Rebetol

REBETOL®
(ribavirin USP)

DESCRIPTION

REBETOL (ribavirin), is 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

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

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

INDICATIONS

Chronic Hepatitis C (CHC)

REBETOL® (ribavirin) in combination with interferon alfa-2b (pegylated and nonpegylated) is indicated for the treatment of Chronic Hepatitis C (CHC) 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 combination therapy with PegIntron® 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/PegIntron is preferred over REBETOL/INTRON A as this combination provides substantially better response rates [see Clinical Studies].
• Patients with the following characteristics are less likely to benefit from re-treatment 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 capsules be opened, crushed, or broken. REBETOL should be taken with food [see CLINICAL PHARMACOLOGY]. REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.

REBETOL/PegIntron Combination Therapy

Adult Patients

The recommended dose of PegIntron is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg REBETOL capsules orally based on patient body weight (see Table 1). The volume of PegIntron to be injected depends on the strength of PegIntron and patient's body weight, refer to labeling for PegIntron for additional dosing information.

Duration of Treatment – Interferon Alpha-naïve 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 log₁₀ 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 – Re-treatment with PegIntron/REBETOL 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 Dosing for REBETOL in Combination Therapy with PegIntron (Adults)

Body Weight kg (lbs)	REBETOL Daily Dose	REBETOL Number of Capsules
< 66 ( < 144)	800 mg/day	2 x 200-mg capsules A.M. 2 x 200-mg capsules P.M.
66-80 (145-177)	1000 mg/day	2 x 200-mg capsules A.M. 3 x 200-mg capsules P.M.
81-105 (178-231)	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.

Pediatric Patients

Dosing for pediatric patients is determined by body surface area for PegIntron and by body weight for REBETOL. The recommended dose of PegIntron is 60 mcg/m²/week subcutaneously in combination with 15 mg/kg/day of REBETOL orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving PegIntron/REBETOL 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* Dosing in Combination Therapy (Pediatrics)

Body Weight kg (lbs)	REBETOL Daily Dose	REBETOL Number of Capsules
< 47 ( < 103)	15 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 to be used in combination with PegIntron 60 mcg/m² weekly. † REBETOL Oral Solution may be used for any patient regardless of body weight.

REBETOL/INTRON A Combination Therapy

Adults

Duration of Treatment – Interferon Alpha-naïve Patients

The recommended dose of INTRON A is 3 million IU three times weekly subcutaneously. The recommended dose of REBETOL 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 AND USAGE, 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 – Re-treatment with INTRON A/REBETOL 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
≤ 75 kg	2 x 200-mg capsules AM 3 x 200-mg capsules PM daily orally
> 75 kg	3 x 200-mg capsules AM 3 x 200-mg capsules PM daily orally

Pediatrics

The recommended dose of REBETOL is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of REBETOL 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 greater than 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, 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/INTRON A therapy or REBETOL/PegIntron therapy, modify, 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 PegIntron in adult patients on REBETOL/PegIntron combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Refer to labeling for PegIntron for additional information regarding dose reduction of PegIntron.

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

Dose reduction in pediatric patients is accomplished by modifying the recommended PegIntron dose in a two-step process from the original starting dose of 60 mcg/m²/week, to 40 mcg/m²/week, then to 20 mcg/m²/week, if needed (see Table 4). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving PegIntron 60 mcg/m² weekly and REBETOL 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended REBETOL dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 4).

REBETOL should not be used in patients with creatinine clearance less than 50 mL/min. Patients 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 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 greater than or equal to 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains less than 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 dose modified or discontinued per Table 4 [see WARNINGS AND PRECAUTIONS].

