Intron A Rebetol

DESCRIPTION

REBETOL ® (ribavirin, interferon alfa-2b, recombinant)

REBETOL is Schering Corporations brand name for ribavirin, a nucleoside analog with antiviral activity. The chemical name of ribavirin is 1-J-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.

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.

INTRON ® A

INTRON A is Schering Corporations brand name for interferon alfa-2b, recombinant, a purified, sterile, recombinant interferon product.

Interferon alfa-2b, recombinant has been classified as an alpha interferon and is a water-soluble protein composed of 165 amino acids with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon alfa-2b gene from human leukocytes. The fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride at a concentration of 5 to 10 mg/L; the presence of this antibiotic is not detectable in the final product.

INTRON A Injection is a clear, colorless solution. The 3 million IU vial of INTRON A Injection contains 3 million IU of interferon alfa-2b, recombinant per 0.5 mL. The 18 million IU multidose vial of INTRON A Injection contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL (3 million IU/0.5 mL) in order to provide the delivery of six 0.5 mL doses, each containing 3 million IU of INTRON A (for a label strength of 18 million IU). The 18 million IU INTRON A Injection multidose pen contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL (3 million IU/0.2 mL) in order to provide the delivery of six 0.2 mL doses, each containing 3 million IU of Intron A (for a label strength of 18 million IU). Each mL also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg polysorbate 80, and 1.5 mg m-cresol as a preservative.

Based on the specific activity of approximately 2.6 x 10 IU/mg protein as measured by HPLC assay, the corresponding quantities of interferon alfa-2b, recombinant in the vials and pen described above are approximately 0.012 mg, 0.088 mg, and 0.087 mg protein, respectively.

Mechanism of Action

Ribavirin/Interferon alfa-2b, recombinant The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with REBETOL and INTRON A has not been established.

INDICATIONS

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

Description of Clinical Studies

Previously Untreated Patients

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

Study results are summarized in Table 2 .

Table 2. Virologic and Histologic Responses: Previously Untreated Patients*

	US Study				International Study
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment	48 weeks of treatment
	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus REBETOL (N=265)	INTRON A plus REBETOL (N=268)	INTRON A plus Placebo (N=266)
Virologic Response -Responder 1 -Nonresponder -Missing Data	65(29) 147(64) 16(7)	13(6) 194(84) 24(10)	85(37) 110(48) 33(14)	27(12) 168(75) 30(13)	86(32) 158(60) 21(8)	113(42) 120(45) 35(13)	46(17) 196(74) 24(9)
Histologic Response -Improvement2 -No improvement -Missing Data	102(45) 77(34) 49(21)	77(33) 99(43) 55(24)	96(42) 61(27) 71(31)	65(29) 93(41) 67(30)	103(39) 85(32) 77(29)	102(38) 58(22) 108(40)	69(26) 111(41) 86(32)

* Number (%) of Patients

1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

2. Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points.

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

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

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL 1200 mg/day (1000 mg/day for patients weighing £75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy

follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in table 3 .

Table 3. Virologic and Histologic Responses: Relapse Patients*

	US Study		International Study
	INTRON A plus REBETOL N=77	INTRON A plus Placebo N=76	INTRON A plus REBETOL N=96	INTRON A plus Placebo N=96
Virologic Response -Responder1 -Nonresponder -Missing Data	33(43) 36(47) 8(0)	3(4) 66(87) 7(9)	46(48) 45(47) 5(5)	5(5) 91(95) 0(0)
Histologic Response -Improvement2 -No improvement -Missing Data	38(49) 23(30) 16(21)	27(36) 37(49) 12(16)	49(51) 29(30) 18(19)	30(31) 44(46) 22(23)

* Number (%) of Patients.

1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

2. Defined as post treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points.

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

DOSAGE AND ADMINISTRATION

INTRON A Injection should be administered subcutaneously and Rebetol Capsules should be administered orally (see Table 6).

The recommended dose of REBETOL Capsules depends on the patients body weight. The recommended doses of Rebetol and INTRON A are given in Table 6.

