Peginterferon alfa-2a 003580

Categories, Drug Classes, Brand Names & Cost Of Therapy

Categories: Hepatitis C; Pregnancy Category X; FDA Approved 2002 Dec

Drug Classes: Antivirals; Immunomodulators

Brand Names: Pegasys

Warning

Description

Each vial contains approximately 1.2 ml of solution to deliver 1.0 ml of drug product. Subcutaneous (SC) administration of 1.0 ml delivers 180 µg of drug product (expressed as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.05 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ± 0.01.

Clinical Pharmacology

Interferons bind to specific receptors on the cell surface initiating intracellular signaling via a complex cascade of protein-protein interactions leading to rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation, and immunomodulation. The clinical relevance of these in vitro activities is not known.

Peginterferon alfa-2a stimulates the production of effector proteins such as serum neopterin and 2′, 5′-oligoadenylate synthetase.

Pharmacokinetics

Maximal serum concentrations (C_max) occur between 72-96 hours post dose. The C_max and AUC measurements of peginterferon alfa-2a increase in a dose-related manner. Week 48 mean trough concentrations (16 ng/ml; range 4-28) at 168 hours post dose are approximately 2-fold higher than week 1 mean trough concentrations (8 ng/ml; range 0-15). Steady-state serum levels are reached within 5-8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2.0.

The mean systemic clearance in healthy subjects given peginterferon alfa-2a was 94 ml/h, which is 48 approximately 100- fold lower than that for interferon alfa-2a (interferon alfa-2b). The mean terminal half- life after SC dosing in patients with chronic hepatitis C was 80 hours (range 50-140 hours) compared to 5.1 hours (range 3.7-8.5 hours) for interferon alfa-2b.

Special Populations

Gender and Age

Peginterferon alfa-2a administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295-1663 ng·h/ml in subjects older than 62 years taking 180 µg peginterferon alfa-2a, but peak concentrations were similar (9 vs 10 ng/ml) in those older and younger than 62 years.

Pediatric Patients

The pharmacokinetics of peginterferon alfa-2a have not been adequately studied in pediatric patients.

Renal Dysfunction

In patients with end stage renal disease undergoing hemodialysis, there is a 25-45% reduction in peginterferon alfa-2a clearance (see PRECAUTIONS, Renal Impairment).

The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance <50 ml/min. Therefore, patients with creatinine clearance <50 ml/min should not be treated with ribavirin (see WARNINGS and DOSAGE AND ADMINISTRATION).

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (T_max was doubled) and the AUC(0-192h) and C_max increased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Nucleoside Analogues

Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased anti-retroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5′-triphosphate) is increased when didanosine is co-administered with ribavirin (see DRUG INTERACTIONS).

Clinical Studies

The safety and effectiveness of peginterferon alfa-2a for the treatment of hepatitis C virus infection were assessed in three randomized, open- label, active-controlled clinical studies. All patients were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All patients received therapy by SC injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled patients with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

In study 1 (n=630), patients received either interferon alfa-2a 3 MIU 3 times/week (TIW), peginterferon alfa-2a 135 µg once each week (qw) or peginterferon alfa-2a 180 µg qw. In study 2 (n=526), patients received either interferon alfa-2b 6 MIU TIW for 12 weeks followed by 3 MIU TIW for 36 weeks or peginterferon alfa-2a 180 µg qw. In study 3 (n=269), patients received interferon alfa-2b 3 MIU TIW, peginterferon alfa-2a 90 µg qw or peginterferon alfa-2a 180 µg once each week.

In all three studies, treatment with peginterferon alfa-2a 180 µg resulted in significantly more patients who experienced a sustained response (defined as undetectable HCV RNA and normalization of ALT on or after study week 68) compared to treatment with interferon alfa-2b. In study 1, response to peginterferon alfa-2a 135 µg was not different from response to 180 µg. In study 3, response to peginterferon alfa-2a 90 µg was intermediate between peginterferon alfa-2a 180 µg and interferon alfa-2b.

Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of 109 patients. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups.

Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2-log10 drop in HCV RNA titer from baseline by 12 weeks of peginterferon alfa-2a 180 µg therapy, 2% (3/156) achieved a sustained virologic response (see DOSAGE AND ADMINISTRATION).

