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Peglntron™/REBETOL® Combo Pack

Peglntron™ REDIPEN® Single-dose Delivery System
(peginterferon alfa-2b)

REBETOL®
(ribavirin, USP) Capsules

DESCRIPTION

Peglntron™/REBETOL® Combo Pack contains Peglntron™ REDIPEN® Single-dose Delivery System (peginterferon alfa-2b) and REBETOL® (ribavirin) capsules.

Peglntron™

Peglntron™, peginterferon alfa-2b, Powder for Injection is a covalent conjugate of recombinant human alfa-2b interferon with monomethoxy polyethylene glycol (PEG). The average molecular weight of the PEG portion of the molecule is 12,000 daltons. The average molecular weight of the Peglntron™ molecule is approximately 31,000 daltons. The specific activity of peginterferon alfa-2b is approximately 0.7 x 108 Ill/mg protein.

Interferon alfa-2b, is a water-soluble protein 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 gene from human leukocytes.

REDIPEN®

REDIPEN® is a dual-chamber glass cartridge containing lyophilized Peglntron™ as a white to off-white tablet or powder that is whole or in pieces in the sterile active chamber and a second chamber containing Sterile Water for Injection, USP. Each Peglntron™ REDIPEN® contains either 67.5 meg, 108 meg, 162 meg, or 202.5 meg of Peglntron™, and 1.013 mg dibasic sodium phosphate anhydrous, 1.013 mg

monobasic sodium phosphate dihydrate, 54 mg sucrose and 0.0675 mg polysorbate 80. Each cartridge is reconstituted to allow for the administration of up to 0.5 mL of solution. Following reconstitution, each REDIPEN® contains Peglntron™ at strengths of either 50 meg per 0.5 mL, 80 meg per 0.5 mL, 120 meg per 0.5 mL or 150 meg per 0.5 mL for a single use. Because a small volume of reconstituted solution is lost during preparation of Peglntron™, each REDIPEN® contains an excess amount of Peglntron™ powder and diluent to ensure delivery of the labeled dose.

REBETOL®

REBETOL® is Schering Corporation's brand name for ribavirin, a nucleoside analog. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3- carboxamide and has the following structural formula:

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C8H12N405 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.

INDICATIONS

Peglntron™/REBETOL® Combo Pack therapy is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age.

DOSAGE AND ADMINISTRATION

There are no safety and efficacy data on treatment for longer than one year. A patient should self-inject Peglntron™ only if it has been determined that it is appropriate and the patient agrees to medical follow-up as necessary and training in proper injection technique has been given to him/her.

Treatment discontinuation is also recommended for patients who do not achieve an undetectable HCV RNA viral load at 24 weeks of therapy of therapy. The recommended dose of Peglntron™ is 1.5 mcg/kg/week in combination with 8001400 mg REBETOL® based on patient body weight. The volume of Peglntron™ to be injected depends on the strength of Peglntron™ and patient's body weight. (See Table 5.)

The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

TABLE 5: Recommended Peglntron™/REBETOL® Combo Pack Therapy Dosing

Body weight kg (lbs)	Peglntron™ REDIPEN® Strength to Use	Amount of Peglntron™ (meg) to Administer	Volume (mL)* of Peglntron™ to Administer	REBETOL® Daily Dose	REBETOL® Number of Capsules
< 40 ( < 87)	50 meg per 0.5 mL	50	0.5	800 mg/day	2x200 mgcapsules A.M. 2x200 mgcapsules P.M.
40-50 (87-111)	80 meg per 0.5 mL	64	0.4	800 mg/day	2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.
51-60 (112-133)		80	0.5	800 mg/day	2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.
61-65 (134-144)	120 meg per 0.5 mL	96	0.4	800 mg/day	2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.
66-75 (145-166)		96	0.4	1000 mg/day	2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.
76-85 (167-188)		120	0.5	1000 mg/day	2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.
86-105 (189-231)	150 meg per 0.5 mL	150	0.5	1200 mg/day	3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.
> 105 ( > 231)				1400 mg/day	3 x 200 mg capsules A.M. 4 x 200 mg capsules P.M.
* When reconstituted as directed.

REBETOL® should be taken with food. Peglntron™/REBETOL® Combo Pack therapy should not be used in patients with creatinine clearance < 50 mL/min.

Dose Reduction

If a serious adverse reaction develops during the course of treatment (See WARNINGS) discontinue or modify the dosage of Peglntron™ and/or REBETOL® until the adverse event abates or decreases in severity. If persistent or recurrent serious adverse events develop despite adequate dosage adjustment, discontinue treatment. For guidelines for dose modifications and discontinuation based on laboratory parameters, see Tables 6 and 7. Dose reduction of Peglntron™ may be accomplished by utilizing a lower dose strength as shown in Table 8.

Renal Function

Peglntron™/REBETOL® Combo Pack therapy should not be used in patients with creatinine clearance < 50 mL/min. (See PRECAUTIONS and CLINICAL PHARMACOLOGY, Special populations.) Subjects with impaired renal function and/or those over the age of 50 should be more carefully monitored with respect to development of anemia.

In the combination therapy trial, dose reductions occurred among 42% of patients receiving Peglntron™ 1.5 mcg/kg/REBETOL® 800 mg daily including 57% of those patients weighing 60 kg or less (see ADVERSE REACTIONS).

Table 6: Guidelines for Modification or Discontinuation of Peglntron™/REBETOL® Combo Pack Therapy and for Scheduling Visits for Patients with Depression

Depression Severity1	Initial Management (4-8 wks)			Depression
	Dose modification	Visit schedule	Remains stable	Improves	Worsens
Mild	No change	Evaluate once weekly by visit and/or phone.	Continue weekly visit schedule.	Resume normal visit schedule.	(See moderate or severe depression)
Moderate	Decrease IFN dose 50%	Evaluate once weekly (office visit at least every other week).	Consider psychiatric consultation. Continue reduced dosing.	If symptoms improve and are stable for 4 wks, may resume normal visit schedule. Continue reduced dosing or return to normal dose.	(See severe depression)
Severe	Discontinue IFN/R permanently.	Obtain immediate psychiatric consultation.	Psychiatric therapy as necessary
1 See DSM-IV for definitions.

Table 7: Guidelines for Dose Modification and Discontinuation of Peglntron™/REBETOL® Combo Pack Therapy for Hematologic Toxicity

Laboratory Values		Peglntron™	REBETOL®
Hgb*	< 10 g/dL	-----------	Decrease by 200 mg/day
	< 8.5 g/dL	Permanently discontinue	Permanently discontinue
WBC	< 1.5 x 109/L	Reduce dose by 50%	-----------
	< 1 x 109/L	Permanently discontinue	Permanently discontinue
Neutrophil	< 0.75 x 109/L	Reduce dose by 50%	-----------
	< 0.5 x109/L	Permanently discontinue	Permanently discontinue
Platelets	< 80 x 109/L	Reduce dose by 50%	-----------
	< 50 x 109/L	Permanently discontinue	Permanently discontinue
* For patients with a history of stable cardiac disease receiving Peglntron™ in combination with ribavirin, the Peglntron™ dose should be reduced by half and the ribavirin dose by 200 mg/day if a > 2 g/dL decrease in hemoglobin is observed during any 4-week period. Both Peglntron™ and ribavirin should be permanently discontinued if patients have hemoglobin levels < 12 g/dL after this ribavirin dose reduction.

