  1.0 to 1.4 0.9 0 2 0 0 0 0
   < 1.0 0 0 0 0 0 0 0
Neutrophils (x109/L)
  1.0 to 1.49 30 32 31 44 42 34 37
  0.75 to 0.99 14 15 14 11 16 18 15
  0.5 to 0.74 9 9 14 7 8 4 16
   < 0.5 11 8 11 5 5 8 3
Platelets (x109/L)
  70 to 99 9 11 11 14 6 12 0.8
  50 to 69 2 3 2 3 0 5 2
  30 to 49 0 0.4 0 0.4 0 0 0
   < 30 0.9 0 1 0.9 0 0 0
Total Bilirubin (mg/dL)
  1 .5 to 3.0 27 13 32 13 21 7 2
  3.1 to 6.0 0.9 0.4 2 0 3 0 0
  6.1 to 12.0 0 0 0.4 0 0 0 0
   > 12.0 0 0 0 0 0 0 0

Postmarketing Experiences

The following adverse reactions have been identified and reported during post approval use of REBETOL (ribavirin) in combination with INTRON A or Peglntron. 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.

Blood and Lymphatic System disorders

Pure red cell aplasia, aplastic anemia

Ear and Labyrinth disorders

Hearing disorder, vertigo

Respiratory, Thoracic and mediastinal disorders

Pulmonary hypertension

Eye disorders

Serous retinal detachment

Endocrine disorders

Diabetes

Read the Rebetol (ribavirin) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Didanosine

Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore, coadministration of REBETOL (ribavirin) Capsules or Oral Solution and didanosine is contraindicated. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials.

Nucleoside Analogues

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 (see Individual NRTI Product Information). 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 cell culture 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.

Drugs Metabolized by Cytochrome P-450

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 (ribavirin) Capsules In a multiple-dose pharmacoklnetlc study.

Azathioprine

The use of ribavirin for the treatment of chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [See WARNINGS AND PRECAUTIONS]

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Pregnancy

REBETOL (ribavirin) Capsules and Oral Solution may cause birth defects and death of the unborn child. REBETOL (ribavirin) 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. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL (ribavirin) has demonstrated significant teratogenic and 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 (ribavirin) therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy [see BOXED WARNING, CONTRAINDICATIONS, Use in Specific Populations, and PATIENT INFORMATION].

Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of REBETOL (ribavirin) /INTRON A-treated subjects in clinical trials. The anemia associated with REBETOL (ribavirin) 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 DOSAGE AND ADMINISTRATION].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by REBETOL (ribavirin) . 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]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use REBETOL (ribavirin) .

Pancreatitis

REBETOL (ribavirin) and INTRON A or Peglntron therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.

Pulmonary Disorders

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during therapy with REBETOL (ribavirin) with alpha interferon combination therapy; 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 therapy should be discontinued.

Ophthalmologic Disorders

Ribavirin is used in combination therapy with alpha interferons. Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by treatment with alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferon treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Laboratory Tests

Peglntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.

Patients on Peglntron/REBETOL (ribavirin) 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 DOSAGE AND ADMINISTRATION].

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 (ribavirin) and interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations If vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Concomitant administration of Azathioprine

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. Peglntron, Rebetol (ribavirin) and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see DRUG INTERACTIONS].

Impact on Growth - Pediatric Use

Data on the effects of Peglntron plus REBETOL (ribavirin) 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 Peglntron plus REBETOL (ribavirin) 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 53rd percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57th percentile). After about 6 months posttreatment, height gain stabilized and subjects treated with Peglntron plus REBETOL (ribavirin) had an average height percentile of 44th percentile, which was less than the average of the normative population and less than their average baseline height (51st percentile). Severely inhibited growth velocity ( < 3rd percentile) was observed in 70% of the subjects while on treatment. Of the subjects experiencing severely inhibited growth, 20% had continued inhibited growth velocity ( < 3rd percentile) after 6 months of follow-up.

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.

Usage Safeguards

Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, REBETOL (ribavirin) Capsules or Oral Solution must not be used alone. The safety and efficacy of REBETOL (ribavirin) Capsules and Oral Solution have only been established when used together with INTRON A or Peglntron (not other interferons) as a combination therapy.

The safety and efficacy of REBETOL (ribavirin) /INTRON A and Peglntron therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. REBETOL (ribavirin) 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 (ribavirin) /INTRON A or Peglntron 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 Peglntron package inserts should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, 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 noncarcinogenic 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 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times 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 teratogenic effects at doses well below the recommended human dose 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 times 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 times the maximum recommended human 24-hour dose of ribavirin) [see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].