Averaged over study 1, study 2, and study 3, response rates to peginterferon alfa-2a were 23% among patients with viral genotype 1 and 48% in patients with other viral genotypes. The treatment response rates were similar in men and women.

Peginterferon alfa-2a/Ribavirin Combination Therapy (Studies 4 and 5)

The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A).

In study 4, patients were randomized to receive either peginterferon alfa-2a 180 µg SC once weekly (qw) with an oral placebo, peginterferon alfa-2a 180 µg qw with ribavirin 1000 mg PO (body weight <75 kg) or 1200 mg PO (body weight ≥75 kg) or interferon alfa-2b 3 MIU SC TIW plus ribavirin 1000 mg or 1200 mg PO. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded. Peginterferon alfa-2a in combination with ribavirin resulted in a higher SVR (defined as undetectable HCV RNA at the end of the 24 week treatment-free follow-up period) compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (TABLE 2). In all treatment arms, patients with viral genotype 1 regardless of viral load, had a lower response rate compared to patients with other viral genotypes.

In study 5, all patients received peginterferon alfa-2a 180 µg SC qw and were randomized to treatment for either 24 or 48 weeks and to a ribavirin dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg / ≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 × 10 6 HCV RNA copies/ml serum) were preferentially assigned to treatment for 48 weeks.

Genotype 1

Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24 week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin.

Genotype Non-1

Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see TABLE 3).

Among the 36 patients with genotype 4, response rates were similar to those observed in patients with genotype 1 (data not shown). The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

Treatment Response in Patient Subgroups

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in patients older than 40 years (50% vs 66%), in patients with cirrhosis (47% vs 59%), in patients weighing over 85 kg (49% vs 60%), and in patients with genotype 1 with high versus low viral load (43% vs 56%). African American patients had lower response rates compared to Caucasians.

Paired liver biopsies were performed on approximately 20% of patients in Studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups.

In studies 4 and 5, lack of early virologic response at 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response at 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response at 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

Indications And Usage

Contraindications

Peginterferon alfa-2a is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications in neonates and infants, which are sometimes fatal.

Peginterferon alfa-2a and ribavirin combination therapy is additionally contraindicated in:

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 have their therapy withdrawn (see BOXED WARNING).

Neuropsychiatric

Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving therapy with peginterferon alfa-2a and include suicide, suicidal ideation, depression, relapse of drug addiction and drug overdose. These reactions may occur in patients with and without previous psychiatric illness.

Peginterferon alfa-2a should be used with extreme caution in patients who report a history of depression. Neuropsychiatric adverse events observed with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar disorders and mania. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Patients should be advised to report any sign or symptom of depression or suicidal ideation to their prescribing physicians. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Infections

Serious and severe bacterial infections, some fatal, have been observed in patients treated with alpha interferons including peginterferon alfa-2a. Some of the infections have been associated with neutropenia. Peginterferon alfa-2a should be discontinued in patients who develop severe infections and appropriate antibiotic therapy instituted.

Bone Marrow Toxicity

Peginterferon alfa-2a suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including peginterferon alfa-2a. Very rarely alpha interferons may be associated with aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy (see PRECAUTIONS, Laboratory Tests).

Peginterferon alfa-2a and ribavirin should be used with caution in patients with baseline neutrophil counts <1500 cells/mm³ , with baseline platelet counts <90,000 cells/mm³ or baseline hemoglobin <10 g/dl. Peginterferon alfa-2a therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts (see DOSAGE AND ADMINISTRATION, Dose Modification).

Cardiovascular Disorders

Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients treated with peginterferon alfa-2a.

Peginterferon alfa-2a should be administered with caution to patients with preexisting cardiac disease. Because cardiac disease may be worsened by ribavirin- induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin (see WARNINGS, Anemia and the ribavirin package insert).

Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued and appropriate medical therapy immediately instituted.

Endocrine Disorders

Peginterferon alfa-2a causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with peginterferon alfa-2a. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin peginterferon alfa-2a therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of peginterferon alfa-2a therapy.