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

Description of Clinical Studies and ADVERSE REACTIONS). After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

Table 6. Recommended Dosing

Body weight	REBETOL Capsules	INTRON A Injection
£ 75 kg	2 x 200 mg capsules Am, 3 x 200 mg capsules PM daily p.o.	3 million IU 3 times weekly s. c.
> 75 kg	3 x 200 mg capsules AM, 3 x 200 mg capsules PM, daily p.o.	3 million IU 3 times weekly s. c.

REBETOL may be administered without regard to food, but should be administered in a consistent manner. (See CLINICAL PHARMACOLOGY.)

Dose Modifications ( TABLE 7 )

In clinical trials, approximately 26% of patients required modification of their dose of REBETOL Capsules, INTRON A Injection, or both agents. If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, REBETOL/INTRON A therapy should be discontinued. REBETOL/INTRON A therapy 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. )

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ³2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination REBETOL/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL dose reduced to 600 mg daily (1 x 200 mg capsule AM , 2 x 200 mg capsules PM ). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL/INTRON A therapy. (See WARNINGS.)

It is recommended that a patient who experiences moderate depression (persistent low mood, loss of interest, p.o. self image, and/or hopelessness) have his/her INTRON A dose temporarily reduced and/or be considered for medical therapy. A patient experiencing severe depression or suicidal ideation/attempt should be discontinued from REBETOL/INTRON A therapy and followed closely with appropriate medical management. (See WARNINGS.)

TABLE 7. Guidelines for Dose Modifications

	Dose Reduction * REBETOL - 600 mg daily INTRON A - 1.5 million IU TIW	Permanent Discontinuation of Treatment REBETOL and INTRON A
Hemoglobin	<10 g/dL (REBETOL)	<8.5 g/dL
	Cardiac History Patients only. ³2 g/dL decrease during any 4-week period during treatment (REBETOL/INTRON A)	Cardiac History Patients only. <12 g/dL after 4 weeks of dose reduction
White blood count	<1.5 x 109 /L (INTRON A)	<1.0 x 109 /L
Neutrophil count	<0.75 x 109 /L (INTRON A)	<0.5 x 109 /L
Platelet count	<50 x 109 /L (INTRON A)	<25 x 109 /L

* Study medication to be dose reduced is shown in parenthesis

Administration of INTRON A Injection

At the discretion of the physician, the patient may self-administer the INTRON A. (See illustrated MEDICATION GUIDE for instructions.)

The Intron A Injection is supplied as a clear and colorless solution. The appropriate INTRON A dose should be withdrawn from the vial or set on the multidose pen and injected subcutaneously. After administration of INTRON A Injection, it is essential to follow the procedure for proper disposal of syringes and needles. (See MEDICATION GUIDE for detailed instructions.)

Vial/Pen Label Strength	Fill Volume	Concentration
3 million IU vial	0.5 mL	3 million IU/0.5 mL
18 million IU multidose vial†	3.8 mL	3 million IU/0.5 mL
18 million IU multidose pen††	1.5 mL	3 million IU/0.2 mL

†This is a multidose vial which contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL in order to provide the delivery of six 0.5-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU).

†† This is a multidose pen which contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide the delivery of six 0.2-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INTRON A Injection may be administered using either sterilized glass or plastic disposable syringes.

Stability

INTRON A Injection provided in vials is stable at 35^o C(95^o F) for up to 7 days and at 30^o C (86^o F) for up to 14 days. INTRON A Injection provided in a multidose pen is stable at 30^o C (86^o F) for up to 2 days. The solution is clear and colorless.

HOW SUPPLIED

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 blisters.

INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.