TABLE 8: Reduced Peglntron™ Dose (0.75 mcg/kg) for (1.5 mcg/kg) Combination Therapy

Body weight kg (lbs)	Peglntron™ REDIPEN® Strength to Use	Amount of Peglntron™ (meg) to Administer	Volume (mL)** of Peglntron™ to Administer
< 40 ( < 87)	50 meg per 0.5 mL*	25	0.25
40-50 ( < 87-111)	50 meg per 0.5 mL	30	0.3
51-60 (112-133)		40	0.4
61-75 (134-166)	50 meg per 0.5 mL	50	0.5
76-85 (167-188)	80 meg per 0.5 mL	64	0.4
> 85 ( > 188)		80	0.5
* Must use vial. Minimum delivery for REDIPEN® 0.3 Ml ** When reconstituted as directed

Preparation and Administration

Peglntron™ REDIPEN®

Peglntron™ REDIPEN® consists of a dual-chamber glass cartridge with sterile,  lyophilized peginterferon alfa-2b in the active chamber and Sterile Water for Injection, USP in the diluent chamber. The Peglntron™ in the glass cartridge should appear as a white to off-white tablet-shaped solid that is whole or in pieces, or powder. To reconstitute the lyophilized peginterferon alfa-2b in the REDIPEN®, hold the REDIPEN® upright (dose button down) and press the two halves of the pen together until there is an audible click. Gently invert the pen to mix the solution. DO NOT SHAKE. The reconstituted solution has a concentration of either 50 meg per 0.5 mL, 80 meg per 0.5 mL, 120 meg per 0.5 mL, or 150 meg per 0.5 mL for a single subcutaneous injection. Visually inspect the solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear and colorless. Do not use the solution if it is discolored or not clear, or if particulates are present.

Keeping the pen upright, attach the supplied needle and select the appropriate Peglntron™ dose by pulling back on the dosing button until the dark bands are visible and turning the button until the dark band is aligned with the correct dose.  The prepared Peglntron™ solution is to be injected subcutaneously.

The Peglntron™ REDIPEN® is a single-use pen and does not contain a preservative. The reconstituted solution should be used immediately and cannot be stored for more than 24 hours at 2°-8°C (See Storage). DO NOT REUSE THE REDIPEN®. The sterility of any remaining product can no longer be guaranteed.  DISCARD THE UNUSED PORTION. Pooling of unused portions of some medications has been linked to bacterial contamination and morbidity.

After preparation and administration of the Peglntron™ REDIPEN®, it is essential to follow the state and/or local procedures for proper disposal of the REDIPEN®. A puncture-resistant container should be used for disposal. Patients should be instructed in how to properly dispose of used REDIPEN® and be cautioned against the reuse of these items.

Storage

Peglntron™/REBETOL® Combo Pack package should be stored at 2°- 8°C (36°-46°F).

When separated, the individual 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].

When separated, the Peglntron™ REDIPEN® should be stored at 2°- 8°C (36°- 46°F). After reconstitution, the solution should be used immediately, but may be stored up to 24 hours at 2°-8°C (36°-46°F). The reconstituted solution contains no preservative, and is clear and colorless. DO NOT FREEZE.

HOW SUPPLIED

Peglntron™ REDIPEN® is a dual-chamber glass cartridge containing lyophilized Peglntron™ as a white to off-white tablet or powder that is whole or in pieces in the sterile active chamber and a second chamber containing Sterile Water for Injection,  USP.

REBETOL® 200 mg Capsules are white, opaque capsules with REBETOL®, 200 mg,  and the Schering Corporation logo imprinted on the capsule shell.

Each Peglntron™/REBETOL® Combo Pack Consists of:
A box containing four 50 meg per 0.5 mL Peglntron™ REDIPEN® Units, each containing 1 BD® needle and 2 alcohol swabs, and two bottles of 56 REBETOL® Capsules.	(NDC 0085-1367-01)
A box containing four 80 meg per 0.5 mL Peglntron™ REDIPEN® Units, each containing 1 BD® needle and 2 alcohol swabs, and two bottles of 56 REBETOL® Capsules.	(NDC 0085-1375-01)
A box containing four 120 meg per 0.5 mL Peglntron™ REDIPEN® Units, each containing 1 BD® needle and 2 alcohol swabs, and two bottles of 70 REBETOL® Capsules.	(NDC 0085-1456-01)
A box containing four 150 meg per 0.5 mL Peglntron™ REDIPEN® Units, each containing 1 BD® needle and 2 alcohol swabs, and two bottles of 84 REBETOL® Capsules.	(NDC 0085-1555-01)
A box containing four 150 meg per 0.5 mL Peglntron™ REDIPEN® Units, each containing 1 BD® needle and 2 alcohol swabs, and two bottles of 98 REBETOL® Capsules.	(NDC 0085-1684-01)

Schering Corporation, Kenilworth, NJ 07033 USA.  Revision: 5/08

SIDE EFFECTS

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1-4 weeks of therapy. Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients. (See WARNINGS.)

Clinical Trial Experience

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

Study 2 compared combination therapy of Peglntron™/REBETOL® with combination therapy with INTRON® A/REBETOL®. In this study, nearly all study patients in clinical trials experienced one or more adverse events. As shown in Table 4 the most common adverse events ( > 5%) in this study were comparable for both the Peglntron™/REBETOL® and INTRON® A/REBETOL® combination therapies.

Table 4: Adverse Events Occurring in > 5% of Patients

Adverse Events	Percentage of Patients Reporting Adverse Events* Study 2
	Peglntron™ 1.5 mcg/kg/ REBETOL® (n=511)	INTRON® A/REBETOL® (n=505)
Application Site
Injection Site	75	49
Inflammation/Reaction
Autonomic Nervous Sys.
Mouth Dry	12	8
Sweating Increased	11	7
Flushing	4	3
Body as a Whole
Fatigue/Asthenia	66	63
Headache	62	58
Rigors	48	41
Fever	46	33
Weight Decrease	29	20
RUQ Pain	12	6
Chest Pain	8	7
Malaise	4	6
Central/Periph. Nerv. Sys.
Dizziness	21	17
Endocrine
Hypothyroidism	5	4
Gastrointestinal
Nausea	43	33
Anorexia	32	27
Diarrhea	22	17
Vomiting	14	12
Abdominal Pain	13	13
Dyspepsia	9	8
Constipation	5	5
Hematologic Disorders
Neutropenia	26	14
Anemia	12	17
Leukopenia	6	5
Thrombocytopenia	5	2
Liver and Biliary System
Hepatomegaly	4	4
Musculoskeletal
Myalgia	56	50
Arthralgia	34	28
Musculoskeletal Pain	21	19
Psychiatric
Insomnia	40	41
Depression	31	34
Anxiety/Emotional Lability/Irritability	47	47
Concentration Impaired	17	21
Agitation	8	5
Nervousness	6	6
Reproductive, Female
Menstrual Disorder	7	6
Resistance Mechanism
Infection Viral	12	12
Infection Fungal	6	1
Respiratory System
Dyspnea	26	24
Coughing	23	16
Pharyngitis	12	13
Rhinitis	8	6
Sinusitis	6	5
Skin and Appendages
Alopecia	36	32
Pruritus	29	28
Rash	24	23
Skin Dry	24	23
Special Senses Other,
Taste Perversion	9	4
Vision Disorders
Vision Blurred	5	6
Conjunctivitis	4	5
*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.

The adverse event profile in Study 3, which compared Peglntron/weight-based REBETOL combination to a Peglntron/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. The incidence of serious adverse events was comparable in all studies. In Study 2, the incidence of serious adverse events was 17% in the Peglntron™/REBETOL® group. In Study 3, there was a similar incidence of serious adverse events reported for the weight-based REBETOL® group (12%) and with the flat dose REBETOL® regimen. 

In many but not all cases, adverse events resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse events during the 6-month follow-up period. There have been 19 patient deaths which occurred during treatment or during follow-up in these clinical trials.  There was one suicide in a patient receiving Peglntron monotherapy and two deaths among patients receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was one suicide in a patient receiving Peglntron/REBETOL combination therapy; and 1 patient death in the INTRON A/REBETOL group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of which were probable suicides and one was an unexplained death in a person with a relevant medical history of depression.

In Study 2, 14% of patients receiving Peglntron™ in combination with REBETOL®, discontinued therapy compared with 13% treated with INTRON® A in combination with REBETOL®. Similarly in Study 3, 15% of patients receiving Peglntron™ in combination with weight-based REBETOL® and 14% of patients receiving Peglntron™ and flat dose REBETOL® discontinued therapy. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of patients receiving Peglntron™ (1.5 mcg/kg)/REBETOL® and in 34% of those receiving INTRON® A/REBETOL®. The majority of patients (57%) weighing 60 kg or less receiving Peglntron™ (1.5 mcg/kg)/REBETOL® required dose reduction. Reduction of interferon was dose related (Peglntron 1.5 mcg/kg > Peglntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL® was similar across all three groups, 33-35%. 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 events occurred more frequently with WBD compared flat dosing (29% and 23%, respectively). 

