Pegasys

Black Box Warnings

Alfa interferons cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders

Monitor closely with periodic clinical and laboratory evaluations

Discontinue drug if persistently severe or worsening signs or symptoms of the above conditions are present; disorders typically resolve after stopping therapy

Contraindications

Known hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson) syndrome to alpha interferons

Autoimmune hepatitis Hepatic decompensation (Child-Pugh score >6 [class B and C]) in cirrhotic patients before treatment with or without HIV coinfection

Neonates and infants (contains benzyl alcohol); associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants

When used in combination with other HCV antiviral drugs, the contraindications applicable to those agents are applicable to combination therapies

Combination treatment with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant

Cautions

Ribavirin may cause birth defects and/or death of the exposed fetus; patients must avoid pregnancy (female patients or female partners of male patients) while taking PEG-INF-alfa-2a and ribavirin combination therapy

Life-threatening or fatal neuropsychiatric reactions may manifest and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose; these reactions may occur with and without history of previous psychiatric illness

Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction reported; caution with pre-existing cardiovascular disease

Suppresses bone marrow function and may result in severe cytopenias; ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons; rare occurrences of aplastic anemia observed

Development or exacerbation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus reported

May cause or aggravate endocrine disorders including hypothyroidism, hyperthyroidism, hyperglycemia, hypoglycemia, and diabetes mellitus

Alpha interferons may induce or exacerbate ophthalmic disorders including 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

Patients with CHC with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons

Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by alpha interferons

Serious and severe infections (bacterial, viral, or fungal), some fatal, have been reported during treatment with alpha interferons

Ulcerative and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment

Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment

Severe acute hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, and anaphylaxis) observed

Pediatric patients treated with PEG-INF-alfa-2a plus ribavirin showed a delay in weight and height increases after 48 weeks of therapy compared with baseline; after 2 yr follow-up, most children had returned to baseline normative growth curve percentiles for weight and height

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine

Growth inhibition observed in pediatric subjects 5 -17 years of age receiving peginterferon alfa-2a plus ribavirin thearpy combination for up to 48 weeks

Mechanism Of Action

Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune response [see Microbiology].

Pharmacodynamics

PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5'-oligoadenylate synthetase.

Pharmacokinetics

Maximal serum concentrations (Cmax) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mcg of PEGASYS. Maximal serum concentrations (Cmax) occur between 72 to 96 hours post-dose.

Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON®-A). The mean terminal half-life after subcutaneous dosing in subjects with chronic hepatitis C was 160 hours (range 84 to 353 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A.

Special Populations

PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng·h/mL in subjects older than 62 years taking 180 mcg PEGASYS, but peak concentrations were similar (9 vs. 10 ng/mL) in those older and younger than 62 years.

In a population pharmacokinetics study, 14 children 2 to 8 years of age with CHC received PEGASYS based on their body surface area (BSA of the child x 180 mcg/1.73 m²). The clearance of PEGASYS in children was nearly 4-fold lower compared to the clearance reported in adults.

Steady-state trough levels in children with the BSA-adjusted dosing were similar to trough levels observed in adults with 180 mcg fixed dosing. Time to reach the steady state in children is approximately 12 weeks, whereas in adults, steady state is reached within 5 to 8 weeks. In these children receiving the BSA adjusted dose, the mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing.

A clinical trial evaluated 50 CHC subjects with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). Subjects with moderate renal impairment receiving PEGASYS 180 mcg once weekly dose exhibited similar peginterferon alfa-2a plasma exposures compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of PEGASYS. No PEGASYS dose adjustment is required for patients with mild or moderate renal impairment [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

For subjects with severe renal impairment, peginterferon alfa-2a apparent clearance was 43% lower as compared to subjects with normal renal function. A reduced dose of 135 mcg once weekly PEGASYS is recommended in patients with severe renal impairment. This dose may result in 30% higher peginterferon alfa2a exposure compared to that of the recommended dose for patients with normal renal function. Signs and symptoms of interferon toxicity should be closely monitored in patients with severe renal impairment and the dose reduced to 90 mcg once weekly as appropriate [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