INTRON A Injection and REBETOL Capsules are available in the following combination package presentations:

Each REBETRON Combination Package Consists of:
For Patients £75 kg	A box containing 6 vials of Intron A Injection (3 million IU in 0.5 mL per vial) and 6 syringes and alcohol swabs. Two boxes containing 35 Rebetol Capsules each for a total of 70 capsules (5 capsules per blister card).	(NDC 0085-241-02)
	one 18 million IU multidose vial of Intron A Injection (NDC 0085-1236-02) (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL) and 6 syringes and alcohol swabs. Two boxes containing 35 Rebetol Capsules each for a total of 70 capsules (5 capsules per blister card).
	One 18 million IU INTRON A Injection multidose pen (NDC 0085-1258-02) (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL) and 6 disposable needles and alcohol swabs. Two boxes containing 35 Rebetol Capsules each for a total of 70 capsules (5 capsules per blister card).
For Patients >75 kg	A box containing 6 vials of Intron A Injection (3 million IU in 0.5 mL per vial) and 6 syringes and alcohol swabs. Two boxes containing 42 Rebetol Capsules each for a total of 84 capsules (6 capsules per blister card).	(NDC 0085-1241-01)
	one 18 million IU multidose vial of Intron A Injection (NDC 0085-1236-01) (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL) and 6 syringes and alcohol swabs. Two boxes containing 42 Rebetol Capsules each for a total of 84 capsules (6 capsules per blister card).
	One 18 million IU INTRON A Injection multidose pen (NDC 0085-1258-01) (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL) and 6 disposable needles and alcohol swabs. Two boxes containing 42 Rebetol Capsules each for a total of 84 capsules (6 capsules per blister card).
For REBETOL Dose Reduction	A box containing 6 vials of Intron A Injection (3 million IU in 0.5 mL per vial) and 6 syringes and alcohol swabs. One box containing 42 Rebetol Capsules (6 capsules per blister card).	(NDC 0085-1241-03)
	one 18 million IU multidose vial of Intron A Injection (NDC 0085-1236-03) (22. million IU per 3.8 mL; 3 million IU/0.5 mL) 8 and 6 syringes and alcohol swabs. One box containing 42 Rebetol Capsules (6 capsules per blister card).
	One 18 million IU INTRON A Injection multidose pen (NDC 0085-1258-03) (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL) and 6 disposable needles and alcohol swabs. One box containing 42 Rebetol Capsules (6 capsules per blister card).

Storage Conditions

Store the REBETOL Capsules plus INTRON A Injection combination package refrigerated between 2ºC and 8ºC (36ºF and 46º F).

When separated, the individual carton of REBETOL Capsules should be stored refrigerated between 2º C; and 8ºC (36ºand 46ºF) or at 25ºC (77ºF); excursions are permitted between 15 and 30ºC (59º and 86ºF).

When separated, the individual carton or vial of INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2º and 8ºC (36º and 46ºF).

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 Lability/Irritability	47	47
Fatigue/Asthenia	66	63	Concentration Impaired	17	21
Headache	62	58	Agitation	8	5
Rigors	48	41	Nervousness	6	6
Fever	46	33	Reproductive, Female
Weight Loss	29	20	Menstrual Disorder	7	6
Right Upper Quadrant Pain	12	6	Resistance Mechanism
Chest Pain	8	7	Viral Infection	12	12
Malaise	4	6	Fungal Infection	6	1
Central/Peripheral Nervous System			Respiratory System
Dizziness	21	17	Dyspnea	26	24
Endocrine			Coughing	23	16
Hypothyroidism	5	4	Pharyngitis	12	13
Gastrointestinal			Rhinitis	8	6
Nausea	43	33	Sinusitis	6	5
Anorexia	32	27	Skin and Appendages
Diarrhea	22	17	Alopecia	36	32
Vomiting	14	12	Pruritus	29	28
Abdominal Pain	13	13	Rash	24	23
Dyspepsia	9	8	Skin Dry	24	23
Constipation	5	5	Special Senses, Other
Hematologic Disorders			Taste Perversion	9	4
Neutropenia	26	14	Vision Disorders
Anemia	12	17	Vision Blurred	5	6
Leukopenia	6	5	Conjunctivitis	4	5
Thrombocytopenia	5	2
Liver and Biliary System
Hepatomegaly	4	4
* A subject may have reported more than one adverse reaction within a body system/organ class category.