In the Peglntron™/REBETOL® combination trials, the most common adverse events were psychiatric which occurred among 77% of patients in Study 2 and 68-69% of patients in Study 3. These psychiatric adverse events included most commonly depression, irritability, and insomnia, each reported by approximately 30-40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides)  occurred in 2% of all patients during treatment or during follow-up after treatment cessation (See WARNINGS).

Peglntron™ induces fatigue or headache in approximately two-thirds of patients,  with fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. 

In Study 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with Peglntron™ therapies (in up to 75% of patients) compared with INTRON® A. However, injection site pain was infrequent (2-3%) in all groups. In Study 3 there was a 23-24% incidence overall for injection site reactions or inflammation.

In Study 2, many patients continued to experience adverse events several months after discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing adverse events by body class in the Peglntron™ 1.5/REBETOL® group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for Gl). In approximately 10-15% of patients weight loss, fatigue, and headache had not resolved.

Individual serious adverse events occurred at a frequency < 1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction,  relapse of drug addiction/overdose; nerve palsy (facial, oculomotor);  cardiomyopathy, myocardial infarction, angina, pericardial effusion, retinal ischemia,  retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis,  transient ischemic attack, supraventricular arrhythmias, loss of consciousness;  neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema,  bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout,  hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis; urticaria, injection-site necrosis,  vasculitis, and phototoxicity.

Laboratory Values

Changes in selected laboratory values during treatment with Peglntron™ in combination with REBETOL® treatment are described below. Decreases in hemoglobin, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)

Hemoglobin

Hemoglobin levels decreased to < 11 g/dL in about 30% of patients in Study 2. In Study 3, 47% of patients receiving WBD REBETOL® and 33% on flat dose REBETOL® had decreases in hemoglobin levels < 11 g/dL. Reduction in hemoglobin to < 9 g/dL occurred more frequently in patients receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of patients in the Peglntron™/REBETOL® and INTRON® A/REBETOL® groups. 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. Hemoglobin levels return to baseline between 4 and 12 weeks posttreatment (see DOSAGE AND ADMINISTRATION:  Dose Reduction).

Neutrophils

Decreases in neutrophil counts were observed in a majority of patients treated with Peglntron™/REBETOL® combination therapy (85%) and INTRON® A/REBETOL® (60%) in Study 2. Severe potentially life-threatening neutropenia ( < 0.5 x 109/L) occurred in 2% of patients treated with INTRON® A/REBETOL®, and in approximately 4% of patients treated with Peglntron™/REBETOL®. In Study 2, 18% of patients receiving Peglntron™/REBETOL® required modification of interferon dosage. Few patients ( < 1%) required permanent discontinuation of treatment.  Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)

Platelets

Platelet counts decreased to < 100,000/mm³ in approximately 20% of patients treated with Peglntron™/REBETOL® and in 6% of patients treated with INTRON® A/REBETOL®. Severe decreases in platelet counts ( < 50,000/mm³) occur in < 4% of patients. Patients may require discontinuation or dose modification as a result of platelet decreases. (See DOSAGE AND ADMINISTRATION: Dose Reduction.) In Study 2, 1% or 3% of patients required dose modification of INTRON® A or Peglntron™, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Triglycerides

Elevated triglyceride levels have been observed in patients treated with interferon alphas including Peglntron™.

Thyroid Function

Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among patients treated with either INTRON® A or Peglntron™ (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, 10-14% of patients developed hyperbilirubinemia and 33-38% developed hyperuricemia in association with hemolysis.  Six patients developed mild to moderate gout.

Postmarketing Experience

The following adverse reactions have been identified and reported during postapproval use of Peglntron™ therapy: aphthous stomatitis, erythema multiforme,  hearing impairment, hearing loss, memory loss, migraine headache, myositis,  peripheral neuropathy, renal insufficiency, renal failure, rhabdomyolysis, seizures,  Stevens Johnson syndrome, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, and vertigo. In addition, the following adverse reactions have been identified during use with Peglntron™/REBETOL® combination therapy: hearing disorder, aplastic anemia and pure red cell aplasia. Because the reports of these reactions are voluntary and the population of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Immunogenicity

Approximately 2% of patients receiving Peglntron™ (32/1759) or INTRON® A (11/728) with or without REBETOL® developed low-titer ( < 160)  neutralizing antibodies to Peglntron™ or INTRON® A. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. The incidence of posttreatment-binding antibody ranged from 8 to 15 percent. The data reflect the percentage of patients whose test results were considered positive for antibodies to Peglntron™ in a Biacore assay that is used to measure binding antibodies, and in an antiviral neutralization assay, which measures serumneutralizing antibodies. The percentage of patients whose test results were considered positive for antibodies is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in these assays may be influenced by several factors including sample timing and handling, concomitant medications, and underlying disease. For these reasons,  comparison of the incidence of antibodies to Peglntron™ with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

Caution should be used when administering Peglntron™/REBETOL® Combo Pack therapy with medications metabolized by CYP2C8/9 (e.g., warfarin and phenytoin) or CYP2D6 (e.g., flecainide) (see CLINICAL PHARMACOLOGY; Drug Interactions).

Methadone

In a pharmacokinetic study of 18 chronic hepatitis C patients concomitantly receiving methadone, treatment with Peglntron™ once weekly for 4 weeks was associated with a mean increase of 16% in methadone AUC; in 2 out of 18 patients, methadone AUC doubled (See CLINICAL PHARMACOLOGY; Drug Interactions). The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of increased narcotic effect.

Nucleoside Analogues

Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon-alfa and ribavirin. Adding treatment with alpha interferons in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and Nucleoside Reverse Transcriptase Inhibitors (NRTls) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTls should be considered as medically appropriate (See Individual NRTI Product Information). Dose reduction or discontinuation should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6).

Lamivudine, Stavudine and Zidovudine: Cell culture studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine, stavudine and zidovudine. Therefore, concomitant use of Peglntron™/REBETOL® Combo Pack therapy with these drugs should be used with caution. However, in a study with another pegylated interferon-alfa, no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression)  interaction was seen when ribavirin was co-administered with lamivudine zidovudine or stavudine in HIV/HCV co-infected patients (See CLINICAL PHARMACOLOGY; Drug Interactions).

Although there was no evidence of loss of HIV/HCV virologic suppression when ribavirin was co-administered with zidovudine, HIV/HCV co-infected patients who were administered zidovudine in combination with pegylated interferon alpha and ribavirin developed severe neutropenia (ANC < 500) and severe anemia (hemoglobin < 8 g/dL) more frequently than similar patients not receiving zidovudine.

Didanosine: Co-administration of REBETOL® Capsules and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy,  pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials (See CLINICAL PHARMACOLOGY; Drug Interactions).

WARNINGS

Pregnancy

REBETOL® Capsules may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL® has demonstrated significant teratogenic and/or 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. Patients should be instructed to use at least two forms of effective contraception during treatment and during the 6 month period after treatment has been stopped based on multiple-dose half-life of ribavirin of 12 days. Pregnancy testing should occur monthly during REBETOL® therapy and for 6 months after therapy has stopped (See BOXED WARNING,  CONTRAINDICATIONS and PRECAUTIONS: Pregnancy Category X and PATIENT INFORMATION).

Anemia

Ribavirin caused hemolytic anemia in 10% of Peglntron™/REBETOL®-treated patients within 1-4 weeks of initiation of therapy. Complete blood counts 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.

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 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: Guidelines for Dose Modification.) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use Peglntron™/REBETOL® Combo Pack (See ADVERSE REACTIONS).

Neuropsychiatric events

Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior sometimes directed towards others have occurred in patients with and without a previous psychiatric disorder during Peglntron™ treatment and follow-up.  Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with alpha interferons. Peglntron™/REBETOL® Combo Pack should be used with extreme caution in patients with a history of psychiatric disorders.  Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with Peglntron™/REBETOL® Combo Pack be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, Peglntron™/REBETOL® Combo Pack therapy should be stopped immediately and psychiatric intervention instituted (see DOSAGE AND ADMINISTRATION: Dose Reduction). Cases of encephalopathy have been observed in some patients, usually elderly, treated with higher doses of Peglntron™.