Table 4: Guidelines for Dose Modification and Discontinuation of REBETOL in combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and Pediatrics

Laboratory Parameters	Reduce REBETOL Daily Dose (see note 1) if:	Reduce PegIntron or INTRON A Dose (see note 2) if:	Discontinue Therapy if:
WBC	N/A	1.0 to < 1.5 x 109/L	< 1.0 x 109/L
Neutrophils	N/A	0.5 to < 0.75 x 109/L	< 0.5 x 109/L
Platelets	N/A	25 to < 50 x 109/L (adults)	< 25 x 109/L (adults)
	N/A	50 to < 70 x 109/L (pediatrics)	< 50 x 109/L (pediatrics)
Creatinine	N/A	N/A	> 2 mg/dL (pediatrics)
Hemoglobin in patients without history of cardiac disease	8.5 to < 10 g/dL	N/A	< 8.5 g/dL
	Reduce REBETOL Dose by 200 mg/day and PegIntron or INTRON A Dose by Half if:
Hemoglobin in patients with history of stable cardiac disease*†	> 2 g/dL decrease in hemoglobin during any four week period during treatment		< 8.5 g/dL or < 12 g/dL after four weeks of dose reduction
Note 1: Adult patients: 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. Pediatric patients: 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day. Note 2: Adult patients treated with REBETOL and PegIntron: 1st dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2nd dose reduction of PegIntron is to 0.5 mcg/kg/week. Pediatric patients treated with REBETOL and PegIntron: 1st dose reduction of PegIntron is to 40 mcg/m²/week, 2nd dose reduction of PegIntron is to 20 mcg/m²/week. For patients on REBETOL/INTRON A combination therapy: reduce INTRON A dose by 50%. * Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing. † These guidelines are for patients with stable cardiac disease. Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron /REBETOL combination therapy [see WARNINGS AND PRECAUTIONS].

Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an INTRON A or PegIntron dose.

Discontinuation Of Dosing

Adults

In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron in combination with ribavirin, discontinuation of therapy is recommended if there is not at least a 2 log₁₀ drop or loss of HCV-RNA at 12 weeks of therapy, or if HCV-RNA levels remain detectable 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 PegIntron/REBETOL combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped less than 2 log₁₀ compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.

HOW SUPPLIED

Dosage Forms And Strengths

REBETOL Capsules 200 mg

REBETOL Oral Solution 40 mg per mL

Storage And Handling

REBETOL 200 mg Capsules are white, opaque capsules with REBETOL, 200 mg, and the Schering Corporation logo imprinted on the capsule shell; the capsules are packaged in a bottle containing 56 capsules (NDC 0085-1351-05), 70 capsules (NDC 0085-1385-07), and 84 capsules (NDC 0085-1194-03).

REBETOL Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble gum-flavored liquid and it is packaged in 4-oz amber glass bottles (100 mL/bottle) with child-resistant closures (NDC 0085-1318-01).

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

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

REBETOL Oral Solution manufactured for: Merck Sharp & Dohme Corp., a subsidiary of Whitehouse Station, NJ 08889, USA. Manufactured by: Schering-Plough Canada, Inc.,  Pointe Claire, Quebec, Canada REBETOL Capsules manufactured by: Merck Sharp & Dohme Corp., a subsidiary of Whitehouse Station, NJ 08889, USA. Revised: Dec 2014.

SIDE EFFECTS

Clinical trials with REBETOL in combination with PegIntron or INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age.

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [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 PegIntron or INTRON A in combination with REBETOL were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving REBETOL in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The Adverse Reactions section references the following clinical trials:

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

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without REBETOL [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. The most common serious events occurring in subjects treated with PegIntron and REBETOL 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 PegIntron and REBETOL 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience – REBETOL/PegIntron Combination Therapy

Adult Subjects

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

Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects

Adverse Reactions	Percentage of Subjects Reporting Adverse Reactions*		Adverse Reactions	Percentage of Subjects Reporting Adverse Reactions*
	PegIntron 1.5 mcg/kg/ REBETOL (N=511)	INTRON A/ REBETOL (N=505)		PegIntron 1.5 mcg/kg/ REBETOL (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	47	47
			Lability/Irritability
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 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence.

Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By Descending Frequency

Adverse Reactions	Study 4 Percentage of Subjects Reporting Treatment-Related Adverse Reactions
	PegIntron 1.5 mcg/kg with REBETOL (N=1019)	PegIntron 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 trials. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and for the flat-dose REBETOL regimen. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/REBETOL groups compared to 14% in the INTRON A/REBETOL 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 PegIntron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects, weight loss, fatigue, and headache had not resolved.