Table 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/kgwith REBETOL (N=1019)	PegIntron 1 mcg/kgwith REBETOL (N=1016)	Pegasys 180 mcg withCopegus (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

	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)	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)
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 treatment-associated 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

Pregnancy

Category X, may cause birth defects. See CONTRAINDICATIONS boxed CONTRAINDICATIONS AND

WARNINGS

Anemia

HEMOLYTIC Anemia (hemoglobin <10 g/dl) was observed in APPROXIMATELY 10% of REBETOL/INTRON A- treated patients in clinical trials (see adverse reactions laboratory values - hemoglobin ). anemia occurred within 1-2 weeks of initiation of ribavirin therapy. because of this initial acute drop in hemoglobin, it is advised that complete blood counts (cbc) should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate.

The anemia associated with REBETOL/INTRON A therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease. Patients should be assessed before initiation of therapy 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 combination REBETOL/INTRON A therapy. (See ADVERSE REACTIONS. )

Similarly, patients with hemoglobinopathies (eg, thalassemia, sickle-cell anemia) should not be treated with combination REBETOL/INTRON A therapy.

Psychiatric

SEVERE PSYCHIATRIC ADVERSE EVENTS, INCLUDING DEPRESSION AND SUICIDAL BEHAVIOR (SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND SUICIDES) HAVE OCCURRED DURING COMBINATION REBETOL/INTRON A THERAPY AND WITH INTERFERON ALPHA MONOTHERAPY (including INTRON A therapy), BOTH IN PATIENTS WITH AND WITHOUT A PREVIOUS PSYCHIATRIC ILLNESS. REBETOL/INTRON A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders who report a history of severe depression, and physicians should monitor all patients for evidence of depression. In severe cases, therapy should be stopped and psychiatric intervention sought. In general, the adverse events resolve on cessation of therapy; however, adjunctive psychiatric medications may be required. (See ADVERSE REACTIONS.)

Pulmonary

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, including fatality, have been reported during therapy with REBETOL/INTRON A. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination REBETOL/INTRON A treatment should be discontinued.

Other

• REBETOL Capsule monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication.
• Combination REBETOL/INTRON A therapy should be used with caution in patients with creatinine clearance <50 mL/min.
• Diabetes mellitus and hyperglycemia have been observed in patients treated with INTRON A.
• Ophthalmologic disorders have been reported with treatment with alpha interferons (including INTRON A therapy). Investigators using alpha interferons have reported the occurrence of retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction in rare instances. Any patient complaining of loss of visual acuity or visual field should have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual exam prior to initiation of combination REBETOL/INTRON A therapy is recommended in patients with diabetes mellitus or hypertension.
• Acute serious hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed in INTRON A- treated patients; if such an acute reaction develops, combination REBETOL/INTRON A therapy should be discontinued immediately and appropriate medical therapy instituted.
• Combination REBETOL/INTRON A therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be controlled by medication.

PRECAUTIONS

Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). REBETOL/INTRON A therapy should be used with caution in patients with other autoimmune disorders.

There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant), exacerbating pre-existing psoriasis; therefore, combination REBETOL/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.

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

The safety and efficacy of REBETOL Capsule monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and REBETOL Capsules should not be used for these indications.

There is no information regarding the use of REBETOL Capsules with other interferons.

Information for Patients

See PATIENT INFORMATION section.

Laboratory Tests

The following laboratory tests are recommended for all patients on combination REBETOL/INTRON A therapy, prior to beginning treatment and then periodically thereafter.

Standard hematologic tests - including hemoglobin (pretreatment, week 2 and week 4 of therapy, and as clinically appropriate [see

WARNINGS

]), complete and differential white blood cell counts, and platelet count.

Blood chemistries - liver function tests and TSH.

Pregnancy - including monthly monitoring for women of childbearing potential.

