Pegintron

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

Alpha interferons, including Pegintron, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping Pegintron therapy [see Warnings and Precautions (5) and Adverse Reactions (6.1)].

Use with Ribavirin

Ribavirin may cause birth defects and death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. [See REBETOL package insert.]

Indications and Usage for Pegintron

Chronic Hepatitis C

 Pegintron®, as part of a combination regimen, is indicated for the treatment of Chronic Hepatitis C in patients with compensated liver disease.

•  Pegintron in combination with REBETOL® (ribavirin) and an approved Hepatitis C Virus (HCV) NS3/4A protease inhibitor is indicated in adult patients (18 years of age and older) with HCV genotype 1 infection (see the Package Insert of the specific HCV NS3/4A protease inhibitor for further information).


•  Pegintron in combination with REBETOL is indicated in patients with genotypes other than 1, pediatric patients (3-17 years of age), or in patients with genotype 1 infection where use of an HCV NS3/4A protease inhibitor is not warranted based on tolerability, contraindications or other clinical factors.

 Pegintron monotherapy should only be used in the treatment of Chronic Hepatitis C in patients with compensated liver disease if there are contraindications to or significant intolerance of REBETOL and is indicated for use only in previously untreated adult patients. Combination therapy provides substantially better response rates than monotherapy [see Clinical Studies (14)].

Pegintron Dosage and Administration

Pegintron Combination Therapy

 Adults

 The recommended dose of Pegintron is 1.5 mcg/kg/week. The volume of Pegintron to be injected depends on the strength of Pegintron and patient's body weight (see Table 1).

 The recommended dose of REBETOL for use with Pegintron is 800 to 1400 mg orally based on patient body weight. REBETOL should be taken with food. REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.

 See the Package Insert of the specific HCV NS3/4A protease inhibitor for information regarding dosing regimen and administration of the protease inhibitor in combination with Pegintron and ribavirin.

 Duration of Treatment – Treatment with Pegintron/REBETOL of Interferon Alpha-naïve Patients

The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks.

Duration of Treatment – Retreatment with Pegintron/REBETOL of Prior Treatment Failures

 For patients with genotype 1 infection, Pegintron and REBETOL without an HCV NS3/4A protease inhibitor should only be used if there are contraindications, significant intolerance or other clinical factors that would not warrant use of an HCV NS3/4A protease inhibitor. The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies (14.1)].

TABLE 1 Recommended Pegintron Combination Therapy Dosing (Adults)

Body weight kg (lbs)	Pegintron REDIPEN® or Vial Strength to Use	Amount of Pegintron (mcg) to Administer	Volume (mL)* of Pegintron to Administer	REBETOL Daily Dose	REBETOL Number of Capsules
* When reconstituted as directed. † For patients weighing greater than 105 kg (greater than 231 pounds), the Pegintron dose of 1.5 mcg/kg/week should be calculated based on the individual patient weight. Two vials of Pegintron may be necessary to provide the dose.
<40 (<88)	50 mcg per 0.5 mL	50	0.5	800 mg/day	2 × 200 mg capsules A.M. 2 × 200 mg capsules P.M.
40 – 50 (88 – 111)	80 mcg per 0.5 mL	64	0.4	800 mg/day	2 × 200 mg capsules A.M. 2 × 200 mg capsules P.M.
51 – 60 (112 – 133)		80	0.5	800 mg/day	2 × 200 mg capsules A.M. 2 × 200 mg capsules P.M.
61 – 65 (134 – 144)	120 mcg per 0.5 mL	96	0.4	800 mg/day	2 × 200 mg capsules A.M. 2 × 200 mg capsules P.M.
66 – 75 (145 – 166)		96	0.4	1000 mg/day	2 × 200 mg capsules A.M. 3 × 200 mg capsules P.M.
76 – 80 (167 – 177)		120	0.5	1000 mg/day	2 × 200 mg capsules A.M. 3 × 200 mg capsules P.M.
81 – 85 (178 – 187)				1200 mg/day	3 × 200 mg capsules A.M. 3 × 200 mg capsules P.M.
86 – 105 (188 – 231)	150 mcg per 0.5 mL	150	0.5	1200 mg/day	3 × 200 mg capsules A.M. 3 × 200 mg capsules P.M.
>105 (>231)	†	†	†	1400 mg/day	3 × 200 mg capsules A.M. 4 × 200 mg capsules P.M.

