PEG-Intron Powder for Injection (Schering)

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DESCRIPTION

PEG-Intron®, peginterferon alfa-2b, Powder for Injection is a covalent conjugate of recombinant 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 PEG-Intron molecule is approximately 31,000 daltons. The specific activity of peginterferon alfa-2b is approximately 0.7 × 10 ⁸ IU/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.

PEG-Intron is supplied in both vials and the Redipen® for subcutaneous use.

Vials

Each vial contains either 74 µg, 118.4 µg, 177.6 µg, or 222 µg of PEG-Intron as a white to off-white tablet-like solid, that is whole/in pieces or as a loose powder, and 1.11 mg dibasic sodium phosphate anhydrous, 1.11 mg monobasic sodium phosphate dihydrate, 59.2 mg sucrose and 0.074 mg polysorbate 80. Following reconstitution with 0.7 mL of the supplied Sterile Water for Injection, USP, each vial contains PEG-Intron at strengths of either 50 µg per 0.5 mL, 80 µg per 0.5 mL, 120 µg per 0.5 mL, or 150 µg per 0.5 mL.

Redipen ®

Redipen® is a dual-chamber glass cartridge containing lyophilized PEG-Intron 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 PEG-Intron Redipen® contains either 67.5 µg, 108 µg, 162 µg, or 202.5 µg of PEG-Intron, 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 PEG-Intron at strengths of either 50 µg per 0.5 mL, 80 µg per 0.5 mL, 120 µg per 0.5 mL, or 150 µg per 0.5 mL for a single use. Because a small volume of reconstituted solution is lost during preparation of PEG-Intron, each Redipen® contains an excess amount of PEG-Intron powder and diluent to ensure delivery of the labeled dose.

CLINICAL PHARMACOLOGY

General:    The biological activity of PEG-Intron 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 the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells. Interferon alfa upregulates the Th1 T-helper cell subset in in vitro studies. The clinical relevance of these findings is not known.

Pharmacodynamics:    PEG-Intron 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:    Following a single subcutaneous (SC) dose of PEG-Intron, the mean absorption half-life (t ½ k _a ) was 4.6 hours. Maximal serum concentrations (C _max ) occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours. The C _max and AUC measurements of PEG-Intron increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PEG-Intron. 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 PEG-Intron elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent clearance of PEG-Intron 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 (PEG-Intron) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON A, PEG-Intron (1.0 µ/kg) has approximately a seven-fold lower mean apparent clearance and a five-fold greater mean half-life permitting a reduced dosing frequency. At effective therapeutic doses, PEG-Intron has approximately ten-fold greater C _max and 50-fold greater AUC than interferon alfa-2b.

Special Populations

Renal Dysfunction

Following multiple dosing of PEG-Intron (1 mcg/kg SC given every week for four weeks) the clearance of PEG-Intron 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 dose of PEG-Intron for monotherapy should be reduced in patients with moderate or severe renal impairment (See DOSAGE AND ADMINISTRATION : DOSE REDUCTION ). REBETOL should not be used in patients with creatinine clearance < 50 mL/min (See REBETOL Package Insert, WARNINGS ).

Gender

During the 48 week treatment period with PEG-Intron, no differences in the pharmacokinetic profiles were observed between male and female patients with chronic hepatitis C infection.

Geriatric Patients

The pharmacokinetics of geriatric subjects (> 65 years of age) treated with a single subcutaneous dose of 1.0 µg/kg of PEG-Intron were similar in C _max , AUC, clearance, or elimination half-life as compared to younger subjects (28 to 44 years of age).

Effect of Food on Absorption of Ribavirin Both AUC _tf and C _max increased by 70% when REBETOL Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. (See DOSAGE AND ADMINISTRATION ).

Drug Interactions:    It is not known if PEG-Intron therapy causes clinically significant drug-drug interactions with drugs metabolized by the liver in patients with hepatitis C. In 12 healthy subjects known to be CYP2D6 extensive metabolizers, a single subcutaneous dose of 1 µg/kg PEG-Intron did not inhibit CYP1A2, 2C8/9, 2D6, hepatic 3A4 or N-acetyltransferase; the effects of PEG-Intron on CYP2C19 were not assessed.