Fertile women and partners of fertile women should not receive REBETOL (ribavirin) unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple-dose half-life (t½) of ribavirin of 12 days, effective contraception must be utilized for 6 months post-therapy (e.g., 15 half-lives of clearance for ribavirin).

REBETOL (ribavirin) 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 to 12.5 mg/kg/day, based on body surface area adjustment for a 60-kg adult; 0.1-0.8 times 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.

Use In Specific Populations

Pregnancy - Pregnancy Category X

[See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Nonclinical Toxicology].

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 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times 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 (ribavirin) unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months post-therapy based on a multiple-dose half-life (t½) of ribavirin of 12 days.

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

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 6 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 (ribavirin) 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 (ribavirin) .

PediatricUse

Safety and effectiveness of REBETOL (ribavirin) in combination with Peglntron has not been established in pediatric patients below the age of 3 years. For treatment with REBETOL (ribavirin) /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.

Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see WARNINGS AND PRECAUTIONS]. As in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see WARNINGS AND PRECAUTIONS].

Geriatric Use

Clinical studies of REBETOL (ribavirin) /INTRON A or Peglntron therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

REBETOL (ribavirin) 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 (ribavirin) should not be used in patients with creatinine clearance < 50 mL/min [see CONTRAINDICATIONS].

In general, REBETOL (ribavirin) 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 WARNINGS AND PRECAUTIONS].

Organ Transplant Recipients

The safety and efficacy of INTRON A and Peglntron alone or in combination with REBETOL (ribavirin) for the treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center's previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.

HIV or HBV Co-infection

The safety and efficacy of Peglntron/REBETOL (ribavirin) and INTRON A/REBETOL (ribavirin) for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There is limited experience with overdosage. Acute ingestion of up to 20 g of REBETOL (ribavirin) 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 (ribavirin) . 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 (ribavirin) overdose, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of these agents.

CONTRAINDICATIONS

REBETOL (ribavirin) combination therapy is contraindicated in:

  • women who are pregnant. REBETOL (ribavirin) may cause fetal harm when administered to a pregnant women. REBETOL (ribavirin) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see WARNINGS AND PRECAUTIONS, Use in Specific Populations, and PATIENT INFORMATION]
  • men whose female partners are pregnant
  • patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product
  • patients with autoimmune hepatitis
  • patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
  • patients with creatinine clearance < 50 mL/min. [see Use in Specific Populations and CLINICAL PHARMACOLOGY]
  • Coadministration of REBETOL (ribavirin) and didanosine is contraindicated as because exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin [see DRUG INTERACTIONS].

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Ribavirin is an antiviral agent.

Pharmacokinetics

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 12. 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 AUCtf (AUC from time zero to last measurable concentration) following single doses of 200 to 1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400 to 600 mg.

Upon multiple oral dosing, based on AUC12hr, 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.

Effect of Antacid on Absorption of Ribavirin

Coadministration of REBETOL (ribavirin) Capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta®) resulted in a 14% decrease in mean ribavirin AUQf. The clinical relevance of results from this single-dose study is unknown.

Table 12: Mean (% CV) Pharmacokinetic Parameters for REBETOL (ribavirin) When Administered Individually to Adults

Parameter REBETOL
Single-Dose 600 mg Oral Solution (N=14) Single-Dose 600 mg Capsules (N=12) Multiple-Dose 600 mg Capsules twice daily (N=12)
Tmax (hr) 1.00(34) 1.7(46)* 3(60)
Cmax (ng/mL) 872 (42) 782 (37) 3680 (85)
AUCtf (ng hr/mL) 14,098 (38) 13,400 (48) 228,000 (25)
T1/2 (hr)   43.6 (47) 298 (30)
Apparent Volume of Distribution (L)   2825 (9)  
Apparent Clearance (L/hr)   38.2 (40)  
Absolute Bioavailability   64% (44)  
* N = 11
Data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5
N = 6

Tissue Distribution

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an es-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.

Metabolism and Excretion

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 of 14C-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.

Special Populations

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 AUCtf value 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, AUCtf was twofold greater when compared to control subjects. The increased AUCtf appears to be due to reduction of renal and nonrenal clearance in these subjects. 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 [see CONTRAINDICATIONS].

Hepatic Dysfunction

The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf values 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 Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Elderly Patients

Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender

There were no clinically significant pharmacokinetic differences noted in a single-dose study of 18 male and 18 female subjects.