There have been 31 subject deaths that occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron 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 PegIntron/REBETOL combination therapy; and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). 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 PegIntron/REBETOL combination therapy, 5 in the PegIntron 1.5 mcg/REBETOL arm (N=1019) and 1 in the PegIntron 1 mcg/REBETOL arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035); there were 3 suicides that occurred during the off treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/REBETOL combination therapy.

In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based REBETOL and 14% of subjects receiving PegIntron and flat dose REBETOL 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 PegIntron 1.5 mcg/REBETOL arm, 10% in the PegIntron 1 mcg/REBETOL 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 PegIntron (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PegIntron 1.5 mcg/kg greater than PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL 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 weight-based dosing (WBD) compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 mcg/week with Pegasys.

In the PegIntron/REBETOL 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 PegIntron 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm.

PegIntron 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) tended to decrease as treatment continued. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron 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/PegIntron as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naïve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric trial, 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 trial 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, three with clinical hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lagged behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment.

Dose modifications of PegIntron 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 a greater than or equal to 10% incidence in the pediatric trial subjects are provided in Table 7.

Table 7: 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%

Ninety-four of 107 subjects enrolled in a 5 year long-term follow-up trial. The long-term effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to correlate with initiation of combination therapy during the years of expected peak growth velocity. [See WARNINGS AND PRECAUTIONS]

Laboratory Values

Adult and Pediatric Subjects

The adverse reaction profile in Study 3, which compared PegIntron/weight-based REBETOL combination to a PegIntron/flat dose REBETOL 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 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 8. Most of the changes in laboratory values in the PegIntron/REBETOL trial with pediatrics were mild or moderate.

Table 8: Selected Laboratory Abnormalities During Treatment with REBETOL and PegIntron or REBETOL and INTRON A in Previously Untreated Subjects

Laboratory Parameters*	Percentage of Subjects
	Adults (Study 2)		Pediatrics
	PegIntron/ REBETOL (N=511)	INTRON A/ REBETOL (N=505)	PegIntron/ REBETOL (N=107)*
Hemoglobin (g/dL)
9.5 to < 11.0	26	27	30
8.0 to < 9.5	3	3	2
6.5-7.9	0.2	0.2	-
Leukocytes (x 109/L)
2.0-2.9	46	41	39
1.5 to < 2.0	24	8	3
1.0-1.4	5	1	-
Neutrophils (x 109/L)
1.0-1.5	33	37	35
0.75 to < 1.0	25	13	26
0.5 to < 0.75	18	7	13
< 0.5	4	2	3
Platelets (x 109/L)
70-100	15	5	1
50 to < 70	3	0.8	-
30-49	0.2	0.2	-
25 to < 50	-	-	1
Total Bilirubin	(mg/dL)		(μmole/L)
1.5-3.0	10	13	-
1.26-2.59 x ULN†	-	-	7
3.1-6.0	0.6	0.2	-
2.6-5 x ULN†	-	-	-
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. † ULN=Upper limit of normal.

Hemoglobin

Hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in hemoglobin levels less than 11 g/dl. Reductions in hemoglobin to less than 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 PegIntron/REBETOL and INTRON A/REBETOL groups. In Study 4, subjects receiving PegIntron (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 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 became 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 PegIntron 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 in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (less than 0.5 x 10⁹/L) occurred in 2% of subjects treated with INTRON A/REBETOL and in approximately 4% of subjects treated with PegIntron/REBETOL in Study 2. Eighteen percent of subjects receiving PegIntron/REBETOL in Study 2 required modification of interferon dosage. Few subjects (less than 1%) required permanent discontinuation of treatment. Neutrophil counts generally returned to pre-treatment levels 4 weeks after cessation of therapy [see DOSAGE AND ADMINISTRATION].

Platelets

Platelet counts decreased to less than 100,000/mm³ in approximately 20% of subjects treated with PegIntron alone or with REBETOL and in 6% of adult subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (less than 50,000/mm³) occur in less than 4% of adult subjects. Patients 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 PegIntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Thyroid Function

Development of TSH abnormalities, with or without clinical manifestations, is associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with either INTRON A or PegIntron (with or without REBETOL) 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 Trials Experience – REBETOL/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 trials with greater than or equal to 5% incidence are provided by treatment group (see Table 9). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international trials as compared to the US trials, 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 greater than or equal to 5% incidence among all pediatric subjects who received the recommended dose of REBETOL/INTRON A combination therapy are provided in Table 9.

Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects

Subjects 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/REBETOL (N=228)	INTRON A/Placebo (N=231)	INTRON A/REBETOL (N=228)	INTRON A/Placebo (N=225)	INTRON A/REBETOL (N=77)	INTRON A/Placebo (N=76)	INTRON A/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 subject may have reported more than one adverse reaction within a body system/organ class category.

During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment period. Long-term data in a limited number of patients, however, suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients [see WARNINGS AND PRECAUTIONS].

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 10).

Hemoglobin. Hemoglobin decreases among subjects receiving REBETOL 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 trial and 2.9 g/dL in the international trial. In relapse subjects, the mean maximum decrease from baseline was 2.8 g/dL in the US trial and 2.6 g/dL in the international trial. 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 occurred most frequently in subjects with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 10: Selected Laboratory Abnormalities During Treatment With REBETOL and 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/REBETOL (N=228)	INTRON A/Placebo (N=231)	INTRONA/ REBETOL (N=228)	INTRON A/Placebo (N=225)	INTRON A/REBETOL (N=77)	INTRON A/Placebo (N=76)	INTRON A/ 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 (x 109/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 (x 109/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 (x 109/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 in combination with INTRON A or PegIntron. 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

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 capsules or oral solution and didanosine is contraindicated. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/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 population. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatmentassociated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate (see labeling for individual NRTI product). 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 greater than 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 in 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 P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A and REBETOL capsules in a multiple-dose pharmacokinetic 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].

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Pregnancy

REBETOL capsules and oral solution may cause birth defects and death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL 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 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/INTRON A-treated subjects in clinical trials. The anemia associated with REBETOL capsules occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained before the start of treatment 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. 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.

Pancreatitis

REBETOL and INTRON A or PegIntron 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 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

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

Patients on PegIntron/REBETOL combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood counts (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 and pegylated or nonpegylated 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. PegIntron, REBETOL, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be reintroduced with concomitant azathioprine [see DRUG INTERACTIONS].

Impact On Growth - Pediatric Use

Data on the effects of PegIntron and REBETOL on growth come from an open-label study in subjects 3 through 17 years of age, in which weight and height changes are compared to US normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron and REBETOL lags behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3^rd percentile) was observed in 70% of the subjects while on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with REBETOL may induce a growth inhibition that results in reduced adult height in some patients [see ADVERSE REACTIONS].

Similarly, an impact on growth was seen in subjects after treatment with REBETOL and INTRON A combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects, combination therapy resulted in reduced final adult height in some subjects [see ADVERSE REACTIONS].

Usage Safeguards

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

The safety and efficacy of REBETOL/INTRON A and PegIntron therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. REBETOL capsules should not be used for these indications. Ribavirin for inhalation has separate labeling, which should be consulted if ribavirin inhalation therapy is being considered.

There are significant adverse reactions caused by REBETOL/INTRON A or PegIntron therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. Labeling for INTRON A and PegIntron should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

Patient Counseling Information

Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide).

Anemia

The most common adverse experience occurring with REBETOL 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 capsules and oral solution may cause birth defects and death of the unborn child. REBETOL must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking REBETOL. REBETOL should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months post therapy.

Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during REBETOL and for 6 months post therapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy [see 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 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. Prescribers should report such cases by calling 1-800-593-2214.

Risks Versus Benefits

Patients receiving REBETOL capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient Medication Guide. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

Patients should be informed about what to do in the event they miss a dose of REBETOL; the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to contact their healthcare provider if they have questions.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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).

Mutagenesis

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 unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple-dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months post-therapy (e.g., 15 half-lives of clearance for ribavirin).

REBETOL should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 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 Post-treatment:

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 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 (t1/2) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with REBETOL and for the 6- month 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 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.

Pediatric Use

Safety and effectiveness of REBETOL in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with REBETOL/INTRON A, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the safety findings observed.