Methadone

The pharmacokinetics of concomitant administration of methadone and PEG-Intron were evaluated in 18 PEG-Intron na[iuml ]ve chronic hepatitis C patients receiving 1.5 µg/kg/week PEG-Intron SC weekly. All patients were on stable methadone maintenance therapy receiving >/=40 mg/day prior to initiating PEG-Intron. Mean methadone AUC was approximately 16% higher after 4 weeks of PEG-Intron treatment as compared to baseline. In 2 patients, methadone AUC was approximately double after 4 weeks of PEG-Intron treatment as compared to baseline (see PRECAUTIONS : Drug Interactions ).

CLINICAL STUDIES

PEG-Intron Monotherapy-Study 1

A randomized study compared treatment with PEG-Intron (0.5, 1.0, or 1.5 µg/kg once weekly SC) to treatment with INTRON A, (3 million units three times weekly SC) in 1219 adults with chronic hepatitis from HCV infection. The patients were not previously treated with interferon alfa, had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. Patients were treated for 48 weeks and were followed for 24 weeks post-treatment. Seventy percent of all patients were infected with HCV genotype 1, and 74 percent of all patients had high baseline levels of HCV RNA (more than 2 million copies per mL of serum), two factors known to predict poor response to treatment.

Response to treatment was defined as undetectable HCV RNA and normalization of ALT at 24 weeks post-treatment. The response rates to the 1.0 and 1.5 µg/kg PEG-Intron doses were similar (approximately 24%) to each other and were both higher than the response rate to INTRON A (12%). (See Table 1 .)

Patients with both viral genotype 1 and high serum levels of HCV RNA at baseline were less likely to respond to treatment with PEG-Intron. Among patients with the two unfavorable prognostic variables, 8% (12/157) responded to PEG-Intron treatment and 2% (4/169) responded to INTRON A. Doses of PEG-Intron higher than the recommended dose did not result in higher response rates in these patients.

Patients receiving PEG-Intron with viral genotype 1 had a response rate of 14% (28/199) while patients with other viral genotypes had a 45% (43/96) response rate.

Ninety-six percent of the responders in the PEG-Intron groups and 100% of responders in the INTRON A group first cleared their viral RNA by week 24 of treatment. (See DOSAGE AND ADMINISTRATION .)

The treatment response rates were similar in men and 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 (9% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 60% of patients. A modest reduction in inflammation compared to baseline that was similar in all four treatment groups was observed.

PEG-Intron/REBETOL Combination Therapy-Study 2

A randomized study compared treatment with two PEG-Intron/REBETOL regimens [PEG-Intron 1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PEG-Intron 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/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 na[iuml ]ve 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 PEG-Intron 1.5 µg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (see Table 2 ). The response rate to PEG-Intron 1.5 -> 0.5 µg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-Intron (1.5 µg/kg)/REBETOL 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 PEG-Intron/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.

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.

INDICATIONS AND USAGE

PEG-Intron, peginterferon alfa-2b, is indicated for use alone or in combination with REBETOL (ribavirin, USP) 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.

CONTRAINDICATIONS

PEG-Intron is contraindicated in patients with:

• hypersensitivity to PEG-Intron or any other component of the product
• autoimmune hepatitis
• decompensated liver disease

PEG-Intron/REBETOL combination therapy is additionally contraindicated in:

• patients with hypersensitivity to ribavirin or any other component of the product
• women who are pregnant
• men whose female partners are pregnant
• patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
• patients with creatinine clearance < 50 mL/min

WARNINGS

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.

Neuropsychiatric events

Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in patients with and without a previous psychiatric disorder during PEG-Intron treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with alpha interferons. PEG-Intron 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. In severe cases, PEG-Intron should be stopped immediately and psychiatric intervention instituted. (See DOSAGE AND ADMINISTRATION : Dose Reduction .)

Bone marrow toxicity

PEG-Intron suppresses bone marrow function, sometimes resulting in severe cytopenias. PEG-Intron 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.

Endocrine disorders

PEG-Intron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with PEG-Intron. 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 PEG-Intron therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue PEG-Intron therapy.

Cardiovascular events

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

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 PEG-Intron or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PEG-Intron combination 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. PEG-Intron 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. PEG-Intron 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 (eg, thyroiditis, thrombocytopenia, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, psoriasis) have been observed in patients receiving PEG-Intron. PEG-Intron 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 (eg, 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.

Hypersensitivity

Serious, acute hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, 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 PEG-Intron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Use with Ribavirin-(See also REBETOL Package Insert .)

REBETOL may cause birth defects and/or death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests (see BOXED WARNING , CONTRAINDICATIONS and PRECAUTIONS : Information for Patients and REBETOL package insert).

Anemia

Ribavirin caused hemolytic anemia in 10% of PEG-Intron/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. 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 : Dose Reduction .)