Pediatric Patients

Multiple-dose pharmacokinetic properties for REBETOL (ribavirin) Capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 13. The pharmacokinetics of REBETOL (ribavirin) and INTRON A (dose-normalized) are similar in adults and pediatric subjects.

Complete pharmacokinetic characteristics of REBETOL (ribavirin) Oral Solution have not been determined in pediatric subjects. Ribavirin Cmin values were similar following administration of REBETOL (ribavirin) Oral Solution or REBETOL (ribavirin) Capsules during 48 weeks of therapy in pediatric patients (3 to 16 years of age).

Table 13: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and REBETOL (ribavirin) Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C

Parameter REBETOL (ribavirin)
15 mg/kg/day as 2 divided doses
(N=17)
INTRON A
3 MIU/m2 three times weekly
(N=54)
Tmax (hr) 1 .9 (83) 5.9 (36)
Cmax (ng/mL) 3275 (25) 51 (48)
AUC* 29774 (26) 622 (48)
Apparent clearance L/hr/kg 0.27 (27) ND
* AUC12 (ng-hr/mL) for REBETOL (ribavirin) ; AUC0-24 (IU-hr/mL) for INTRON A
ND=not done
Note: numbers in parenthesis indicate % coefficient of variation.

A clinical study in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was conducted in which pharmacokinetics for Peglntron and REBETOL (ribavirin) (Capsules and Oral Solution) were evaluated. In pediatric subjects receiving body surface area-adjusted dosing of Peglntron at 60 mcg/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58% [90% Cl: 141 %, 177%] higher than observed in adults receiving 1.5 mcg/kg/week. The pharmacokinetics of REBETOL (ribavirin) (dose-normalized) in this trial were similar to those reported in a prior study of REBETOL (ribavirin) in combination with INTRON A in pediatric subjects and in adults subjects.

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when REBETOL (ribavirin) 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 [see DOSAGE AND ADMINISTRATION].

Microbiology

Mechanism of Action

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

The anti-viral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin. Direct anti-viral activity has been observed in tissue culture of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell containing self-replicating HCV-RNS (HCV replicon cells) or HCV infection.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.

Animal Toxicology and Pharmacology

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.

Clinical Studies

Clinical Study 1 evaluated Peglntron monotherapy. See Peglntron Powder for Injection Package Insert for information about this study.

REBETOL (ribavirin) /Peglntron Combination Therapy

Adult Subjects

Study 2

A randomized study compared treatment with two Peglntron/REBETOL (ribavirin) regimens [Peglntron 1.5 meg/kg subcutaneously once weekly/REBETOL (ribavirin) 800 mg orally daily (in divided doses); Peglntron 1.5 meg/kg subcutaneously once weekly for 4 weeks then 0.5 meg/kg subcutaneously once weekly for 44 weeks/REBETOL (ribavirin) 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU! subcutaneously three times weekly/REBETOL (ribavirin) 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naTve subjects were treated for 48 weeks and followed for 24 weeks posttreatment. Eligible subjects 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 14). The response rate to the Peglntron 1.5 meg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (ribavirin) (see Table 14).The response rate to Peglntron 1.5→0.5 mcg/kg/REBETOL (ribavirin) was essentially the same as the response to INTRON A/REBETOL (ribavirin) (data not shown).

Table 14: Rates of Response to Combination Treatment

  Peglntron 1.5 meg/kg once weekly REBETOL 800 mg once daily INTRON A 3 MIU three times weekly REBETOL 1000/1200 mg once daily
Overall response*, 52% (264/511) 46% (231/505)
Genotype 1 41% (141/348) 33% (11 2/343)
Genotype 2-6 75% (123/1 63) 73% (11 9/1 62)
Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.
Difference in overall treatment response (Peglntron/REBETOL (ribavirin) vs. INTRON A/REBETOL (ribavirin) ) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment.

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to Peglntron (1.5 meg/kg)/REBETOL (ribavirin) (800 mg) compared to subjects with other viral genotypes. Subjects 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 (ribavirin) combination therapy.

Subjects with lower body weight tended to have higher adverse-reaction rates [see ADVERSE REACTIONS] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with Peglntron/REBETOL (ribavirin) combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic subjects 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 in this study.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

Study 3

In a large, United States, community-based study (Study 3), 4913 subjects with chronic hepatitis C were randomized to receive Peglntron 1.5 meg/kg subcutaneously once weekly in combination with a REBETOL (ribavirin) dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on an assay with a lower limit of detection of 125 lU/mL) at 24 weeks posttreatment.