Bone marrow toxicity

Peglntron™ suppresses bone marrow function, sometimes resulting in severe cytopenias. Peglntron™/REBETOL® Combo Pack therapy should be discontinued in patients who develop severe decreases in neutrophil or platelet counts (see DOSAGE AND ADMINISTRATION: Dose Reduction). Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia.

Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including Peglntron™. Cirrhotic CHC patients co-infected with HIV receiving highly active antiretroviral therapy (HAART) and alpha interferons with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients' clinical status and hepatic function should be closely monitored, and Peglntron™/REBETOL® Combo Pack treatment should be immediately discontinued if decompensation (Child-Pugh score > 6) is observed (see CONTRAINDICATIONS).

Endocrine disorders

Peglntron™ causes or aggravates hypothyroidism and hyperthyroidism.  Hyperglycemia has been observed in patients treated with Peglntron™. Diabetes mellitus has been observed in patients treated with alpha interferons. Patients with these conditions who cannot be effectively treated by medication should not begin Peglntron™/REBETOL® Combo Pack therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue Peglntron™/REBETOL® Combo Pack therapy.

Cardiovascular events

Cardiovascular events, which include hypotension, arrhythmia, tachycardia,  cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with Peglntron™. Peglntron™/REBETOL® Combo Pack therapy should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require Peglntron™/REBETOL® Combo Pack_therapy should be closely monitored (see Laboratory Tests). Patients with a history of significant or unstable cardiac disease should not be treated with Peglntron™/REBETOL® Combo Pack.

Cerebrovascular disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients with interferon alpha-based therapies, including Peglntron™. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alpha-based therapies and these events is difficult to establish.

Pulmonary disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by Peglntron™ or alpha interferon therapy.  Recurrence of respiratory failure has been observed with interferon rechallenge.  Peglntron™/REBETOL® Combo Pack treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.

Colitis

Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. Peglntron™/REBETOL® Combo Pack treatment should be discontinued immediately in patients who develop these symptoms and signs. The colitis usually resolves within 1-3 weeks of discontinuation of alpha interferons.

Pancreatitis

Fatal and nonfatal pancreatitis have been observed in patients treated with alpha interferon. Peglntron™/REBETOL® Combo Pack therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.

Autoimmune disorders

Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis) have been observed in patients receiving Peglntron™. Peglntron™/REBETOL® Combo Pack therapy should be used with caution in patients with autoimmune disorders.

Ophthalmologic disorders

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Peglntron™/REBETOL® Combo Pack treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Hypersensitivity

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema,  bronchoconstriction, and anaphylaxis) and cutaneous eruptions (Stevens Johnson syndrome, toxic epidermal necrolysis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with Peglntron™/REBETOL® Combo Pack, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

PRECAUTIONS

• Peglntron™ in combination with REBETOL® has not been studied in patients who have failed other alpha interferon treatments.
• The safety and efficacy of Peglntron™ in combination with REBETOL® for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. 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.
• The safety and efficacy of Peglntron™/REBETOL® for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

Triglycerides

Elevated triglyceride levels have been observed in patients treated with interferon alpha including Peglntron™ therapy. Hypertriglyceridemia may result in pancreatitis (See WARNINGS: Pancreatitis). Elevated triglyceride levels should be managed as clinically appropriate. Discontinuation of Peglntron™/REBETOL® Combo Pack therapy should be considered for patients with symptoms of potential pancreatitis,  such as abdominal pain, nausea, or vomiting and persistently elevated triglycerides (e.g., triglycerides > 1000 mg/dL).

Patients with renal insufficiency

Increases in serum creatinine levels have been observed in patients with renal insufficiency receiving interferon alpha products, including Peglntron™. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and Peglntron™ dosing should be adjusted accordingly or discontinued (See CLINICAL PHARMACOLOGY:  Pharmacokinetics and DOSAGE AND ADMINISTRATION: Dose Reduction).  Peglntron Patients with renal ™/REBETOL® Combo Pack therapy must not be used in patients with creatinine clearance < 50 mL/min (See CLINICAL PHARMACOLOGY, Special populations).  

Information for Patients

Patients receiving Peglntron™/REBETOL® Combo Pack therapy should be directed in its appropriate use, informed of the benefits and risks associated with treatment,  and referred to the MEDICATION GUIDE.

Patients must be informed that REBETOL® may cause birth defects and/or 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 during treatment with Peglntron™/REBETOL® Combo Pack therapy and for 6 months posttherapy. Peglntron™/REBETOL® Combo Pack 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 treatment 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 and WARNINGS).

If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the teratogenic risk of REBETOL® therapy to the fetus.  Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians should report such cases by calling 1-800- 593-2214.

The most common adverse experience occurring with REBETOL® Capsules is anemia,  which may be severe. (See ADVERSE REACTIONS.) Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter (See Laboratory Tests). It is advised that patients be well hydrated,  especially during the initial stages of treatment. “Flu-like” symptoms associated with administration of Peglntron™ may be minimized by bedtime administration of Peglntron™ or by use of antipyretics.

Patients should be advised to use a puncture-resistant container for disposal of the used REDIPEN®. The full container should be disposed of in accordance with state and local laws. Patients should be thoroughly instructed in the importance of proper disposal. Patients should also be cautioned against reusing or sharing the REDIPEN®

Dental and periodontal disorders

Dental and periodontal disorders have been reported in patients receiving Peglntron™/REBETOL® 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 Peglntron™. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, patients should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests

Pregnancy testing should occur monthly during therapy and for 6 months after therapy has stopped in women of childbearing potential.

Peglntron™/REBETOL® Combo Pack therapy may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g.,TSH), and hepatic abnormalities. Transient elevations in ALT (2- to 5-fold above baseline) were observed in 10% of patients treated with Peglntron™, and was not associated with deterioration of other liver function. Triglyceride levels are frequently elevated in patients receiving alpha interferon therapy including Peglntron™ and should be periodically monitored.

Patients on Peglntron™/REBETOL® Combo Pack therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the clinical trial CBC (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week intervals or more frequently if abnormalities developed. TSH levels were measured every 12 weeks during the treatment period. HCV RNA should be measured at 6 months of treatment. Peglntron™/REBETOL® Combo Pack therapy should be discontinued in patients with persistent high viral levels.

Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Peglntron™/REBETOL® Combo Pack.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis and Mutagenesis

Peglntron™ has not been tested for its carcinogenic potential. Neither Peglntron™, nor its components interferon or methoxypolyethylene glycol caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.

 Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was non-carcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult). However, this dose was less than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin.

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20-200 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. 

Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.

Impairment of Fertility

No reproductive toxicology studies have been performed using peginterferon alfa-2b, recombinant in combination with ribavirin. However,  evidence for peginterferon alfa-2b and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effect produced by either agent alone will also be caused by the combination of the two agents.

Peglntron™ may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 mcg/m² Peglntron™ alone every other day for one month (approximately 345 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone,  suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of Peglntron™ treatment. Every other day dosing with 262 mcg/m² (approximately 21 times the weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of Peglntron™ on male fertility have not been studied. 

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 Peglntron™/REBETOL® Combo Pack therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose halflife (t½) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (e.g., 15 half-lives of clearance for ribavirin). 

REBETOL® should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150mg/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.

Pregnancy Category X

(see CONTRAINDICATIONS)

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 Peglntron™/REBETOL® Combo Pack 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 (t½) of ribavirin of 12 days. 

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

Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.  

Nursing Mothers

It is not known whether the components of Peglntron™ and/or REBETOL® are excreted in human milk. Studies in mice have shown that mouse interferons are excreted in breast milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue Peglntron™/REBETOL® Combo Pack treatment,  taking into account the importance of the therapy to the mother.

Pediatric

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

Geriatric

In general, younger patients tend to respond better than older patients to interferon-based therapies. Clinical studies of Peglntron™ in combination with REBETOL® did not include sufficient numbers of subjects aged 65 and over,  however, to determine whether they respond differently than younger subjects.  Treatment with alpha interferons, including Peglntron™, is associated with neuropsychiatric, cardiac, pulmonary, Gl, and systemic (flu-like) adverse effects.  Because these adverse reactions may be more severe in the elderly, caution should be exercised in the use of Peglntron™ in this population. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in patients with impaired renal function (See CLINICAL PHARMACOLOGY: Special Populations: Renal Dysfunction). Peglntron™/REBETOL® Combo Pack therapy should not be used in patients with creatinine clearance < 50 mL/min.