PRECAUTIONS

· PEG-Intron alone or in combination with REBETOL has not been studied in patients who have failed other alpha interferon treatments.

· The safety and efficacy of PEG-Intron alone or 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 PEG-Intron/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-alfa including PEG-Intron therapy. Hypertriglyceridemia may result in pancreatitis (see WARNINGS : Pancreatitis ). Elevated triglyceride levels should be managed as clinically appropriate. Discontinuation of PEG-Intron therapy should be considered for patients with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting and persistently elevated triglycerides (eg. triglycerides >1000 mg/dL).

Patients with renal insufficiency:    Increases in serum creatinine levels have been observed in patients with renal insufficiency receiving interferon alfa products, including PEG-Intron. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and PEG-Intron dosing should be adjusted accordingly or discontinued (see CLINICAL PHARMACOLOGY : Pharmacokinetics and DOSAGE AND ADMINISTRATION : Dose Reduction ). PEG-Intron monotherapy should be used with caution in patients with creatinine clearance <50 mL/min; the potential risks should be weighed against the potential benefits in these patients. Combination therapy with REBETOL must not be used in patients with creatinine clearance < 50 mL/min (see REBETOL Package Insert WARNINGS ).

Information for Patients:    Patients receiving PEG-Intron alone or in combination with REBETOL should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the MEDICATION GUIDES for PEG-Intron and, if applicable, REBETOL (ribavirin, USP).

Patients must be informed that REBETOL may cause birth defects and/or death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during treatment with combination PEG-Intron/REBETOL therapy and for 6 months post-therapy. Combination PEG-Intron/REBETOL therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. It is recommended that patients undergo monthly pregnancy tests during therapy and for 6 months post-therapy. (See CONTRAINDICATIONS and REBETOL package insert.)

Patients should be informed that there are no data regarding whether PEG-Intron therapy will prevent transmission of HCV infection to others. Also, it is not known if treatment with PEG-Intron will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.

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 PEG-Intron may be minimized by bedtime administration of PEG-Intron or by use of antipyretics.

Patients should be advised to use a puncture-resistant container for the disposal of used syringes, needles, and the 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 needles, syringes, or the Redipen®.

Laboratory Tests:    PEG-Intron alone or in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (eg, TSH) and hepatic abnormalities. Transient elevations in ALT (2-5 fold above baseline) were observed in 10% of patients treated with PEG-Intron, and was not associated with deterioration of other liver functions. Triglyceride levels are frequently elevated in patients receiving alpha interferon therapy including PEG-Intron and should be periodically monitored.

Patients on PEG-Intron or PEG-Intron/REBETOL combination 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. PEG-Intron or PEG-Intron/REBETOL combination 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 PEG-Intron/REBETOL.

Drug Interactions

In a pharmacokinetic study of 18 chronic hepatitis C patients concomitantly receiving methadone, treatment with PEG-Intron 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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis and Mutagenesis:    PEG-Intron has not been tested for its carcinogenic potential. Neither PEG-Intron, nor its components interferon or methoxy polyethylene glycol caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.

Use with Ribavirin:    Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. See REBETOL package insert for additional warnings relevant to PEG-Intron therapy in combination with ribavirin.

Impairment of Fertility:    PEG-Intron may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 µg/m ² PEG-Intron alone every other day for 1 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 PEG-Intron treatment. Every other day dosing with 262 µg/m ² (approximately 21 times the weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of PEG-Intron on male fertility have not been studied.

Pregnancy Category C: PEG-Intron monotherapy:    Non-pegylated Interferon alfa-2b, has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). PEG-Intron should be assumed to also have abortifacient potential. There are no adequate and well-controlled studies in pregnant women. PEG-Intron therapy is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Therefore, PEG-Intron is recommended for use in fertile women only when they are using effective contraception during the treatment period.

Pregnancy Category X: Use with Ribavirin

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. See CONTRAINDICATIONS and the REBETOL Package Insert.

If pregnancy occurs in a patient or partner of a patient during treatment with PEG-Intron and REBETOL or during the 6 months after treatment cessation, physicians should report such cases by calling (800) 727-7064.

Nursing Mothers:    It is not known whether the components of PEG-Intron 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 adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue the PEG-Intron and REBETOL 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 PEG-Intron alone or 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 PEG-Intron, is associated with neuropsychiatric, cardiac, pulmonary, GI 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 PEG-Intron 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 ). REBETOL should not be used in patients with creatinine clearance <50 mL/min. When using PEG-Intron/REBETOL therapy, refer also to the REBETOL Package Insert.