Long-term follow-up data in pediatric subjects indicates that REBETOL in combination with PegIntron or with INTRON A may induce a growth inhibition that results in reduced height in some patients [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

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 trials of REBETOL/INTRON A or PegIntron therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

REBETOL is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments should be made accordingly. REBETOL should not be used in patients with creatinine clearance less than 50 mL/min [see CONTRAINDICATIONS].

In general, REBETOL capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than younger patients (28%) [see WARNINGS AND PRECAUTIONS].

Organ Transplant Recipients

The safety and efficacy of INTRON A and PegIntron alone or in combination with REBETOL 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 PegIntron/REBETOL and INTRON A/REBETOL for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

OVERDOSE

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

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

CONTRAINDICATIONS

REBETOL combination therapy is contraindicated in:

• women who are pregnant. REBETOL may cause fetal harm when administered to a pregnant woman. REBETOL is contraindicated in women who are or may become pregnant. If REBETOL is used during pregnancy, or if the patient becomes pregnant while taking REBETOL, the patient should be apprised of the potential hazard to her 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 less than 50 mL/min. [see Use in Specific Populations and CLINICAL PHARMACOLOGY]
• Coadministration of REBETOL and didanosine is contraindicated because exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) is increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving didanosine in combination with ribavirin [see DRUG INTERACTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ribavirin is an antiviral agent [see Microbiology].

Pharmacokinetics

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. 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 capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

Table 11: Mean (% CV) Pharmacokinetic Parameters for REBETOL 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)
T½ (hr)		43.6 (47)	298 (30)
Apparent Volume of Distribution (L)		2825 (9)1
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 greater than 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 3 efficacy trials included subjects with creatinine clearance values greater than 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 less than 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 trial of 18 male and 18 female subjects.

Pediatric Patients

Multiple-dose pharmacokinetic properties for REBETOL capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric subjects.

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

Table 12: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and REBETOL Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C

Parameter	REBETOL 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*	29,774 (26)	622 (48)
Apparent Clearance L/hr/kg	0.27 (27)	ND†
* AUC12 (ng·hr/mL) for REBETOL; AUC0-24 (IU·hr/mL) for INTRON A. † ND=not done. Note: numbers in parenthesis indicate % coefficient of variation.

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

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when REBETOL capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study [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 antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin. Direct antiviral 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 ribavirintreated 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 PegIntron monotherapy. See PegIntron labeling for information about this trial.

REBETOL/PegIntron Combination Therapy

Adult Subjects

Study 2

A randomized trial compared treatment with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg subcutaneously once weekly/REBETOL 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44 weeks/REBETOL 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously three times weekly/REBETOL 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks post-treatment. 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 post-treatment (see Table 13). The response rate to the PegIntron 1.5 mcg/kg and ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (see Table 13).The response rate to PegIntron 1.5→0.5 mcg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Table 13: Rates of Response to Combination Treatment – Study 2

	PegIntron 1.5 mcg/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% (112/343)
Genotype 2-6	75% (123/163)	73% (119/162)
* Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory. † Difference in overall treatment response (PegIntron/REBETOL vs. INTRON A/REBETOL) 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 post-treatment.

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5 mcg/kg)/REBETOL (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 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 PegIntron/REBETOL 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 trial.

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 trial, 4913 subjects with chronic hepatitis C were randomized to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a REBETOL 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 IU/mL) at 24 weeks post-treatment.

Treatment with PegIntron 1.5 mcg/kg and REBETOL 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron in combination with a flat 800 mg daily dose of REBETOL. Subjects weighing greater than 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing greater than 85 to 105 kg (see Table 14). The benefit of WBD in subjects weighing greater than 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 14: SVR Rate by Treatment and Baseline Weight - Study 3

Treatment Group	Subject Baseline Weight
	< 65 kg ( < 143 lb)	65-85 kg (143-188 lb)	> 85-105 kg ( > 188-231 lb)	> 105 kg ( > 231 lb)
WBD*	50% (173/348)	45% (449/994)	42% (351/835)	47% (138/292)
Flat	51% (173/342)	44% (443/1011)	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 greater than 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 trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in combination with REBETOL 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided doses) in 3070 treatment-naïve adults with chronic hepatitis C genotype 1. In this trial, lack of early virologic response (undetectable HCV-RNA or greater than or equal to 2 log₁₀ reduction from baseline) by treatment Week 12 was the criterion for discontinuation of treatment. SVR was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24 weeks post-treatment (see Table 15).