Treatment with Peglntron 1.5 meg/kg and REBETOL (ribavirin) 800 to 1400 mg resulted in a higher sustained virologic response compared to Peglntron in combination with a flat 800 mg daily dose of REBETOL (ribavirin) . Subjects weighing > 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing > 85 to 105 kg (see Table 15). The benefit of WBD in subjects weighing > 85 kg was observed with HCV genotypes 1-3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see ADVERSE REACTIONS].

Table 15: SVR Rate by Treatment and Baseline Weight - Study 3

Treatment Group Subject Baseline Weight
< 65kg
( < 143 Ib)
65-85 kg
(143-188 Ib)
> 85-1 05 kg
( > 188-231 Ib)
> 105 kg
( > 231 Ib)
WBD* 50% (173/348) 45% (449/994) 42% (351/835) 47% (138/292)
Flat 51% (173/342) 44% (443/1 011) 39% (318/819) 33% (91/272)
* p=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and presence/absence of advanced fibrosis, in the model).

A total of 1552 subjects weighing > 65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

Study 4

A large randomized study compared the safety and efficacy of treatment for 48 weeks with two Peglntron/REBETOL (ribavirin) regimens [Peglntron 1.5 meg/kg and 1 meg/kg subcutaneously once weekly both in combination with REBETOL (ribavirin) 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 meg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided doses) in 3070 treatment-naTve adults with chronic hepatitis C genotype 1. In this study, lack of early virologic response by treatment Week 12 (subjects who do not achieve undetectable HCV-RNA or ≥ 2 Iog10 reduction from baseline) was the criteria for discontinuation of treatment. Sustained Virologic Response (SVR) to the treatment was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 lU/mL) at 24 weeks posttreatment [see Table 16].

Table 16: Response Rate by Treatment

Treatment Group % (number) of Patients
Peglntron 1.5 mcg/kg /REBETOL Peglntron 1 mcg/kg REBETOL Pegasys 1 80 mcg/Copegus
SVR 40(406/1019) 38(386/1016) 41 (423/1035)

In all three treatment groups, overall SVR rates were similar. In subjects with poor prognostic factors, subjects randomized to Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) or Pegasys/Copegus achieved higher SVR rates compared to those randomized to the Peglntron 1 mcg/kg/REBETOL (ribavirin) arm. In all arms, SVR rates were lower in subjects with poor prognostic factors compared to those without. For the Peglntron 1.5 meg/kg plus REBETOL (ribavirin) dose, SVR rates for those with and without, respectively, the following baseline factors were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load > 600,000 lU/mL (35% vs. 61%), > 40 years old (38% vs. 50%), and African American subjects (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment week 12 who received Peglntron (1.5 meg/kg)/REBETOL (ribavirin) , the SVR rate was 81 % (328/407).

Study 5 - REBETOL (ribavirin) /Peglntron Combination Therapy in Prior Treatment Failures

In a noncomparative trial, 2293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were re-treated with Peglntron, 1.5 meg/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Eligible patients included prior nonresponders (patients who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (patients who were HCV-RNA negative at the end of a minimum 12 weeks of treatment and subsequently relapsed after posttreatment follow-up). Patients who were negative at Week 12 were treated for 48 weeks and followed for 24 weeks posttreatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment (measured using a research-based test, limit of detection 125 lU/mL). The overall response rate was 22% (497/2293) (99% Cl: 19.5, 23.9). Patients with the following characteristics were less likely to benefit from retreatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

The retreatment sustained virologic response rates by baseline characteristics are summarized in Table 17.

Table 17: SVR Rates by Baseline Characteristics of Prior Treatment Failures

HCV Genotype/ Metavir Fibrosis Score Overall SVR by Previous Response and Treatment
Nonresponder Relapser
alfa interferon/ribavirin % (number of patients) peginterferon (2a and 2b combined)/ribavirin % (number of patients) alfa interferon/ribavirin % (number of patients) peginterferon (2a and 2b combined)/ribavirin % (number of patients)
Overall 18(158/903) 6 (30/476) 43(130/300) 35(113/344)
HCV1 13(98/761) 4(19/431) 32 (67/208) 23 (56/243)
  F2 18(36/202) 6(7/117) 42 (33/79) 32 (23/72)
  F3 16(38/233) 4(4/112) 28(16/58) 21 (14/67)
  F4 7 (24/325) 4 (8/202) 26(18/70) 18(19/104)
HCV 2/3 49(53/109) 36 (10/28) 67(54/81) 57 (52/92)
  F2 68 (23/34) 56 (5/9) 76(19/25) 61 (11/18)
  F3 39(11/28) 38 (3/8) 67(18/27) 62(18/29)
  F4 40(19/47) 18(2/11) 59 (17/29) 51 (23/45)
HCV 4 17 (5/29) 7 (1/15) 88 (7/8) 50 (4/8)