In 18 subjects with ESRD receiving chronic HD, PEGASYS was administered at a dose of 135 mcg once weekly. The apparent clearance of peginterferon alfa-2a was similar between subjects with ESRD and subjects with normal renal function. Despite a lower exposure to peginterferon alfa-2a with the 135 mcg dose, subjects with ESRD had a high rate of adverse events and discontinuations of PEGASYS in the trial. Therefore, a dose of 135 mcg once weekly should be used for patients with ESRD on HD. However, the potential for reduced efficacy and increased interferon toxicity in patients with ESRD receiving chronic HD should be closely monitored. The dose may be reduced to 90 mcg once weekly as appropriate [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Microbiology

The biological activity of PEGASYS is derived from its recombinant human interferon α-2a moiety. Peginterferon α-2a binds to the human type 1 interferon receptor leading to receptor dimerization. Receptor dimerization activates multiple intracellular signal transduction pathways initially mediated by the JAK/STAT pathway. Given the diversity of cell types that respond to interferon α-2a, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon α-2a is expected to have pleiotropic biological effects in the body.

In the stable HCV cell culture model system (HCV replicon), PEG-IFN α-2a inhibited HCV RNA replication, with an EC50 value of 0.1-3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance between IFN-α and ribavirin has not been observed.

Clinical Studies

Chronic Hepatitis C Studies 1, 2, And 3: PEGASYS/COPEGUS Combination Therapy

The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All subjects 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 subjects in both studies had compensated cirrhosis (Child-Pugh class A). Subjects coinfected with HIV were excluded from these studies.

In Study 1, subjects were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS 180 mcg once weekly with COPEGUS 1000 mg by mouth (body weight less than 75 kg) or 1200 mg by mouth (body weight greater than or equal to 75 kg) or Rebetron® (interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth). All subjects received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table 10). In all treatment arms, subjects with viral genotype 1, regardless of viral load, had a lower response rate.

Table 10 : Sustained Virologic Response to Combination Therapy (Study 1)

In Study 2 (see Table 11), all subjects received PEGASYS 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight less than 75 kg/greater than or equal to 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Subjects with genotype 1 and high viral titer (defined as greater than 2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS 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 COPEGUS.

HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS (see Table 11).

The numbers of subjects with genotype 5 and 6 were too few to allow meaningful assessment.

Table 11 : Sustained Virologic Response as a Function of Genotype (Study 2)

Treatment response rates are lower in subjects with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 1 and 2, treatment response rates were lower in subjects older than 40 years (50% vs. 66%), in subjects with cirrhosis (47% vs. 59%), in subjects weighing over 85 kg (49% vs. 60%), and in subjects with genotype 1 with high vs. low viral load (43% vs. 56%). African-American subjects had lower response rates compared to Caucasians.

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

In studies 1 and 2, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of subjects who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of subjects who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

Previously untreated pediatric subjects 5 through 17 years of age (55% less than 12 years old) with chronic hepatitis C, compensated liver disease and detectable HCV RNA were treated with COPEGUS approximately 15 mg/kg/day plus PEGASYS 180 mcg/1.73 m² x body surface area once weekly for 48 weeks. All subjects were followed for 24 weeks post-treatment. Sustained virological response (SVR) was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of 114 subjects were randomized to receive either combination treatment of COPEGUS plus PEGASYS or PEGASYS monotherapy; subjects failing PEGASYS monotherapy at 24 weeks or later could receive open-label COPEGUS plus PEGASYS. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of COPEGUS plus PEGASYS and 59 received PEGASYS plus placebo; in the overall intent-to-treat population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are summarized in Table 12.

Table 12 : Sustained Virologic Response in Pediatric Subjects (NV17424 - Study 3)

Chronic Hepatitis C And Coinfection With HIV (CHC/HIV)

In Study 4, subjects with CHC/HIV were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly plus an oral placebo, PEGASYS 180 mcg once weekly plus COPEGUS 800 mg by mouth daily or ROFERON-A (interferon alfa-2a), 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All subjects received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS treatment arms. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Subjects also had CD4+ cell count greater than or equal to 200 cells/mm³or CD4+ cell count greater than or equal to 100 cells/mm³but less than 200 cells/mm³and HIV-1 RNA less than 5,000 cells/mm³, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in Table 13.

Table 13 : Sustained Virologic Response in Subjects with Chronic Hepatitis C Coinfected with HIV (Study 4)

Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.

Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and ribavirin combination therapy, 2% (2/85) achieved an SVR.

In CHC subjects with HIV coinfection who received 48 weeks of PEGASYS alone or in combination with ribavirin treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

Chronic Hepatitis C Studies 5, 6, And 7: PEGASYS Monotherapy

The safety and effectiveness of PEGASYS for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All subjects were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All subjects received therapy by subcutaneous injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 5 and 6, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 7 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

In Study 5 (n=630), subjects received either ROFERON-A (interferon alfa-2a) 3 MIU three times a week, PEGASYS 135 mcg once weekly or PEGASYS 180 mcg once weekly. In Study 6 (n=526), subjects received either ROFERON-A 6 MIU three times a week for 12 weeks followed by 3 MIU three times a week for 36 weeks or PEGASYS 180 mcg once weekly. In Study 7 (n=269), subjects received ROFERON-A 3 MIU three times a week, PEGASYS 90 mcg once weekly or PEGASYS 180 mcg once each week.

In all three studies, treatment with PEGASYS 180 mcg resulted in significantly more subjects who experienced a sustained response (defined as undetectable HCV RNA [less than 50 IU/mL] using the COBAS AMPLICOR® HCV Test, version 2 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A.

In Study 5, response to PEGASYS 135 mcg was not different from response to 180 mcg. In Study 7, response to PEGASYS 90 mcg was intermediate between PEGASYS 180 mcg and ROFERON-A.

Table 14 : Sustained Response to Monotherapy Treatment

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

Of the subjects 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 PEGASYS 180 mcg therapy, 2% (3/156) achieved a sustained virologic response [see DOSAGE AND ADMINISTRATION].

Averaged over Study 5, Study 6, and Study 7, response rates to PEGASYS were 23% among subjects with viral genotype 1 and 48% among subjects with other viral genotypes. The treatment response rates were similar in men and women.

Chronic Hepatitis B Studies 8 And 9: PEGASYS Monotherapy

The safety and effectiveness of PEGASYS for the treatment of chronic hepatitis B were assessed in controlled clinical trials in HBeAg positive (Study 8) and HBeAg negative (Study 9) subjects with chronic hepatitis B.

Subjects were randomized to PEGASYS 180 mcg subcutaneous once weekly, PEGASYS 180 mcg subcutaneous once weekly combined with lamivudine 100 mg once daily by mouth or lamivudine 100 mg once daily by mouth. All subjects received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of PEGASYS or no PEGASYS was not masked.

All subjects were adults with compensated liver disease, had chronic hepatitis B virus (HBV) infection, and evidence of HBV replication (serum HBV greater than 500,000 copies/mL for Study 8 and greater than 100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR®HBV Assay). All subjects had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic hepatitis.

The results observed in the PEGASYS and lamivudine monotherapy groups are shown in Table 15.

Table 15 : Percentage of Subjects with Serological, Virological, Biochemical, and Histological Response

PEGASYS co-administered with lamivudine did not result in any additional sustained response when compared to PEGASYS monotherapy.

Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.

You should not use this medication if you are allergic to peginterferon alfa-2a, or if you have:

• liver failure or autoimmune hepatitis;
• a hemoglobin blood cell disorder such as sickle-cell anemia or thalassemia;
• if you are pregnant; or
• if you are a man and your sexual partner is pregnant.

To make sure you can safely use peginterferon alfa-2a, tell your doctor if you have any of these other conditions:

• anemia (a lack of red blood cells);
• liver problems other than hepatitis;
• kidney disease (or if you are on dialysis);
• HIV or AIDS;
• diabetes;
• a thyroid disorder;
• lung disease;
• a bleeding or blood clotting disorder;
• heart disease or prior heart attack;
• eye problems;
• problems with your sleep;
• colitis, or a history of stomach or intestinal bleeding;
• an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus (SLE), or psoriasis;
• a history of cancer;
• history of liver or other organ transplant;
• history of depression, anxiety, mental illness, suicidal thoughts, or drug or alcohol addiction;
• if you have both hepatitis B and hepatitis C; or
• if you have used interferon alfa in the past and it was not effective.

Peginterferon alfa-2a is often used together with another medication called ribavirin. Ribavirin is known to cause birth defects or death in an unborn baby. You may need to have a negative pregnancy test before taking these two medications together.