Pediatric Patients

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

TABLE 2 Recommended REBETOL* Dosing in Combination Therapy (Pediatrics)

Body weight kg (lbs)	REBETOL Daily Dose	REBETOL Number of Capsules
* REBETOL to be used in combination with Pegintron 60 mcg/m2 weekly. † REBETOL Oral Solution may be used for any patient regardless of body weight.
<47 (<103)	15 mg/kg/day	Use REBETOL Oral Solution†
47 – 59 (103–131)	800 mg/day	2 × 200 mg capsules A.M. 2 × 200 mg capsules P.M.
60 – 73 (132–162)	1000 mg/day	2 × 200 mg capsules A.M. 3 × 200 mg capsules P.M.
>73 (>162)	1200 mg/day	3 × 200 mg capsules A.M. 3 × 200 mg capsules P.M.

Pegintron Monotherapy

The recommended dose of Pegintron regimen is 1 mcg/kg/week subcutaneously for 1 year administered on the same day of the week. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable after 24 weeks of therapy. The volume of Pegintron to be injected depends on patient weight (see Table 3).

TABLE 3 Recommended Pegintron Monotherapy Dosing

Body weight kg (lbs)	Pegintron REDIPEN or Vial Strength to Use	Amount of Pegintron (mcg) to Administer	Volume (mL)* of Pegintron to Administer
* When reconstituted as directed.
≤45 (≤100)	50 mcg per 0.5 mL	40	0.4
46 – 56 (101 – 124)		50	0.5
57 – 72 (125 – 159)	80 mcg per 0.5 mL	64	0.4
73 – 88 (160 – 195)		80	0.5
89 – 106 (196 – 234)	120 mcg per 0.5 mL	96	0.4
107 – 136 (235 – 300)		120	0.5
137 – 160 (301 – 353)	150 mcg per 0.5 mL	150	0.5

Dose Reduction

If a serious adverse reaction develops during the course of treatment [see Warnings and Precautions (5)] discontinue or modify the dosage of Pegintron and 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 depression or laboratory parameters see Tables 4 and 5. Dose reduction of Pegintron in adult patients on Pegintron/REBETOL combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Dose reduction in patients on Pegintron monotherapy is accomplished by reducing the original starting dose of 1 mcg/kg/week to 0.5 mcg/kg/week. Dose reduction of Pegintron in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 6 or 7.

In the adult combination therapy Study 2, dose reductions occurred in 42% of subjects receiving Pegintron 1.5 mcg/kg plus REBETOL 800 mg daily, including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of Pegintron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of Pegintron to 0.5 mcg/kg due to adverse events [see Adverse Reactions (6.1)].

Dose reduction in pediatric patients is accomplished by modifying the recommended dose in a 2-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Tables 4 and 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving Pegintron 60 mcg/m2 weekly plus REBETOL 15 mg/kg daily.