Autoimmune Disorders

Development or exacerbation of autoimmune disorders including myositis, hepatitis, ITP, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported in patients receiving alpha interferon. Peginterferon alfa-2a should be used with caution in patients with autoimmune disorders.

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 peginterferon alfa-2a or alpha interferon therapy. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with peginterferon alfa-2a.

Colitis

Ulcerative, and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. Peginterferon alfa-2a should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1-3 weeks of discontinuation of alpha interferon.

Pancreatitis

Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. Peginterferon alfa-2a and ribavirin should be suspended if symptoms or signs suggestive of pancreatitis are observed. Peginterferon alfa-2a and ribavirin should be discontinued in patients diagnosed with pancreatitis.

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 are induced or aggravated by treatment with peginterferon alfa-2a 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-2a treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Use With Ribavirin

Also, see ribavirin package insert.

Ribavirin 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 taking peginterferon alfa-2a and ribavirin combination therapy. RIBAVIRIN THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use 2 forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time (see BOXED WARNING, CONTRAINDICATIONS, PRECAUTIONS, Information for the Patient, and the ribavirin package insert).

Anemia

The primary toxicity of ribavirin is hemolytic anemia. Hemoglobin <10 g/dl was observed in approximately 13% of ribavirin and peginterferon alfa-2a treated patients in clinical trials (see PRECAUTIONS, Laboratory Tests). The anemia associated with ribavirin occurs within 1-2 weeks of initiation of therapy with maximum drop in hemoglobin observed during the first 8 weeks. BECAUSE THE INITIAL DROP IN HEMOGLOBIN MAY BE SIGNIFICANT, IT IS ADVISED THAT HEMOGLOBIN OR HEMATOCRIT 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 ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued (see DOSAGE AND ADMINISTRATION, Dose Modification, Ribavirin). Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin (see ribavirin package insert).

Renal

It is recommended that renal function be evaluated in all patients started on ribavirin. Ribavirin should not be administered to patients with creatinine clearance <50 ml/min (see CLINICAL PHARMACOLOGY, Special Populations).

Precautions

The safety and efficacy of peginterferon alfa-2a alone or in combination with ribavirin for the treatment of hepatitis C have not been established in:

Renal Impairment

A 25-45% higher exposure to peginterferon alfa-2a is seen in subjects undergoing hemodialysis. In patients with impaired renal function, signs and symptoms of interferon toxicity should be closely monitored. Doses of peginterferon alfa-2a should be adjusted accordingly. Peginterferon alfa-2a should be used with caution in patients with creatinine clearance <50 ml/min (see DOSAGE AND ADMINISTRATION, Dose Modification).

Information for the Patient

Patients receiving peginterferon alfa-2a alone or in combination with ribavirin should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the peginterferon alfa-2a and, if applicable, ribavirin medication guides.

Peginterferon alfa-2a and ribavirin combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin therapy and for 6 months posttherapy. Patients should be advised to notify the physician immediately in the event of a pregnancy (see CONTRAINDICATIONS and WARNINGS).

Women of childbearing potential and men must use 2 forms of effective contraception during treatment and during the 6 months after treatment has concluded; routine monthly pregnancy tests must be performed during this time (see CONTRAINDICATIONS and ribavirin package insert).

If pregnancy does occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of ribavirin therapy to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to ribavirin, the Copegus Pregnancy Registry has been established. Physicians and patients are strongly encouraged to register by calling 1-800-526-6367.

Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter (see Laboratory Tests). Patients should be instructed to remain well hydrated, especially during the initial stages of treatment. Patients should be advised to take ribavirin with food.

Patients should be informed that it is not known if therapy with peginterferon alfa-2a alone or in combination with ribavirin will prevent transmission of HCV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HCV infection. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

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

Laboratory Tests

Before beginning peginterferon alfa-2a or peginterferon alfa-2a and ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8, and then every 4 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

Peginterferon alfa-2a treatment was associated with decreases in WBC, ANC, lymphocytes and platelet counts often starting within the first 2 weeks of treatment (see ADVERSE REACTIONS). Dose reduction is recommended in patients with hematologic abnormalities (see DOSAGE AND ADMINISTRATION, Dose Modification).