OVERDOSE

There is limited experience with overdosage. In the clinical studies, a few patients accidentally received a dose greater than that prescribed. There were no instances in which a participant in the combination therapy trials received more than 10.5 times the intended dose of Peglntron™. The maximum dose received by any patient was 3.45 mcg/kg weekly over a period of approximately 12 weeks. The maximum known overdosage of REBETOL® was an intentional ingestion of 10 g (fifty 200 mg capsules). There were no serious reactions attributed to these overdosages. In cases of overdosing, symptomatic treatment and close observation of the patient are recommended.

CONTRAINDICATIONS

Peglntron™/REBETOL® Combo Pack therapy is contraindicated in:

• Patients with hypersensitivity to Peglntron™ or ribavirin or any other component of the product
• Women who are pregnant
• Men whose female partners are pregnant
• Patients with autoimmune hepatitis
• Patients with hepatic decompensation (Child-Pugh score > 6 [class B and C]) in cirrhotic CHC patients before or during treatment.
• Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
• Patients with creatinine clearance < 50 mL/min

CLINICAL PHARMACOLOGY

General

The biological activity of Peglntron™ is derived from its interferon alfa-2b moiety.  Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface and initiate a complex sequence of intracellular events. These include primary effects such as the induction of certain enzymes and suppression of cell proliferation in the interferon receptor bearing cells, and secondary effects including immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. These primary and secondary effects inhibit virus replication in virusinfected cells. Interferon alfa upregulates the Th1 T-helper cell subset in cell culture studies. The clinical relevance of these findings is not known.

The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with ribavirin and interferon products has not been established.

Pharmacodynamics

Peglntron™ raises concentrations of effector proteins such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. The correlation between the in vitro and in vivo pharmacologic and pharmacodynamic and clinical effects is unknown.

Pharmacokinetics

Peginterferon alfa-2b

Following a single subcutaneous (SC) dose of Peglntron™, the mean absorption half-life (t ½ ka) was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours. The Cmax and AUC measurements of Peglntron™ increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of Peglntron™. Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416).  The mean Peglntron™ elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent clearance of Peglntron™ is estimated to be approximately 22.0 mL/hr kg. Renal elimination accounts for 30% of the clearance.

Pegylation of interferon alfa-2b produces a product (Peglntron™) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON® A, Peglntron™ (1 mcg/kg) has approximately a 7-fold lower mean apparent clearance and a 5-fold greater mean half-life permitting a reduced dosing frequency.

At effective therapeutic doses, Peglntron™ has approximately ten-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.

Ribavirin

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

Upon multiple oral dosing, based on AUC12hn a 6-fold 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.

TABLE 1:  Mean (% Coefficient of Variation) Pharmacokinetic Parameters for REBETOL® When Administered Individually to Adults

Parameter	REBETOL®
	Single Dose 600 mg Capsules (N=12)	Multiple Dose 600 mg BID Capsules (N=12)
T max (hr)	1.7(46)***	3(60)
Cmax*	782(37)	3680 (85)
AUCtf **	13400 (48)	228000 (25)
T½ (hr)	43.6 (47)	298 (30)
Apparent Volume of Distribution (L)	2825 (9) †
Apparent Clearance(L/hr)	38.2 (40)
Absolute Bioavailability	64% (44)†,†
*ng/mL ** nghr/mL *** N = 11 † data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5 †† N = 6

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. There are insufficient data to address the clinical relevance of these results.  During clinical studies with Peglntron™/REBETOL®, all subjects were instructed to take REBETOL® Capsules with food. (See DOSAGE AND ADMINISTRATION.)

Effect of Antacid on Absorption of Ribavirin

Coadministration of REBETOL® Capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta®1) resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

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

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 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.

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. 

Special Populations

Renal Dysfunction: Following multiple dosing of Peglntron™ (1 mcg/kg SC given every week for four weeks) the clearance of Peglntron™ is reduced by a mean of 17% in patients with moderate renal impairment (creatinine clearance 30-49 mL/min)  and by a mean of 44% in patients with severe renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal function. Clearance was similar in patients with severe renal impairment not on dialysis and patients who are receiving hemodialysis.

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV infected subjects with varying degrees of renal dysfunction. The mean AUCtf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance > 90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCtf was twofold greater when compared to control subjects. The increased AUCtf appears to be due to reduction of renal and non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values > 50 mL/min. The multiple dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance < 50 mL/min should not be treated with Peglntron™/REBETOL® Combo Pack (see PRECAUTIONS).

Hepatic Dysfunction: The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf values were 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.

Gender: During the 48-week treatment period with Peglntron™, no differences in the pharmacokinetic profiles were observed between male and female patients with chronic hepatitis C infection. In ribavirin trials there were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.

Geriatric Patients: The pharmacokinetics of geriatric subjects ( > 65 years of age)  treated with a single subcutaneous dose of 1 mcg/kg of Peglntron™ were similar in Cmax, AUC, clearance, or elimination half-life as compared to younger subjects (28 to 44 years of age). Pharmacokinetic evaluations in elderly subjects with ribavirin have not been performed.

Pediatric Patients: Pharmacokinetic evaluations for combination Peglntron™ and REBETOL® therapy in pediatric subjects have not been performed.

Drug Interactions

Drugs Metabolized by Cytochrome P-450: The pharmacokinetics of representative drugs metabolized by CYP1A2 (caffeine), CYP2C8/9 (tolbutamide),  CYP2D6 (dextromethorphan), CYP3A4 (midazolam), and N-acetyltransferase (dapsone) were studied in 22 patients with chronic hepatitis C who received Peglntron™ (1.5 mcg/kg) once weekly for 4 weeks. Peglntron™ treatment resulted in a 28% (mean) increase in a measure of CYP2C8/9 activity. Peglntron™ treatment also resulted in a 66% (mean) increase in a measure of CYP2D6 activity; however,  the effect was variable as 13 patients had an increase, 5 patients had a decrease,  and 4 patients had no significant change (See PRECAUTIONS: DRUG INTERACTIONS). 

No significant effect was observed on the pharmacokinetics of representative drugs metabolized by CYP1A2, CYP3A4, or N-acetyltransferase. The effects of Peglntron™ on CYP2C19 activity were not assessed.

Methadone: The pharmacokinetics of concomitant administration of methadone and Peglntron™ were evaluated in 18 Peglntron™ naive chronic hepatitis C patients receiving 1.5 mcg/kg/week Peglntron™ SC weekly. All patients were on stable methadone maintenance therapy receiving > 40 mg/day prior to initiating Peglntron™. Mean methadone AUC was approximately 16% higher after 4 weeks of Peglntron™ treatment as compared to baseline. In 2 patients, methadone AUC was approximately double after 4 weeks of Peglntron™ treatment as compared to baseline (See PRECAUTIONS: DRUG INTERACTIONS).

Zidovudine, Lamivudine, and Stavudine: Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, and stavudine and zidovudine. 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 suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HIV/HCV co-infected patients, (see PRECAUTIONS: DRUG INTERACTIONS).

Didanosine: Exposure to didanosine or its active metabolite (dideoxyadenosine 5'- triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities (See PRECAUTIONS: DRUG INTERACTIONS).

Clinical Studies

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

Peglntron™/REBETOL® Combination Therapy-Study 2

A randomized study compared treatment with two Peglntron™/REBETOL® (ribavirin,  USP) regimens [Peglntron™ 1.5 mcg/kg SC once weekly (QW)/REBETOL® 800 mg PO daily (in divided doses); Peglntron™ 1.5 mcg/kg SC QW for 4 weeks then 0.5 mcg/kg SC QW for 44 weeks/REBETOL® 1000/1200 mg PO daily (in divided doses)] with INTRON® A [3 MIU SC thrice weekly (TIW)/REBETOL® 1000/1200 mg PO daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naive patients were treated for 48 weeks and followed for 24 weeks posttreatment. Eligible patients had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV RNA at 24 weeks posttreatment. The response rate to the Peglntron™ 1.5 mcg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON® A/REBETOL® (See Table 2). The response rate to Peglntron™ 1.5→0.5 mcg/kg/REBETOL® was essentially the same as the response to INTRON® A/REBETOL® (data not shown).