Carcinogenesis and Mutagenesis

Carcinogenicity studies with interferon alfa-2b, recombinant have not been performed because neutralizing activity appears in the serum after multiple dosing in all of the animal species tested.

Adequate studies to assess the carcinogenic potential of ribavirin in animals have not been conducted. However, ribavirin is a nucleoside analog that has produced positive findings in multiple in vitro and animal in vivo genotoxicity assays, and should be considered a potential carcinogen. Further studies to assess the carcinogenic potential of ribavirin in animals are ongoing.

Mutagenicity studies have demonstrated that interferon alfa-2b, recombinant is not mutagenic. Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 - 1 X 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

No reproductive toxicology studies have been performed using interferon alfa-2b, recombinant in combination with ribavirin. However, evidence provided below for interferon alfa-2b, recombinant and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effects produced by either agent alone will also be caused by the combination of the two agents. Interferons may impair human fertility. In studies of interferon alfa- 2b recombinant administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon. In addition, ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.

Fertile women and partners of fertile women should not receive combination REBETOL/INTRON A therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half- life (t _1/2 ) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (eg, 15 half-lives of clearance for ribavirin).

Combination REBETOL/INTRON A therapy should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin- induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 - 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 - 0.8 X the maximum human 24- hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin- induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

Animal Toxicology

Long- term studies in the mouse and rat (18-24 months; doses of 20-75 and 10 - 40 mg/kg/day, respectively estimated human equivalent doses of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 - 0.4 X the maximum human 24-hour dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin- treated rats.

Pregnancy Category X (see CONTRAINDICATIONS)

Interferon alfa-2b, recombinant has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). There are no adequate and well-controlled studies in pregnant women.

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 X 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 X the maximum recommended human 24-hour dose of ribavirin).

Treatment and Posttreatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14-28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 X 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 combination REBETOL/INTRON A therapy unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple dose half-life (t _1/2 ) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with combination REBETOL/INTRON A therapy and for the 6-month posttherapy period (eg, 15 half-lives for ribavirin clearance from the body).

If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, physicians are encouraged to report such cases by calling (800) 727-7064.

Nursing Mothers

It is not known whether REBETOL and INTRON A are excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for nursing or to discontinue combination REBETOL/INTRON A therapy, taking into account the importance of the therapy to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

OVERDOSE

In combination REBETOL/ INTRON A clinical trials, the maximum overdose reported was a dose of 39 million units of INTRON A (13 subcutaneous injections of 3 million IU each) taken with 10 g of REBETOL (fifty 200-mg capsules) in an investigator-initiated trial. The patient was observed for 2 days in the emergency room during which time no adverse event from the overdose was noted.

CONTRAINDICATIONS

Combination REBETOL/INTRON A therapy 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 combination REBETOL/INTRON A therapy. Combination REBETOL/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has been concluded. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin 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 REBETOL Capsules. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment s.o.s. physicians are encouraged to report such cases by calling (800) 727-7064. See boxed CONTRAINDICATIONS AND WARNINGS below. See WARNINGS.

REBETOL Capsules in combination with INTRON A Injection is contraindicated in patients with a history of hypersensitivity to ribavirin and/or alpha interferon or any component of the capsule and/or injection.

Patients with autoimmune hepatitis must not be treated with combination REBETOL/INTRON A therapy.

CONTRAINDICATIONS AND WARNINGS Combination REBETOL/INTRON A therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in female patients, and in female partners of male patients who are taking combination REBETOL/INTRON A therapy. Women of childbearing potential and men must use two reliable forms of effective contraception during treatment and during the 6-month posttreatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species studied. See WARNINGS. REBETOL monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication. See WARNINGS.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Interferon alfa-2b, recombinant

Single and multiple dose pharmacokinetic properties of INTRON A (interferon alfa-2b, recombinant) are summarized in Table 1 . Following a single 3 million IU (MIU) subcutaneous dose in 12 patients with chronic hepatitis C, mean (% CV*) serum concentrations peaked at 7 (44%) hours. Following 4 weeks of subcutaneous dosing with 3 MIU three times a week (TIW), interferon serum concentrations were undetectable predose. However, a twofold increase in bioavailability was noted upon multiple dosing of interferon; the reason for this is unknown. Mean half-life values following single- and multiple- dose administrations were 6.8 (24%) hours and 6.5 (29%) hours, respectively.