While fever is commonly caused by peginterferon alfa-2a therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia (see WARNINGS, Infections).

Transient elevations in ALT (2- to 5-fold above baseline) were observed in some patients receiving peginterferon alfa-2a, and were not associated with deterioration of other liver function tests. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, peginterferon alfa-2a therapy should be discontinued (see DOSAGE AND ADMINISTRATION, Dose Modification).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Peginterferon alfa-2a has not been tested for its carcinogenic potential.

Mutagenesis

Peginterferon alfa-2a did not cause DNA damage when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes, either in the presence or absence of metabolic activation.

Use With Ribavirin

Ribavirin is genotoxic and mutagenic. The carcinogenic potential of ribavirin has not been fully determined. In a p53 (+/-) mouse carcinogenicity study at doses up to the maximum tolerated dose of 100 mg/kg/day ribavirin was not oncogenic. However, on a body surface area basis, this dose was 0.5 times maximum recommended human 24 hour dose of ribavirin. A study in rats to assess the carcinogenic potential of ribavirin is ongoing.

Mutagenesis

See ribavirin package insert.

Impairment of Fertility

Peginterferon alfa-2a may impair fertility in women. Prolonged menstrual cycles and/or 437 amenorrhea were observed in female cynomolgus monkeys given SC injections of 600 µg/kg/dose (7200 µg/m 2 /dose) of peginterferon alfa-2a every other day for 1 month, at approximately 180 times the recommended weekly human dose for a 60 kg person (based on body surface area). Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17β-estradiol and progesterone levels following administration of peginterferon alfa-2a to female monkeys. A return to normal menstrual rhythm followed cessation of treatment. Every other day dosing with 100 µg/kg (1200 µg/m 2 ) peginterferon alfa-2a (equivalent to approximately 30 times the recommended human dose) had no effects on cycle duration or reproductive hormone status.

The effects of peginterferon alfa-2a on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys treated with non-pegylated interferon alfa-2a for 5 months at doses up to 25 × 10 6 IU/kg/day (see ribavirin package insert).

Pregnancy Category C

Peginterferon alfa-2a has not been studied for its teratogenic effect. Non-pegylated interferon alfa-2a treatment of pregnant Rhesus monkeys at approximately 20-500 times the human weekly dose resulted in a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. Peginterferon alfa-2a should be assumed to have abortifacient potential. There are no adequate and well-controlled studies of peginterferon alfa-2a in pregnant women. Peginterferon alfa-2a is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Peginterferon alfa-2a is recommended for use in women of childbearing potential only when they are using effective contraception during therapy.

Pregnancy Category X: Use With Ribavirin

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant (see CONTRAINDICATIONS, WARNINGS, and the ribavirin package insert).

If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, such cases should be reported to the Copegus Pregnancy Registry at 1-800-526-6367.

Nursing Mothers

It is not known whether peginterferon or ribavirin or its components are excreted in human milk. The effect of orally ingested peginterferon or ribavirin from breast milk on the nursing infant has not been evaluated. Because of the potential for adverse reactions from the drugs in nursing infants, a decision must be made whether to discontinue nursing or discontinue peginterferon alfa-2a and ribavirin treatment.

Pediatric Use

The safety and effectiveness of peginterferon alfa-2a, alone or in combination with ribavirin in patients below the age of 18 years have not been established.

Peginterferon alfa-2a contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal (see CONTRAINDICATIONS).

Geriatric Use

Younger patients have higher virologic response rates than older patients. Clinical studies of peginterferon alfa-2a alone or in combination with ribavirin did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (e.g., flu- like) effects may be more severe in the elderly and caution should be exercised in the use of peginterferon alfa-2a in this population. Peginterferon alfa-2a and ribavirin are excreted by the kidney, and the risk of toxic reactions to this therapy may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal func tion, care should be taken in dose selection and it may be useful to monitor renal function. Peginterferon alfa-2a should be used with caution in patients with creatinine clearance <50 ml/min and ribavirin should not be administered to patients with creatinine clearance <50 ml/min.

Drug Interactions

Nucleoside Analogues

Didanosine

Co-administration of ribavirin and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY, Drug Interactions).

Stavudine and Zidovudine

Ribavirin can antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be avoided.