Table 2: Rates of Response to Treatment - Study 2

	Peglntron™ 1.5 mcg/kg QW REBETOL® 800 mg QD	INTRON® A3 MIU TIW REBETOL® 1000/1200 mg QD
Overall response 1,2	52% (264/511)	46% (231/505)
Genotype 1	41% (141/348)	33% (112/343)
Genotype 2-6	75% (123/163)	73% (119/162)
1Serum HCV RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory. 2 Difference in overall treatment response (Peglntron™/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 (100 copies/mL) at 24 weeks posttreatment.

Patients with viral genotype 1, regardless of viral load, had a lower response rate to Peglntron™ (1.5 mcg/kg)/REBETOL® (800 mg) compared to patients with other viral genotypes. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON® A/REBETOL®.

Patients with lower body weight tended to have higher adverse event rates (See ADVERSE REACTIONS) and higher response rates than patients with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with Peglntron™/REBETOL® were 49% in men and 56% in women. Response rates were lower in African American and Hispanic patients and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors in this study.

Liver biopsies were obtained before and after treatment in 68% of patients.  Compared to baseline approximately 2/3 of patients in all treatment groups were observed to have a modest reduction in inflammation.

Peglntron™/REBETOL® Combination Therapy-Study 3

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

Treatment with Peglntron™ 1.5 mcg/kg and REBETOL® 800-1400 mg resulted in a higher sustained virologic response compared to Peglntron™ in combination with a flat 800 mg daily dose of REBETOL® for all treated patients (p=0.01). Subjects weighing > 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing > 85-105 kg (Table 3). The benefit of WBD in subjects weighing > 85 kg was observed with HCV genotypes 1-3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia (see ADVERSE REACTIONS and Laboratory Values).

Table 3: 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], genotypeand presence/absence of advanced fibrosis, in the model).

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

Animal Toxicology

Long-term studies in the mouse and rat ( 1 8 - 2 4 months; doses of 20 - 75 and 1 0 - 4 0 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.

PATIENT INFORMATION

Peglntron™/REBETOL® Combo Pack containing

Peglntron™ REDIPEN® Single-dose Delivery System
(peginterferon alfa-2b) and REBETOL® (ribavirin, USP) Capsules

Including appendix with instructions for using Peglntron™ REDIPEN® Single-dose Delivery System

Read this Medication Guide carefully before you start taking Peglntron™/REBETOL® Combo Pack containing Peglntron™ (Peg In-tron) and REBETOL® (REB-eh-tole). Read the Medication Guide each time you refill your prescription because there may be new information. The information in this Medication Guide does not take the place of talking with your health care provider (doctor, nurse, nurse practitioner, or physician's assistant).

What is the most important information I should know about PegIntron™/REBETOL® Combo Pack therapy?

PegIntron™/REBETOL® Combo Pack is a treatment for some people who are infected with hepatitis C virus. However, PegIntron™/REBETOL® Combo Pack therapy can have serious side effects that may cause death in rare cases. Before you decide to start treatment, you should talk to your health care provider about the possible benefits and side effects of PegIntron™/REBETOL® Combo Pack therapy. If you begin treatment you will need to see your health care provider regularly for medical examinations and lab tests to make sure your treatment is working and to check for side effects.

REBETOL® capsules may cause birth defects and/or death of an unborn child. If you are pregnant, you or your male partner must not take PegIntron™/REBETOL® Combo Pack therapy. You must not become pregnant while either you or your partner are being treated with Peglntron™/REBETOL® Combo Pack therapy, or for 6 months after stopping therapy. During this time you must use two forms of birth control and you must have pregnancy test to show that you are not pregnant. Men and women should use birth control while taking the combination therapy and for 6 months afterwards. If you or your partner are being treated and you become pregnant, either during treatment or within 6 months of stopping treatment, call your health care provider right away. There is a Ribavirin Pregnancy Registry that collects information about pregnancy outcomes in female patients and female partners of male patients exposed to ribavirin. You or your health care provider are encouraged to contact the Registry at 1-800-593-2214.

Be assured that any information you tell the Registry will be kept confidential. (See “What should I avoid while taking Peglntron™/REBETOL® Combo Pack therapy?”)

If you are taking PegIntron™/REBETOL® Combo Pack therapy you should call your health care provider immediately if you develop any of these symptoms:

New or worsening mental health problems, such as thoughts about killing or hurting yourself or others, trouble breathing, chest pain, severe stomach or lower back pain,  bloody diarrhea or bloody bowel movements, high fever, bruising, bleeding, or decreased vision.

The most serious possible side effects of PegIntron™/REBETOL® Combo Pack therapy include:

Problems with Pregnancy. Peglntron™/REBETOL® Combo Pack therapy can cause death, serious birth defects, or other harm to your unborn child.  If you are a woman of childbearing age, you must not become pregnant during treatment and for 6 months after you have stopped therapy. You must have a negative pregnancy test immediately before beginning treatment during treatment, and for 6 months after you have stopped therapy. Both males and female patients must use effective forms of birth control during treatment and for the 6 months after treatment is completed. Male patients should use a condom. If you are a female, you must use birth control even if you believe that you are not fertile or that your fertility is low. You should talk to your health care provider about birth control for you and your partner.

Mental health problems and suicide. PegIntron™/REBETOL® Combo Pack therapy may cause patients to develop mood or behavioral problems. These can include irritability (getting easily upset) and depression (feeling low, feeling bad about yourself, or feeling hopeless). Some patients may have aggressive behavior. Former drug addicts may fall back into drug addiction or overdose. Some patients think about hurting or killing themselves or other people and some have killed (suicide) or hurt themselves or others. You must tell your health care provider if you are being treated for a mental illness or had treatment in the past for any mental illness, including depression and suicidal behavior. You should tell your health care provider if you have ever been addicted to drugs or alcohol.

Heart problems. Some patients taking PegIntron™/REBETOL® Combo Pack therapy may develop problems with their heart, including low blood pressure, fast heart rate, and very rarely, heart attacks. Tell your health care provider if you have had any heart problems in the past.

Blood problems. PegIntron™/REBETOL® Combo Pack therapy commonly lowers two types of blood cells (white blood cells and platelets). In some patients, these blood counts may fall to dangerously low levels. If your blood counts become very low, this could lead to infections or bleeding.

REBETOL® can cause anemia, which is a decrease in the number of red blood cells. This can be dangerous, especially for patients who already have heart or circulatory (cardiovascular) or breathing problems. Talk with your health care provider before taking PegIntron™/REBETOL® Combo Pack therapy if you have, or have ever had any cardiovascular problems. Your health care provider should check your red blood cell count before you start therapy and often during the first 4 weeks of therapy. Your red blood cell count may be checked more often if you have any heart or breathing problems.

• Do not take REBETOL Capsules or Oral Solution alone to treat hepatitis C infection. REBETOL Capsules should be used in combination with interferon alfa-2b (INTRON A) or in combination with peginterferon alfa-2b (Peglntron) for treating chronic hepatitis C infection in adults. In children, safety and effectiveness of REBETOL Capsules or Oral Solution has only been shown when used in combination with interferon alfa-2b (INTRON A). Your health care provider or pharmacist should give you a copy of the INTRON A or Peglntron Medication Guide. They have additional important information about combination therapy not covered in this guide.  PegIntron™/REBETOL® Combo Pack is not approved for the treatment of chronic hepatitis C in children.

Body organ problems. Certain symptoms like severe stomach pain may mean that your internal organs are being damaged. Cases of weakness, loss of coordination, and numbness due to stroke have been reported in patients taking combination Peglntron/REBETOL,  including patients with few or no reported risk factors for stroke.

For other possible side effects, see “What are the possible side effects of PegIntron™/REBETOL® Combo Pack therapy” in this Medication Guide.

What is PepTntron™/REBETOL® Combo Pack therapy?