Ribavirin

Single- and multiple- dose pharmacokinetic properties in adults with chronic hepatitis C are summarized in Table 1 . Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUC_tf (AUC from time zero to last measurable concentration) following single doses of 200-1200 mg ribavirin. The relationship between dose and C_max was curvilinear, tending to asymptote above single doses of 400-600 mg.

Upon multiple oral dosing, based on AUC12 hr , a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Food on Absorption of Ribavirin

Both AUC tf and C_max 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. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies were conducted without instructions with respect to food consumption. (See DOSAGE AND ADMINISTRATION .)

Effect of Antacid on Absorption of Ribavirin

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

Table 1. Mean (% CV) Pharmacokinetic Parameters for Intron A and Rebetol when administered individually to Adults with Chronic Hepatitis C
Parameter	Intron A (N=12)			Rebetol (N=12)
	Single Dose 3 MIU	Multiple Dose 3 MIU tiw		Single Dose 600 mg	Multiple Dose 600 mg bid
Tmax(hr)	7 (44)	5 (37)		1.7 (46) ***	3 (60)
Cmax*	13.9 (32)	29.7 (33)		782 (37)	3680 (85)
AUCtf **	142 (43)	333 (39)		13400 (48)	228000 (25)
T1/2 (hr)	6.8 (24)	6.5 (29)		43.6 (47)	298 (30)
Apparent Volume of Distribution (L)				2825 (9)Â
Apparent Clearance (L/hr)	14.3 (17)			38.2 (40)
Absolute Bioavailability				64% (44)  Â

* IU/mL for Intron A and ng/mL for Rebetol

** IU. hr/mL for Intron A and ng. hr/mL for Rebetol

  data obtained from a single-dose pharmacokinetic study using ¹⁴C labeled ribavirin; N = 5

   N = 6

*** n = 11

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an e_s-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14 C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.

Special Populations

Renal Dysfunction The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to subjects with varying degrees of renal dysfunction. The mean AUC_tf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance >90 mL/min). This appears to be due to reduction of apparent clearance in these patients. Ribavirin was not removed by hemodialysis. Rebetol is not recommended for patients with severe renal impairment (see WARNINGS ).

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

Pediatric Patients Pharmacokinetic evaluations for pediatric subjects have not been performed.

Elderly Patients Pharmacokinetic evaluations for elderly subjects have not been performed.

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

* In this section of the label, numbers in parenthesis indicate % coefficient of variation.

PATIENT INFORMATION

Combination REBETOL/ INTRON A therapy 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 combination REBETOL/ INTRON A therapy. Combination REBETOL/ INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/ embryocidal risks and must be instructed to practice effective contraception during combination REBETOL/ INTRON A therapy and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS.)

If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the significant teratogenic risk of REBETOL therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians are encouraged to report such cases by calling (800) 727- 7064.

Patients receiving combination REBETOL/ INTRON A treatment should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the patient MEDICATION GUIDE . There are no data evaluating whether REBETOL/ INTRON A therapy will prevent transmission of infection to others. Also, it is not known if treatment with REBETOL/ INTRON A therapy will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.

If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see MEDICATION GUIDE ).

The most common adverse experiences occurring with combination REBETOL/ INTRON A therapy are "flu-like" symptoms, such as headache, fatigue, myalgia, and fever (see ADVERSE REACTIONS ) and appear to decrease in severity as treatment continues. Some of these "flu-like" symptoms may be minimized by bedtime administration of INTRON A therapy. Antipyretics should be considered to prevent or partially alleviate the fever and headache. Another common adverse experience associated with INTRON A therapy is thinning of the hair.

Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter (see PRECAUTIONS: Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.