ADVERSE REACTIONS

Nearly all study patients in clinical trials experienced one or more adverse events. In the PEG monotherapy trial the incidence of serious adverse events was similar (about 12%) in all treatment groups. In the PEG-Intron/REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-Intron/REBETOL groups compared to 14% in the INTRON A/REBETOL group.

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. In the PEG-Intron/REBETOL trial 13 patients experienced life-threatening psychiatric events (suicidal ideation or attempt) and one patient accomplished suicide.

There have been five patient deaths which occurred in clinical trials: one suicide in a patient receiving PEG-Intron monotherapy and one suicide in a patient receiving PEG-Intron/REBETOL combination therapy; two deaths among patients receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death) and one patient death in the INTRON A/REBETOL group (motor vehicle accident).

Overall, 10-14% of patients receiving PEG-Intron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. The most common reasons for discontinuation of therapy were related to psychiatric, systemic (eg, fatigue, headache), or gastrointestinal adverse events.

In the combination therapy trial, dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-Intron (1.5 µg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of patients (57%) weighing 60 kg or less receiving PEG-Intron (1.5 µg/kg)/REBETOL required dose reduction. Reduction of interferon was dose related (PEG-Intron 1.5 µg/kg >PEG-Intron 0.5 µg/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 the PEG-Intron/REBETOL combination trial the most common adverse events were psychiatric which occurred among 77% of patients and 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 ).

PEG-Intron induced fatigue or headache in approximately two-thirds of patients, and induced fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (eg, fever and headache) tended to decrease as treatment continues. The incidence tends to be higher with PEG-Intron than with INTRON A therapy alone or in combination with REBETOL.

Application site inflammation and reaction (eg, bruise, itchiness, irritation) occurred at approximately twice the incidence with PEG-Intron therapies (in up to 75% of patients) compared with INTRON A. However injection site pain was infrequent (2-3%) in all groups.

Other common adverse events in the PEG-Intron/REBETOL group included myalgia (56%), arthralgia (34%), nausea (43%), anorexia (32%), weight loss (29%), alopecia (36%), and pruritus (29%).

In the PEG-Intron monotherapy trial the incidence of severe adverse events was 13% in the INTRON A group and 17% in the PEG-Intron groups. In the PEG-Intron/REBETOL combination therapy trial the incidence of severe adverse events was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-Intron/REBETOL groups. The incidence of life-threatening adverse events was </=1% across all groups in the monotherapy and combination therapy trials.

Adverse events that occurred in the clinical trial at >5% incidence are provided in Table 3 by treatment group. Due to potential differences in ascertainment procedures, adverse event rate comparisons across studies should not be made.

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 PEG-Intron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). 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, phototoxicity.

Laboratory Values

Changes in selected laboratory values during treatment with PEG-Intron alone or 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.    REBETOL induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to <11 g/dL in about 30% of patients. Severe anemia (<8 g/dL) occurred in <1% of patients. Dose modification was required in 9% and 13% of patients in the PEG-Intron/REBETOL and INTRON A/REBETOL groups. Hemoglobin levels become stable by treatment week 4-6 on average. Hemoglobin levels return to baseline between 4 and 12 weeks posttreatment. In the PEG-Intron monotherapy trial hemoglobin decreases were generally mild and dose modifications were rarely necessary. (See DOSAGE AND ADMINISTRATION : Dose Reduction .)

Neutrophils.    Decreases in neutrophil counts were observed in a majority of patients treated with PEG-Intron alone (70%) or as combination therapy with REBETOL (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (<0.5 × 10 ⁹ /L) occurred in 1% of patients treated with PEG-Intron monotherapy, 2% of patients treated with INTRON A/REBETOL and in 4% of patients treated with PEG-Intron/REBETOL. Two percent of patients receiving PEG-Intron monotherapy and 18% of patients receiving PEG-Intron/REBETOL required modification of interferon dosage. Few patients (</=1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pretreatment levels within 4 weeks of cessation of therapy. (See DOSAGE AND ADMINISTRATION : Dose Reduction .)

Platelets.    Platelet counts decrease in approximately 20% of patients treated with PEG-Intron alone or with REBETOL and in 6% of patients treated with INTRON A/REBETOL. Severe decreases in platelet counts (<50,000/mm ³ ) occur in <1% of patients. Patients may require discontinuation or dose modification as a result of platelet decreases. (See DOSAGE AND ADMINISTRATION : Dose Reduction .) In the PEG-Intron/REBETOL combination therapy trial 1% or 3% of patients required dose modification of INTRON A or PEG-Intron respectively. Platelet counts generally returned to pretreatment levels within 4 weeks of the cessation of therapy.