PegIntron™/REBETOL® Combo Pack consists of two medications used to treat hepatitis C infection. Patients with hepatitis C have the virus in their blood and in their liver.  Peglntron™ reduces the amount of virus in the body and helps the body's immune system fight the virus. REBETOL® (ribavirin) is a drug that helps to fight the viral infection, but does not work when used by itself to treat chronic hepatitis C.

It is not known if PegIntron™/REBETOL® Combo Pack therapy can cure hepatitis C (permanently eliminate the virus), or if it can prevent liver failure or liver cancer that is caused by hepatitis C infection.

It is also not known if Peglntron™/REBETOL® Combo Pack therapy will prevent one infected person from infecting another person with hepatitis C.

Who should not take PegIntron™/REBETOL® Combo Pack therapy?

Do not take PegIntron™/REBETOL Combo Pack therapy if you:

• are pregnant, planning to get pregnant during treatment or during the 6 months after treatment, or breast-feeding
• are a male patient with a female sexual partner who is pregnant, or plans to become pregnant at any time while you are being treated with REBETOL®, or during the 6 months after your treatment has ended.
• have hepatitis caused by your immune system attacking your liver (autoimmune hepatitis) or unstable liver disease.
• had an allergic reaction to another alpha interferon or are allergic to any of the ingredients in Peglntron™ or REBETOL® Capsules. If you have any doubts, ask your health care provider.
• Do not take PegIntron™/REBETOL® Combo Pack therapy if you have abnormal red blood cells such as sickle-cell anemia or thalassemia major.

If you have any of the following conditions^ or serious medical problems, discuss them with your health care provider before taking Peglntron™/REBETOL® Combo Pack therapy:

• depression or anxiety
• sleep problems
• high blood pressure
• previous heart attack, or other heart problems
• liver problems (other than hepatitis C infection)
• any kind of autoimmune disease (where the body's immune system attacks the body's own cells), such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis
• thyroid problems
• diabetes
• colitis (inflammation of the bowels)
• cancer
• hepatitis B infection
• HIV infection
• kidney problems
• bleeding problems
• alcoholism
• drug abuse or addiction
• body organ transplant and are taking medicine that keeps your body from rejecting your transplant (suppresses your immune system).

How should I take PegIntron™/REBETOL® Combo Pack therapy?

Your health care provider will determine the correct dose (based on your weight).  PegIntron™/REBETOL® Combo Pack therapy is given for one year. Take your prescribed dose of Peglntron™ ONCE A WEEK, on the same day of each week and at approximately the same time. Take the medicine for the full year and do not take more than the prescribed dose. REBETOL® Capsules should be taken with food. It is important to follow your dosing schedule and your health care providers instructions on how to take your medicines.  Under no circumstances should REBETOL Capsules be opened, crushed or broken. When you take REBETOL® with food, more of the medicine (70% more on average) is taken up by your body. You should take REBETOL®' the same way every day (twice a day with food) to keep the medicine in your body at a steady level. This will help your health care provider to decide how your treatment is working and how to change the number of REBETOL® capsules you take if you have side effects from REBETOL®. Be sure to read the Medication Guide for Peglntron™/REBETOL® for complete instructions on how to take this medicine.

You should be completely comfortable with how to prepare Peglntron™, how to set the dose you take, and how to inject yourself before you use Peglntron™ for the first time.  Peglntron™ comes as a REDIPEN® single-use delivery system. See the attached appendix for detailed instructions for preparing and giving a dose of Peglntron™.

If you miss a dose of the Peglntron™ product, take the missed dose as soon as possible during the same day or the next day, then continue on your regular dosing schedule. If several days go by after you miss a dose, check with your health care provider about what to do. Do not double the next dose or take more than one dose a week without talking to your health care provider. Call your health care provider right away if you take more than your prescribed Peglntron™ dose. Your health care provider may wish to examine you more closely, and take blood for testing.

If you miss a dose of REBETOL® capsules, take the missed dose as soon as possible during the same day. If an entire day has gone by, check with your health care provider about what to do. Do not double the next dose.

You must get regular blood tests to help your health care provider check how the treatment is working and to check for side effects.

Tell your health care provider if you are taking or planning to take other prescription or nonprescription medicines, including vitamin and mineral supplements and herbal medicines.

What should I avoid while taking PegIntron™/REBETOL® Combo Pack therapy?

• If you are pregnant do not start taking PegIntron™/REBETOL® Combo Pack therapy.
• Avoid becoming pregnant while taking PegIntron™/REBETOL® Combo Pack therapy.  PegIntron™/REBETOL Combo Pack therapy may harm your unborn child (death or serious birth defects) or cause you to lose your baby (miscarry). If you or your partner becomes pregnant during treatment or during the 6 months after treatment with Peglntron™/REBETOL® Combo Pack therapy, immediately report the pregnancy to your health care provider. You or your health care provider should call 1-800-5932214.  By calling this number, information about you and/or your partner will be added to a pregnancy registry that will be used to help you and your health care provider make decisions about your treatment for hepatitis in the future. You, your partner, and/or your health care provider will be asked to provide follow-up information on the outcome of the pregnancy. Be assured that any information you tell the Registry will be kept confidential.
• Breastfeeding. The medicine may pass through your milk and harm the baby.
• Drinking alcohol, including beer, wine, and liquor. This may make your liver disease worse.
• Taking other medicines. Take only medicines prescribed or approved by your health care provider. These include prescription and nonprescription medicines and herbal supplements.

What are the most common side effects of REBETOL Capsules and Oral Solution?

The most serious possible side effects of REBETOL Capsules and Oral Solution are:

• Harm to unborn children. REBETOL Capsules and Oral Solution may cause birth defects or death of an unborn child. (For more details, see “What is the most important information I should know about REBETOL Capsules or Oral Solution?”)
• Anemia. Anemia is a reduction in the number of red blood cells you have which can be dangerous, especially if you have heart or breathing problems. Tell your health care provider right away if you feel tired, have chest pain or shortness of breath. These may be signs of low red blood cell counts.
• Do not breast-feed your baby while taking Peglntron™.

What are the possible side effects of PegIntron™/REBETOL® Combo Pack therapy?

Possible, serious side effects include:

Mental health problems including suicide, blood problems, heart problems, body organproblems. See “What is the most important information I should know about PegIntron™/REBETOL® Combo Pack therapy?”

Other body organ problems. A few patients have lung problems (such as pneumonia or inflammation of the lung tissue), inflammation of the kidney, and eye disorders.

New or worsening autoimmune disease. Some patients taking PegIntron™/REBETOL® Combo Pack therapy develop autoimmune diseases (a condition where the body's immune cells attack other cells or organs in the body), including rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. In some patients who already have an autoimmune disease, the disease worsens on PegIntron™/REBETOL® Combo Pack therapy.

Common but less serious side effects include:

Flu-like symptoms. Most patients who take PegIntron™/REBETOL® Combo Pack therapy have “flu-like” symptoms (headache, muscle aches, tiredness, and fever). Some of these symptoms (fever, headache) usually lessen after the first few weeks of therapy. You can reduce some of these symptoms by injecting your Peglntron™ dose at bedtime. Over-thecounter pain and fever reducers, such as acetaminophen or ibuprofen, can be used to prevent or reduce the fever and headache.

Extreme fatigue (tiredness). Many patients become extremely tired while on PegIntron™/REBETOL® Combo Pack therapy.

Appetite problems. Nausea, loss of appetite, and weight loss, occur commonly.

Thyroid problems. Some patients develop changes in the function of their thyroid.  Symptoms of thyroid changes include the inability to concentrate, feeling cold or hot all the time, a change in your weight, and changes to your skin.

Blood sugar problems. Some patients develop problems with the way their body controls their blood sugar, and may develop high blood sugar or diabetes.

Skin reactions. Redness, swelling, and itching are common at the site of injection. If after several days these symptoms do not disappear, contact your health care provider. You may get a rash during therapy. If this occurs, your health care provider may recommend medicine to treat the rash.

Hair thinning. Hair thinning is common during PegIntron™/REBETOL® Combo Pack treatment. Hair loss stops and hair growth returns after therapy is stopped.

These are not all of the side effects of PegIntron™/REBETOL® Combo Pack therapy. Your health care provider or pharmacist can give you a more complete list.