Achievement of an undetectable HCV-RNA at treatment week 12 was a strong predictor of sustained virologic response (SVR). In this trial, 1470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36%) subjects who were HCV-RNA undetectable at treatment week 12, those infected with genotype 1 had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39-55%. Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment week 12 had an overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60-83%. For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

Pediatric Subjects

Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with REBETOL (ribavirin) 15 mg/kg per day plus Peglntron 60 mcg/m2 once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks posttreatment. A total of 107 subjects received treatment of whom 52% were female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with Genotypes 1, 4 or Genotype 3 with HCV-RNA ≥ 600,000 lU/mL received 48 weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA < 600,000 lU/mL received 24 weeks of therapy. The study results are summarized in Table 18.

Table 18: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration - Pediatric Study

Genotype All Subjects
n=107
24 Weeks 48 Weeks
Virologic Response n*, (%) Virologic Response n*,(%)
All 26/27 (96.3) 44/80 (55.0)
1 - 38/72 (52.8)
2 14/15 (93.3) -
3 12/12(100) 2/3 (66.7)
4 - 4/5 (80.0)
*: Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment.
: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
: Subjects with genotype 3 low viral load ( < 600,000 lU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment.

REBETOL (ribavirin) /INTRON A Combination Therapy

Adult Subjects

Previously Untreated Subjects

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 (ribavirin) Capsules 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) plus INTRON A for Injection 3 MIU three times weekly or INTRON A for 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 subjects who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (l+ll+lll) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in Table 19.

Table 19: Virologic and Histologic Responses: Previously Untreated Subjects*

  US Study International Study
24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment
INTRON A plus REBETOL
(N=228)
INTRON A plus Placebo
(N=231)
INTRON A plus REBETOL
(N=228)
INTRON A plus Placebo
(N=225)
INTRON A plus REBETOL
(N=265)
INTRON A plus REBETOL
(N=268)
INTRON A plus Placebo
(N=266)
Virologic Response
  Responder 65 (29) 13 (6) 85 (37) 27 (12) 86 (32) 113(42) 46 (17)
  Nonresponder 147 (64) 194 (84) 110 (48) 168 (75) 158 (60) 120 (45) 196 (74)
  Missing Data 16 (7) 24 (10) 33 (14) 30 (13) 21 (8) 35 (13) 24 (9)
Histologic Response
  Improvement 102 (45) 77 (33) 96 (42) 65 (29) 103 (39) 102 (38) 69 (26)
  No improvement 77 (34) 99 (43) 61 (27) 93(41) 85 (32) 58 (22) 111 (41)
  Missing Data 49(21) 55 (24) 71 (31) 67 (30) 77 (29) 108 (40) 86 (32)
* Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.
Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (l+ll+lll) improvement of 5 2 points.

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

Among subjects with HCV Genotype 1 treated with REBETOL (ribavirin) /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 subjects with HCV nongenotype 1 randomized to REBETOL (ribavirin) /INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Subjects

Subjects 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 (ribavirin) 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) plus INTRON A 3 MIL! three times weekly or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 subjects who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (l+ll+lll) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1). Study results are summarized in Table 20.

Table 20: Virologic and Histologic Responses: Relapse Subjects*

  US Study International Study
INTRON A plus REBETOL
(N=77)
INTRON A plus Placebo
(N=76)
INTRON A plus REBETOL
(N=96)
INTRON A plus Placebo
(N=96)
Virologic Response
  Responder 33 (43) 3(4) 46 (48) 5(5)
  Nonresponder 36 (47) 66 (87) 45 (47) 91 (95)
  Missing Data 8(10) 7(9) 5(5) 0(0)
Histologic Response
  Improvement 38 (49) 27 (36) 49(51) 30(31)
  No improvement 23 (30) 37 (49) 29 (30) 44 (46)
  Missing Data 16(21) 12(16) 18(19) 22 (23)
* Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.
Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (l+ll+lll) improvement of ≥ 2 points.