TABLE 4 Guidelines for Modification or Discontinuation of Pegintron or Pegintron/REBETOL and for Scheduling Visits for Patients with Depression

Depression Severity*	Initial Management (4–8 weeks)		Depression Status
	Dose Modification	Visit Schedule	Remains Stable	Improves	Worsens
* See DSM-IV for definitions. For patients on Pegintron/REBETOL combination therapy: 1st dose reduction of Pegintron is to 1 mcg/kg/week, 2nd dose reduction (if needed) of Pegintron is to 0.5 mcg/kg/week. For patients on Pegintron monotherapy: decrease Pegintron dose to 0.5 mcg/kg/week.
Mild	No change	Evaluate once weekly by visit or phone.	Continue weekly visit schedule.	Resume normal visit schedule.	See moderate or severe depression
Moderate	Adults: Adjust Dose* Pediatrics: Decrease dose to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed	Evaluate once weekly (office visit at least every other week).	Consider psychiatric consultation. Continue reduced dosing.	If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced dosing or return to normal dose.	See severe depression
Severe	Discontinue Pegintron/REBETOL permanently.	Obtain immediate psychiatric consultation.	Psychiatric therapy as necessary

TABLE 5 Guidelines for Dose Modification and Discontinuation of Pegintron or Pegintron/REBETOL Based on Laboratory Parameters in Adults and Pediatrics

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

TABLE 6 Reduced Pegintron Dose (0.5 mcg/kg) for (1 mcg/kg) Monotherapy in Adults

Body weight kg (lbs)	Pegintron REDIPEN/Vial Strength to Use	Amount of Pegintron (mcg) to Administer	Volume (mL)* of Pegintron to Administer
* When reconstituted as directed. † Must use vial. Minimum delivery for REDIPEN 0.3 mL.
≤45 (≤100)	50 mcg per 0.5 mL†	20	0.2
46 – 56 (101 – 124)		25	0.25
57 – 72 (125 – 159)	50 mcg per 0.5 mL	30	0.3
73 – 88 (160 – 195)		40	0.4
89 – 106 (196 – 234)	50 mcg per 0.5 mL	50	0.5
107 – 136 (235 – 300)	80 mcg per 0.5 mL	64	0.4
≥137 (≥301)		80	0.5

TABLE 7 Two-Step Dose Reduction of Pegintron in Combination Therapy in Adults

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

Discontinuation of Dosing

Adults

 See the Package Insert of the specific HCV NS3/4A protease inhibitor for information regarding discontinuation of dosing based on treatment futility.

 In HCV genotype 1, interferon-alfa-naïve patients receiving Pegintron, alone or in combination with REBETOL, discontinuation of therapy is recommended if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at Week 12 or 24, are highly unlikely to achieve SVR and discontinuation of therapy is recommended.

Pediatrics (3–17 years of age)

It is recommended that patients receiving Pegintron/REBETOL combination (excluding those with HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped less than 2 log10 compared to pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.

Renal Function

In patients with moderate renal dysfunction (creatinine clearance 30–50 mL/min), the Pegintron dose should be reduced by 25%. Patients with severe renal dysfunction (creatinine clearance 10–29 mL/min), including those on hemodialysis, should have the Pegintron dose reduced by 50%. If renal function decreases during treatment, Pegintron therapy should be discontinued. When Pegintron is administered in combination with REBETOL, subjects with impaired renal function or those over the age of 50 should be more carefully monitored with respect to the development of anemia. Pegintron/REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.

Preparation and Administration

Pegintron REDIPEN

Pegintron 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 Pegintron 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 2 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 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, or 150 mcg 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 Pegintron 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 Pegintron solution is to be injected subcutaneously.

The Pegintron 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 How Supplied/Storage and Handling (16)]. 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.

Pegintron Vials

Two BD® Safety-Lok® syringes are provided in the package; one syringe is for the reconstitution steps and one for the patient injection. There is a plastic safety sleeve to be pulled over the needle after use. The syringe locks with an audible click when the green stripe on the safety sleeve covers the red stripe on the needle. Instructions for the preparation and administration of Pegintron Powder for Injection are provided below.

• Reconstitute the Pegintron lyophilized product with only 0.7 mL of the 1.25 mL of supplied diluent (Sterile Water for Injection USP). The diluent vial is for single use only. The remaining diluent should be discarded. No other medications should be added to solutions containing Pegintron, and Pegintron should not be reconstituted with other diluents.