Table 15: SVR Rate by Treatment – Study 4

% (number) of Subjects
PegIntron 1.5 mcg/kg/REBETOL	PegIntron 1 mcg/kg/REBETOL	Pegasys 180 mcg/Copegus
40 (406/1019)	38 (386/1016)	41 (423/1035)

Overall SVR rates were similar among the three treatment groups. Regardless of treatment group, SVR rates were lower in subjects with poor prognostic factors. Subjects with poor prognostic factors randomized to PegIntron (1.5 mcg/kg)/REBETOL or Pegasys/Copegus, however, achieved higher SVR rates compared to similar subjects randomized to PegIntron 1 mcg/kg/REBETOL. For the PegIntron 1.5 mcg/kg and REBETOL dose, SVR rates for subjects with and without the following prognostic factors were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load greater than 600,000 IU/mL (35% vs. 61%), 40 years of age and older (38% vs. 50%), and African American race (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment Week 12 who received PegIntron (1.5 mcg/kg)/REBETOL, the SVR rate was 81% (328/407).

Study 5 - REBETOL/PegIntron Combination Therapy in Prior Treatment Failures

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

The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table 16.

Table 16: SVR Rates by Baseline Characteristics of Prior Treatment Failures - Study 5

HCV Genotype/ Metavir Fibrosis Score	Overall SVR by Previous Response and Treatment
	Nonresponder		Relapser
	interferon alfa/ribavirin % (number of subjects)	peginterferon (2a and 2b combined)/ribavirin % (number of subjects)	interferon alfa/ribavirin % (number of subjects)	peginterferon (2a and 2b combined)/ribavirin % (number of subjects)
Overall	18 (158/903)	6 (30/476)	43 (130/300)	35 (113/344)
HCV 1	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 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 15 mg/kg per day and PegIntron 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 post-treatment. A total of 107 subjects received treatment, of which 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 greater than or equal to 600,000 IU/mL received 48 weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA less than 600,000 IU/mL received 24 weeks of therapy. The trial results are summarized in Table 17.

Table 17: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration – Pediatric Trial

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 post-treatment. † N=number of responders/number of subjects with given genotype, and assigned treatment duration. ‡ Subjects with genotype 3 low viral load (less than 600,000 IU/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/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 capsules 1200 mg/day (1000 mg/day for subjects weighing less than or equal to 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The international trial did not contain a 24-week INTRON A and placebo treatment arm. The US trial enrolled 912 subjects who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The international trial, conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Trial results are summarized in Table 18.

Table 18: Virologic and Histologic Responses: Previously Untreated Subjects*

	US Trial				International Trial
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment	48 weeks of treatment
	INTRON A/ REBETOL (N=228)	INTRON A/ Placebo (N=231)	INTRON A/ REBETOL (N=228)	INTRON A/ Placebo (N=225)	INTRON A/ REBETOL (N=265)	INTRON A/ REBETOL (N=268)	INTRON A/ 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 post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 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/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among subjects with HCV Genotype 1 treated with REBETOL/INTRON A therapy who achieved HCV-RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24-week treatment group. There was no observed increase in response rates for subjects with HCV non-genotype 1 randomized to REBETOL/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 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US trial enrolled 153 subjects who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The international trial, conducted in Europe, Israel, Canada, and Australia, enrolled 192 subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).  Trial results are summarized in Table 19.

Table 19: Virologic and Histologic Responses: Relapse Subjects*

	US Trial		International Trial
	INTRON A/ REBETOL (N=77)	INTRON A/ Placebo (N=76)	INTRON A/ REBETOL (N=96)	INTRON A/ 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 post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 2 points.

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

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 15 mg/kg per day and 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, of which 57% were male, 80% Caucasian, and 78% genotype 1. Subjects less than 5 years of age received REBETOL oral solution and those 5 years of age or older received either REBETOL oral solution or capsules.

Trial results are summarized in Table 20.

Table 20: Virologic Response: Previously Untreated Pediatric Subjects*

	INTRON A 3 MIU/m² three times weekly/ 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 RTPCR 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 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).

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