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

Pediatric Subjects

Pediatric subjects 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 (ribavirin) 15 mg/kg per day plus INTRON A 3 MIU/m2 three times weekly for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 subjects received treatment who were 57% male, 80% Caucasian, and 78% genotype 1. Subjects < 5 years of age received REBETOL (ribavirin) Oral Solution and those ≥ 5 years of age received either REBETOL (ribavirin) Oral Solution or Capsules.

Study results are summarized in Table 21.

Table 21: Virologic Response: Previously Untreated Pediatric Subjects*

  INTRON A 3 MIU/m2 three times weekly plus REBETOL 15 mg/kg/day
Overall Response (N=118) 54 (46)
Genotype 1 (N=92) 33 (36)
Genotype non-1 (N=26) 21 (81)
* Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.

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

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

[See FDA-Approved Medication Guide]

Anemia

The most common adverse experience occurring with REBETOL (ribavirin) Capsules is anemia, which may be severe [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see DOSAGE AND ADMINISTRATION]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Pregnancy

Patients must be informed that REBETOL (ribavirin) Capsules and Oral Solution may cause birth defects and death of the unborn child. REBETOL (ribavirin) 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 (ribavirin) . REBETOL (ribavirin) 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 (ribavirin) 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

If pregnancy does occur during treatment or during 6 months post therapy, the patient must be advised of the teratogenic risk of REBETOL (ribavirin) 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.

Risks versus Benefits

Patients receiving REBETOL (ribavirin) 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.

Patients should be informed about what to do in the event they miss a dose of REBETOL (ribavirin) ; 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.

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

[See FDA-Approved Medication Guide]

Anemia

The most common adverse experience occurring with REBETOL (ribavirin) Capsules is anemia, which may be severe [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see DOSAGE AND ADMINISTRATION]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Pregnancy

Patients must be informed that REBETOL (ribavirin) Capsules and Oral Solution may cause birth defects and death of the unborn child. REBETOL (ribavirin) 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 (ribavirin) . REBETOL (ribavirin) 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 (ribavirin) 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

If pregnancy does occur during treatment or during 6 months post therapy, the patient must be advised of the teratogenic risk of REBETOL (ribavirin) 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.

Risks versus Benefits

Patients receiving REBETOL (ribavirin) 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.

Patients should be informed about what to do in the event they miss a dose of REBETOL (ribavirin) ; 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.

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Rebetol Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

RIBAVIRIN SOLUTION - ORAL

(RYE-ba-VYE-rin)

COMMON BRAND NAME(S): Rebetol

WARNING: Ribavirin may cause birth defects and/or death in unborn babies that are exposed to it during pregnancy. If you or your sexual partner are or may be pregnant, do not take ribavirin, and contact your doctor immediately. Women and men who are taking ribavirin must avoid pregnancy by using two forms of reliable birth control (such as latex condoms and birth control pills) during treatment with this drug and for 6 months after this medication has been stopped. Consult your doctor or pharmacist for more information.

Patients with certain types of heart disease should not use ribavirin because it can lower your red blood cell level (anemia). This may worsen your condition and can lead to a possibly fatal heart attack. Before using this medication, tell your doctor if you have had any heart problems or chest pain.

Ribavirin should never be used alone to treat hepatitis C infections.

USES: This medication is an antiviral used in combination with interferon to treat ongoing hepatitis C. Long-term hepatitis C infection causes liver swelling that can lead to serious liver conditions such as scarring, cancer, and organ failure. Ribavirin works by reducing the amount of hepatitis C virus in your body, which may help your liver recover. However, this drug is not a cure for hepatitis C infection, and it does not prevent the spread of Hepatitis C to others through sexual contact or blood contamination (e.g., sharing used needles).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat severe acute respiratory syndrome (SARS).

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using ribavirin and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Measure the dose out carefully with a medication spoon/cup. Take this medication by mouth, usually twice daily for 24 to 48 weeks or as directed by your doctor. You may take this medication with or without food, but it is important to choose one way and take this medication the same way with every dose. If you are taking ribavirin with peginterferon, take ribavirin with food.

The dosage and length of treatment is based on your age, weight, medical condition, and response to therapy.

Antiviral medications work best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, use it at the same times each day.

Drink plenty of water while being treated with this medication. Doing so will decrease the risk of serious side effects.