Triglycerides.    Elevated triglyceride levels have been observed in patients treated with interferon alfas including PEG-Intron.

Thyroid Function.    Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. Clinically apparent thyroid disorders occur among patients treated with either INTRON A or PEG-Intron (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 the PEG-Intron/REBETOL trial 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 post-approval use of PEG-Intron therapy: seizures, hearing impairment, hearing loss, peripheral neuropathy, rhabdomyolysis, myositis, aphthous stomatitis, vertigo, renal insufficiency, renal failure, Stevens Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. 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 PEG-Intron (32/1759) or INTRON A (11/728) with or without REBETOL developed low-titer (</=160) neutralizing antibodies to PEG-Intron or INTRON A. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. 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 PEG-Intron in a Biacore assay that is used to measure binding antibodies, and in an antiviral neutralization assay, which measures serum-neutralizing 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 PEG-Intron with the incidence of antibodies to other products may be misleading.

OVERDOSAGE

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 monotherapy or combination therapy trials received more than 10.5 times the intended dose of PEG-Intron. The maximum dose received by any patient was 3.45 µg/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.

DOSAGE AND ADMINISTRATION

There are no safety and efficacy data on treatment for longer than 1 year. A patient should self-inject PEG-Intron 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.

It is recommended that patients receiving PEG-Intron, alone or in combination with ribavirin, be discontinued from therapy if HCV viral levels remain high after 6 months of therapy.

PEG-Intron Monotherapy

The recommended dose of PEG-Intron regimen is 1.0 µg/kg/week subcutaneously for 1 year. The dose should be administered on the same day of the week.

The volume of PEG-Intron to be injected depends on the patient weight (see Table 4 below).

PEG-Intron/REBETOL Combination Therapy

When administered in combination with REBETOL, the recommended dose of PEG-Intron is 1.5 micrograms/kg/week. The volume of PEG-Intron to be injected depends on the strength of PEG-Intron and patient's body weight. (See Table 5 .)

The recommended dose of REBETOL is 800 mg/day in 2 divided doses: two capsules (400 mg) with breakfast and two capsules (400 mg) with dinner. REBETOL 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 PEG-Intron 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 PEG-Intron may be accomplished by utilizing a lower dose strength as shown in Table 8 or 9 . For vials, 50% dose reduction may also be accomplished by reducing the volume administered by one-half without changing the dose strength. In the combination therapy trial dose reductions occurred among 42% of patients receiving PEG-Intron 1.5 µg/kg/REBETOL 800 mg daily including 57% of those patients weighing 60 kg or less (see ADVERSE REACTIONS ).

Renal Function

In patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), the PEG-Intron dose should be reduced by 25%. Patients with severe renal dysfunction (creatinine clearance 10-29 mL/min) including those on hemodialysis, should have the PEG-Intron dose reduced by 50%. If renal function decreases during treatment, PEG-Intron therapy should be discontinued.

Preparation and Administration

PEG-Intron Redipen®

PEG-Intron 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 PEG-Intron 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 µg per 0.5 mL, 80 µg per 0.5 mL, 120 µg per 0.5 mL, or 150 µg 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 if the solution is discolored or cloudy, or if particulates are present.

Keeping the pen upright, attach the supplied needle and select the appropriate PEG-Intron 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 PEG-Intron solution is to be injected subcutaneously.

The PEG-Intron 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.

PEG-Intron Vials

Two B-D 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 PEG-Intron Powder for Injection are provided below.

Reconstitute the PEG-Intron lyophilized product with only 0.7 mL of 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 PEG-Intron, and PEG-Intron 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 PEG-Intron dose should be withdrawn and injected subcutaneously. PEG-Intron 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 Storage ). 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.

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

Storage

PEG-Intron Redipen®

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

PEG-Intron Vials

PEG-Intron should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. After reconstitution with supplied Diluent the solution should be used immediately, but may be stored up to 24 hours at 2° to 8°C (36° to 46°F). The reconstituted solution contains no preservative, is clear and colorless. DO NOT FREEZE .

HOW SUPPLIED

Schering®

Schering Corporation

Kenilworth, NJ 07033 USA

Copyright © 2003, 2005, Schering Corporation. All rights reserved.     Rev. 2/05

   27664431T

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