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

General advice about prescription medicines:

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any concerns about PegIntron™/REBETOL® Combo Pack therapy, ask your health care provider. Your health care provider or pharmacist can give you information about PegIntron™/REBETOL® Combo Pack therapy that was written for health care professionals. Do not use PegIntron™/REBETOL® Combo Pack therapy for a condition for which it was not prescribed. Do not share this medication with other people.

How do I store my PegIntron™/REBETOL Combo Pack package?

The Peglntron™/REBETOL® Combo Pack package should be stored in the refrigerator at 2°-8°C (36°-46°F).

When separated, the individual bottle of REBETOL® Capsules should be stored at room temperature 25°C (77°F).

When separated, the Peglntron™ REDIPEN® should be stored in the refrigerator at 2°-8°C (36°-46°F); avoid exposure to heat. After mixing, the Peglntron™ solution should be used immediately but may be stored in the refrigerator up to 24 hours at 2°-8°C (36°-46°F). The solution contains no preservatives. DO NOT FREEZE.

How do I prepare and inject the Peglntron™ REDIPEN® Dose?

The Peglntron™ REDIPEN® system is for a single use, by one person only, ONCE A  WEEK. The REDIPEN® must not be shared. Use only the injection needle provided in the packaging for the Peglntron™ REDIPEN® system. If you have problems with the REDIPEN® system or the Peglntron™ solution, you should contact your health care provider, or pharmacist.

The following instructions explain how to prepare and inject yourself with the Peglntron™ REDIPEN® system. Please read the instructions carefully and follow them step by step. Your health care provider will instruct you on how to self-iniect with the Peglntron™ REDIPEN®. Do not attempt to inject yourself unless you are sure you understand the procedure and requirements for self-ini ection.

How to use the Peglntron™ REDIPEN® Single-dose Delivery System.

Preparation

1. Find a clean, well-lit, non-slip flat working surface and assemble all of the supplies you will need for an injection. All of the supplies you will need are in the Peglntron™ REDIPEN® package. The package contains:

• a Peglntron™ REDIPEN® Single-dose Delivery System
• one disposable needle
• two alcohol swabs, and
• dosing tray (The dosing tray is the bottom half of the REDIPEN® package.)

2. Take the Peglntron™ REDIPEN® out of the refrigerator and allow the medicine to come to room temperature. Before removing the REDIPEN® from the carton, check the expiration date printed on the Peglntron™ REDIPEN® carton to make sure that the expiration date has not passed. Do not use if the expiration date has passed.

3. After taking the Peglntron™ REDIPEN® out of the carton, look in the window of the REDIPEN® and make sure the Peglntron™ in the cartridge holder window is a white, to off- white tablet that is whole, in pieces, or powdered.

4. Wash your hands thoroughly with soap and water, rinse, and towel dry. It is important to keep your work area, your hands, and the injection site clean to minimize the risk of infection.

1. Mix the Drug

Key points:

Before you mix the Peglntron™, make sure it is at room temperature. It is important that you keep the Peglntron™ REDIPEN® UPRIGHT (Dosing Button down) as shown in Figure 1.

a. Hold the Peglntron™ REDIPEN® UPRIGHT (Figure la) in the dosing tray on a hard,  flat, non-slip surface with the dosing button down. You may want to hold the REDIPEN using the grip.

b. To mix the powder and the liquid, keep the REDIPEN® upright in the dosing tray and press the top half of the REDIPEN® downward toward the hard, flat, non-slip surface until you hear the click (Figure lb).Once you've heard the click, you will notice in the window that both dark stoppers are now touching. The dosing button should be flush with the pen body.

Figure 1a

Figure 1b

c. Wait several seconds for the powder to completely dissolve.

d. Gently turn the Peglntron™ REDIPEN® upside down twice (Figure 2). To avoid excessive foaming, DO NOT SHAKE.

Figure 2

f. Place the Peglntron™ REDIPEN® back into the dosing tray provided in the packaging (Figure 3). The dosing button will be on the bottom.

e. Keep the Peglntron™ REDIPEN UPRIGHT, with the dosing button down. Then, look through the REDIPEN® window to see that the mixed Peglntron™ solution is completely dissolved. The solution should be clear and colorless before use. Before attaching the needle, it is normal to see some small bubbles in the REDIPEN® window,  near the top of the solution. Do not use the solution if it is discolored, or not clear, or if particulates are present.

f.  Place the PegIntron™ REDIPENQ®  back into the dosing tray provided in the 397 packaging (Figure 3). The dosing button will be on the bottom.

Figure 3

2. Attach the Needle

a. Wipe the rubber membrane of the Peglntron™ REDIPEN® with one alcohol swab.

b. Remove the protective paper tab from the injection needle, but do NOT remove either the outer cap or the yellow inner cap from the injection needle. Keeping the Peglntron™ REDIPEN® UPRIGHT in the dosing tray, FIRMLY push the injection needle straight into the REDIPEN® rubber membrane, and screw it firmly in place, in a clockwise direction (Figure 4). Remember to leave the needle caps in place when you attach the needle to the REDIPEN®. Pushing the needle through the rubber membrane, “primes” the needle and allows the extra liquid and air in the pen to be removed.

Figure 4

NOTE: Some fluid will trickle out. This is normal. The dark stoppers move up and you will no longer see the fluid in the window once the needle is successfully primed.

3. Dialing the Dose

a. Remove the Peglntron™ REDIPEN® from the dosing tray (Figure 5a).

Holding the Peglntron™ REDIPEN® firmly, pull the dosing button out as far as it will go. -You will see a dark bandv

Do not push the dosing button in until you are ready to self-inject the Peglntron™ dose.

Figure 5a

b. Turn the dosing button until your prescribed dose is lined up with the dosing tab (Figure 5b).  The dosing button will turn freely. If you have trouble dialing your dose, check to make sure the dosing button has been pulled out as far as it will go (Figure 5c).

Figure 5b Figure 5c

c. Carefully lay the Peglntron™ REDIPEN® down on a hard, flat, non-slip surface. Do NOT remove either of the needle caps and do NOT push the dosing button in until you are ready to self-inject the Peglntron™ dose.

4. Injecting the Peglntron™ Dose

Choosing an Injection Site

The best sites for giving yourself an injection are those areas with a layer of fat between the skin and muscle, like your thigh, the outer surface of your upper arm, and abdomen.  Do not inject yourself in the area near your navel or waistline. If you are very thin, you should only use the thigh or outer surface of the arm for injection.

You should use a different site each time you inject Peglntron™ to avoid soreness at any one site. Do not inject Peglntron™ into an area where the skin is irritated, red, bruised,  infected, or has scars, stretch marks, or lumps.

a. Clean the skin where the injection is to be given with the second alcohol swab provided, and wait for the area to dry.

b. Remove the outer cap from the needle (Figure 6a). There may be some liquid around the yellow inner needle cap (Figure 6b). This is normal.

Figure 6a Figure 6b

c. Once the injection site is dry, remove the yellow inner needle cap (Figure 6c). You are now ready to inject.

Figure 6c

d. Hold the Peglntron™ REDIPEN ® with your fingers wrapped around the pen body barrel and your thumb on the dosing button (Figure 7).

• With your other hand, pinch the skin in the area you have cleaned for injection.
• Insert the needle into the pinched skin at an angle of 45° to 90°.
• Press the dosing button down slowly and firmly until you can't push it any further.
• Keep your thumb pressed down on the dosing button for an additional 5 seconds to ensure that you get the complete dose.
• Remove the needle from your skin.

Figure 7

e. Gently press the injection site with a small bandage or sterile gauze if necessary for a few seconds but do not massage the injection site. If there is bleeding, cover with an adhesive bandage. DO NOT RECAP THE NEEDLE and DO NOT REUSE the REDIPEN®.

How do I Dispose of the REDIPEN ®?

Discard the REDIPEN® and needle and any solution remaining in the REDIPEN® in a sharps container or other puncture-resistant container like a metal coffee can. DO NOT use glass or clear plastic containers. Ask your health care provider how to dispose of a full container.

Always keep the container out of reach of children.  After 2 hours, check the injection site for redness, swelling, or tenderness.  If you have a skin reaction and it doesn't clear up in a few days, contact your health care provider.

This Medication Guide has been approved by the U.S. Food and Drug Administration.