Disclaimer

Rebetol Consumer (continued)

SIDE EFFECTS: Nausea, diarrhea, stomach upset, headache, dizziness, blurred vision, trouble sleeping, flu-like symptoms (e.g., fever, chills, sore throat, muscle aches), cough, hair loss, low appetite, weight loss or gain, dry skin, and changes in taste/hearing may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tooth and gum problems may sometimes occur during ribavirin/interferon treatment. Dry mouth can worsen this side effect. Prevent dry mouth by drinking plenty of water or by using a saliva substitute. Brush your teeth well at least twice daily and see your dentist regularly. If you experience vomiting during treatment, rinse out your mouth afterwards to reduce tooth and gum problems.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual tiredness/weakness, fast/pounding/irregular heartbeat, trouble breathing, mental/mood changes (e.g., severe depression, suicidal thoughts), muscle/joint pain, vision changes, easy bruising/bleeding, dark urine, yellowing of eyes/skin.

Seek immediate medical attention if any of these unlikely but very serious side effects occurs: chest pain, jaw/left arm pain, stomach/lower back pain, black/bloody stools.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Rebetol (ribavirin) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking ribavirin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: other types of hepatitis (e.g., autoimmune hepatitis), blood disorders (e.g., sickle cell anemia, low hemoglobin, thalassemia), kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other liver problems, heart disease, high blood pressure, breathing problems, pancreas problems (e.g., pancreatitis), diabetes.

This drug may make you dizzy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for anemia while using this drug.

Children may be at greater risk for mental/mood changes, including severe depression or suicidal thoughts, while using this drug. Ribavirin/interferon treatment may also slow down a child's rate of growth. It is not known if this will affect final adult height. Monitor your child's height periodically during treatment.

Ribavirin must not be used during pregnancy. It is recommended that female patients or female partners of male patients take a pregnancy test before this medication is started, during treatment, and for 6 months after this drug is stopped. If you become pregnant or think you may be pregnant, inform your doctor immediately. See Warnings for additional information.

It is not known whether this drug passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this medication is not recommended.

Disclaimer

Rebetol Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal medication you may use, especially of: antacids, certain anti-HIV drugs (e.g., NRTIs such as lamivudine, stavudine, zidovudine), didanosine.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., pregnancy, blood counts/hemoglobin, liver function, thyroid function, heart function/EKG, eye exams) should be performed periodically to monitor your progress or check for side effects.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) or in the refrigerator at 36-46 degrees F (2-8 degrees C) away from light and moisture. Do not freeze. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Rebetol Patient Information Including Side Effects

Brand Names: Copegus, Rebetol, RibaPak, Ribasphere, RibaTab

Generic Name: ribavirin (oral) (Pronunciation: rye ba VYE rin)

What is ribavirin (Rebetol)?

Ribavirin is an antiviral medication.

Ribavirin must be used together with an interferon alfa product (such as Pegasys, PegIntron, Sylatron, or Intron A) to treat chronic hepatitis C.

Ribavirin may also be used for purposes not listed in this medication guide.

Copegus 200 mg

oval, pink, imprinted with RIB 200, ROCHE

Ribavirin 200 mg Tab-TEV

round, peach, imprinted with 93, 7232

Ribavirin 200 mg-TEV

white, imprinted with 93 7227

What are the possible side effects of ribavirin (Rebetol)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using ribavirin and call your doctor at once if you have a serious side effect such as:

  • problems with your vision;
  • fever, chills, body aches, flu symptoms;
  • severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
  • stabbing chest pain, wheezing, feeling short of breath;
  • severe depression, hallucinations, thoughts of suicide or hurting yourself;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; or
  • pale or yellowed skin, dark colored urine, easy bruising or bleeding, confusion, or unusual weakness.

Less serious side effects may include:

  • headache;
  • muscle pain;
  • dry mouth;
  • nausea; vomiting, stomach pain, loss of appetite;
  • weight loss;
  • feeling tired or irritable;
  • anxiety, mood changes; or
  • pain, swelling, or irritation where the interferon injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Rebetol (ribavirin) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about ribavirin (Rebetol)?

You should not take ribavirin if you are allergic to it, or if you have severe liver disease, autoimmune hepatitis, a hemoglobin disorder (anemia, thalassemia, and others), if you are also taking didanosine (Videx), or if you are pregnant woman, or a man whose female sexual partner is pregnant.

If you are a woman, do not take ribavirin if you are pregnant.

If you are a man, do not take ribavirin if your female sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin.

Use at least two effective forms of birth control while either sexual partner is taking ribavirin, and for at least 6 months after treatment ends. Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking ribavirin.