Adverse Reactions

The most common life-threatening or fatal events induced or aggravated by peginterferon alfa-2a and ribavirin were depression, suicide, relapse of drug abuse/overdose, and bacterial infections; each occurred at a frequency of <1%.

Nearly all patients in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions were psychiatric reactions, including depression, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors.

Overall 11% of patients receiving 48 weeks of therapy with peginterferon alfa-2a either alone (7%) or in combination with ribavirin (10%) discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders.

The most common reason for dose modification in patients receiving combination therapy was for laboratory abnormalities; neutropenia (20%) and thrombocytopenia (4%) for peginterferon alfa-2a and anemia (22%) for ribavirin. Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000-1200 mg ribavirin for 48 weeks and in 7% of patients receiving 800 mg ribavirin for 24 weeks. ribavirin dose was reduced in 21% of patients receiving 1000-1200 mg ribavirin for 48 weeks and 12% in patients receiving 800 mg ribavirin for 24 weeks.

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice.

Patients treated for 24 weeks with peginterferon alfa-2a and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs 10%), Hgb <10g/dl (3% vs 15%), dose modification of peginterferon alfa-2a (30% vs 36%) and ribavirin (19% vs 38%) and of withdrawal from treatment (5% vs 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 or 1200 mg ribavirin. On the other hand the overall incidence of adverse events appeared to be similar in the 2 treatment groups.

The most common serious adverse event (3%) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of <1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena ( e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosis, rheumatoid arthritis) peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmo nary embolism, coma, myositis, and cerebral hemorrhage.

Laboratory Test Values

Hemoglobin

The hemoglobin concentration decreased below 12g/dl in 17% (median Hgb drop = 2.2 g/dl) of monotherapy and 52% (median Hgb drop = 3.7 g/dl) of combination therapy patients. Severe anemia (Hgb <10 g/dl) was encountered in 13% of patients receiving combination therapy and 2% of monotherapy recipients. Dose modification for anemia was required in 22% of ribavirin recipients treated for 48 weeks. Hemoglobin decreases in peginterferon alfa-2a monotherapy were generally mild and did not require dose modification (see DOSAGE AND ADMINISTRATION, Dose Modification).

Neutrophils

Decreases in neutrophil count below normal were observed in 95% of patients treated with peginterferon alfa-2a either alone or in combination with ribavirin. Severe potentially life-threatening neutropenia (ANC <0.5 × 10 9 /L) occurred in approximately 5% of patients receiving peginterferon alfa-2a either alone or in combination with ribavirin. Seventeen percent (17%) of patients receiving peginterferon alfa-2a monotherapy and 20-24% of patients receiving peginterferon alfa-2a/ribavirin combination therapy required modification of interferon dosage for neutropenia. Two percent of patients required permanent reductions of peginterferon alfa-2a dosage and <1% required permanent discontinuation. Median neutrophil counts return to pre-treatment levels 4 weeks after cessation of therapy (see DOSAGE AND ADMINISTRATION, Dose Modification).

Lymphocytes

Decreases in lymphocyte count are induced by interferon alpha therapy. Lymphopenia was observed during both monotherapy (86%) and combination therapy with peginterferon alfa-2a and ribavirin (94%). Severe lymphopenia (<0.5 x 10 9 /L) occurred in approximately 5% of monotherapy patients and 14% of combination peginterferon alfa-2a and ribavirin therapy recipients. Dose adjustments were not required by protocol. Median lymphocyte counts return to pre-treatment levels after 4-12 weeks of the cessation of therapy. The clinical significance of the lymphopenia is not known.

Platelets

Platelet counts decreased in 52% of patients treated with peginterferon alfa-2a alone (median drop 45% from baseline), 33% of patients receiving combination with ribavirin (median drop 30% from baseline). Median platelet counts return to pretreatment levels 4 weeks after the cessation of therapy.

Triglycerides

Triglyceride levels are elevated in patients receiving alfa interferon therapy and were elevated in the majority of patients participating in clinical studies receiving either peginterferon alfa-2a alone or in combination with ribavirin. Random levels higher ≥400 mg/dl were observed in about 20% of patients.