• Swirl gently to hasten complete dissolution of the powder. The reconstituted solution should be clear and colorless.


• Visually inspect the solution for particulate matter and discoloration prior to administration. The solution should not be used if discolored or cloudy, or if particulates are present.


• The appropriate Pegintron dose should be withdrawn and injected subcutaneously. Pegintron vials are for single use only and do 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 How Supplied/Storage and Handling (16)]. DO NOT REUSE THE VIAL. 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.

Dosage Forms and Strengths

• Single-use vial: 1.25 mL diluent vial: 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, 150 mcg per 0.5 mL.


• Single-use REDIPEN: 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, 150 mcg per 0.5 mL.

Contraindications

Pegintron is contraindicated in patients with:

• known hypersensitivity reactions, such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis to interferon alpha or any other component of the product


• autoimmune hepatitis


• hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment

Pegintron/REBETOL combination therapy is additionally contraindicated in:

• women who are pregnant. REBETOL may cause fetal harm when administered to a pregnant woman. REBETOL is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].


• men whose female partners are pregnant


• patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)


• patients with creatinine clearance less than 50 mL/min

Warnings and Precautions

Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should be withdrawn from therapy.

Use with Ribavirin

Pregnancy

REBETOL may cause birth defects and death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least 2 forms of contraception and have monthly pregnancy tests [see BOXED WARNING, Contraindications (4), Patient Counseling Information (17), and REBETOL package insert].

Anemia

Ribavirin caused hemolytic anemia in 10% of Pegintron/REBETOL-treated subjects within 1 to 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. Anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of REBETOL may be necessary [see Dosage and Administration (2.3) and REBETOL package insert].

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 Pegintron treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with interferon alpha.

 Pegintron should be used with caution in patients with a history of psychiatric disorders. Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is initiated in patients with prior history or existence of psychiatric condition or with a history of substance use disorders, treatment considerations should include the need for drug screening and periodic health evaluation, including psychiatric symptom monitoring. Early intervention for re-emergence or development of neuropsychiatric symptoms and substance use is recommended.

Patients should be advised to report immediately any symptoms of depression 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 Pegintron be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, Pegintron should be stopped immediately and psychiatric intervention instituted [see Dosage and Administration (2.3)]. Cases of encephalopathy have been observed in some patients, usually elderly, treated at higher doses of Pegintron.

Cardiovascular Events

Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with Pegintron. Pegintron should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require Pegintron therapy should be closely monitored [see Warnings and Precautions (5.15)]. Patients with a history of significant or unstable cardiac disease should not be treated with Pegintron /REBETOL combination therapy [see REBETOL package insert].

Endocrine Disorders

Pegintron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with Pegintron. Diabetes mellitus, including cases of new onset Type 1 diabetes, has been observed in patients treated with alpha interferons, including Pegintron. Patients with these conditions who cannot be effectively treated by medication should not begin Pegintron therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue Pegintron therapy.

Ophthalmologic Disorders

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment 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. Peginterferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including Pegintron. 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 alfa-based therapies and these events is difficult to establish.

Bone Marrow Toxicity

Pegintron suppresses bone marrow function, sometimes resulting in severe cytopenias. Pegintron should be discontinued in patients who develop severe decreases in neutrophil or platelet counts [see Dosage and Administration (2.3)]. Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia.

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) has been observed in patients receiving Pegintron. Pegintron should be used with caution in patients with autoimmune disorders.

Pancreatitis

Fatal and nonfatal pancreatitis have been observed in patients treated with alpha interferon. Pegintron therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.

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. Pegintron treatment should be discontinued immediately in patients who develop these signs and symptoms. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferons.

Pulmonary Disorders

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

 Because of the fever and other "flu-like" symptoms associated with Pegintron administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease).

Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including Pegintron. 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 Pegintron treatment should be immediately discontinued if decompensation (Child-Pugh score greater than 6) is observed [see Contraindications (4)].