Ribavirin may decrease the number of red blood cells in your body. This is called anemia and it can be life-threatening in people who have heart disease or circulation problems. Your blood will need to be tested often. Your vision, liver function, and thyroid function may also need to be tested. Visit your doctor regularly.

Call your doctor at once if you have pale or yellowed skin, dark colored urine, fever, confusion, chest pain, weakness, or trouble breathing.

Side Effects Centers

Rebetol Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking ribavirin (Rebetol)?

You should not take ribavirin if you are allergic to it, or if you have:

  • severe liver disease (especially cirrhosis);
  • autoimmune hepatitis;
  • a hemoglobin disorder such as anemia, thalassemia (Mediterranean anemia), or sickle-cell anemia;
  • if you are also taking didanosine (Videx); or
  • if you are pregnant woman, or a man whose female sexual partner is pregnant.

To make sure you can safely take ribavirin, tell your doctor if you have any of these other conditions:

  • kidney or liver disease (other than hepatitis C);
  • hepatitis B infection;
  • a blood cell disorder such as hemolytic anemia (a lack of red blood cells);
  • human immunodeficiency virus (HIV or AIDS);
  • diabetes;
  • a pancreas disorder;
  • sarcoidosis;
  • breathing problems;
  • a thyroid disorder;
  • new or worsening eye problems (such as retinopathy);
  • a history of heart disease, high blood pressure, or a heart attack;
  • a history of depression or suicide attempt;
  • a history of a liver, kidney, or other organ transplant; or
  • if you have ever received treatment for hepatitis C that did not work well.
  • If you are a woman, do not take ribavirin if you are pregnant. You will need frequent pregnancy tests to make sure you are not pregnant while taking ribavirin.
  • If you are a man, do not take ribavirin if your female sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin. Your sexual partner will need frequent pregnancy tests to make sure she is not pregnant while you are taking ribavirin.
  • Use at least two effective forms of birth control while either sexual partner is taking ribavirin, and for at least 6 months after treatment ends.
  • Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking ribavirin.

Your name may need to be listed on a ribavirin pregnancy registry if you become pregnant while you or your male sexual partner are taking this medication or during the 6 months after treatment ends. This is to track the outcome of the pregnancy and to evaluate any effects of ribavirin on the baby.

It is not known whether ribavirin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking ribavirin.

Ribavirin may affect growth in children.

How should I take ribavirin (Rebetol)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take this medicine with food.

Measure the liquid form of ribavirin with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Ribavirin may decrease the number of red blood cells in your body. This is called anemia and it can be life-threatening in people who have heart disease or circulation problems. Your blood will need to be tested often. Your vision, liver function, and thyroid function may also need to be tested. Visit your doctor regularly.

Call your doctor at once if you have pale or yellowed skin, dark colored urine, fever, confusion, chest pain, shortness of breath, or weakness. These may be signs of serious anemia.

Use ribavirin regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Drink extra fluids while you are taking ribavirin to keep from getting dehydrated, especially during exercise or in hot weather.

Ribavirin can cause dry mouth, which could lead to tooth decay or gum disease. If you vomit while taking ribavirin, rinse your mouth out with water to prevent damage to your teeth or gums. Be sure to have regular dental exams while you are taking this medication.

Store ribavirin tablets and capsules at room temperature away from moisture, heat, and light.

Store ribavirin liquid (oral solution) in the refrigerator. Do not allow it to freeze.

Side Effects Centers

Rebetol Patient Information including If I Miss a Dose

What happens if I miss a dose (Rebetol)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. If you have not taken the medication for longer than 24 hours, call your doctor for instructions. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Rebetol)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include easy bruising or bleeding, urinating less than usual or not at all, chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, or a general ill feeling.

What should I avoid while taking ribavirin (Rebetol)?

Treatment with ribavirin does not prevent spread of the hepatitis C virus to other people. Follow your doctor's instructions about how to prevent passing the disease to another person.

Avoid drinking alcohol. It may increase your risk of liver damage.

Ribavirin may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What other drugs will affect ribavirin (Rebetol)?

Tell your doctor about all other medicines you use, especially:

  • abacavir (Ziagen);
  • azathiopriine (Azasan, Imuran);
  • lamivudine (Combivir, Epivir, Epzicom, Trizivir);
  • stavudine (Zerit);
  • tenofovir (Viread);
  • zalcitabine (Hivid); or
  • zidovudine (Retrovir, AZT).

This list is not complete and other drugs may interact with ribavirin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about ribavirin.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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