• If you are a woman, do not use peginterferon alfa-2a and ribavirin if you are pregnant.
• If you are a man, do not use peginterferon alfa-2a and ribavirin if your sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin.
• Use at least 2 effective forms of birth control while either sexual partner is using peginterferon alfa-2a with ribavirin. Keep using 2 forms of birth control for at least 6 months after treatment ends.
• Tell your doctor right away if a pregnancy occurs while either the mother or the father is using peginterferon alfa-2a together with ribavirin.

It is not known whether peginterferon alfa-2a passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medication.

Pegasys is part of the drug class:

• interferon

• Store Pegasys single use vials and prefilled syringes in a refrigerator, at 36°F to 46°F (2°C to 8°C).
• Do not freeze or shake Pegasys.
• Protect Pegasys from light. Keep Pegasys vials, prefilled syringes, and all medicines out of the reach of children.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended. If your doctor changes your brand, strength, or type of interferon, your dosage needs may change. Do not change your doses or medication schedule without your doctor's advice.

Peginterferon alfa-2a is injected under the skin, usually once per week. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

Do not shake the medication bottle or you may ruin the medicine. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Peginterferon alfa-2a can lower blood cells that help your body fight infections and help your blood to clot. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Your blood pressure, vision, and lung function may also need to be checked.

If you have hepatitis B you may develop liver symptoms after you stop taking this medicine. Your doctor may want to check your liver function for several months after you stop using peginterferon alfa-2a.

Store in the refrigerator, protected from light. Do not freeze. Each single-use vial (bottle), prefilled syringe, or auto-injector device is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use the medicine as soon as you remember the missed dose, then go back to your regular schedule on the day your next dose is due. If you are more than 2 days late in using your injection, call your doctor for instructions. Do not use extra medicine to make up a missed dose.

Peginterferon alfa-2a injection is used alone or together with other medicines, such as ribavirin (Copegus®, Rebetol®), boceprevir (Victrelis®), and telaprevir (Incivek®), to treat chronic hepatitis C infection. It is also used to treat adult patients with chronic hepatitis B infection. Peginterferon alfa-2a is a synthetic (man-made) version of a substance that is normally produced in the body. It helps your immune system fight hepatitis infections.

This medicine is available only with your doctor's prescription.

Refer to the prescribing information of the other HCV antiviral drugs, including ribavirin, for their Warnings and Precautions.

Pregnancy: Use with Ribavirin

Ribavirin may cause birth defects and/or death of the exposed fetus. Patients must avoid pregnancy (female patients or female partners of male patients) while taking Pegasys and ribavirin combination therapy. Ribavirin therapy should not be started unless a confirmed negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time [see Contraindications (4), Patient Counseling Information (17) and ribavirin labeling].

Neuropsychiatric Reactions

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

Pegasys should be used with extreme caution in all 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 Boxed Warning, Adverse Reactions (6.1) and Dosage and Administration (2.5)].

Cardiovascular Disorders

Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients treated with Pegasys. Pegasys should be administered with caution to patients with pre-existing cardiac disease. Because cardiac disease may be worsened by ribavirin-induced anemia, patients with a history of significant or unstable cardiac disease should not receive Pegasys/ribavirin [see ribavirin prescribing information].

Bone Marrow Suppression

Pegasys suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including Pegasys. 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 ribavirin prescribing information].

Pegasys/ribavirin should be used with caution in patients with baseline neutrophil counts less than 1,500 cells/mm3, with baseline platelet counts less than 90,000 cells/mm3 or baseline hemoglobin less than 10 g/dL. Pegasys therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts [see Dosage and Administration (2.5)].

Severe neutropenia and thrombocytopenia occur with a greater incidence in HIV coinfected patients than monoinfected patients and may result in serious infections or bleeding [see Adverse Reactions (6.1)].

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Pegasys, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.

Autoimmune Disorders

Development or exacerbation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported in patients receiving alpha interferon. Pegasys should be used with caution in patients with autoimmune disorders [see Boxed Warning].

Endocrine Disorders

Pegasys causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with Pegasys. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin Pegasys therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of Pegasys 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 are induced or aggravated by treatment with Pegasys or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing 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. Pegasys 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 Pegasys. 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 [see Boxed Warning].

Hepatic Failure and Hepatitis Exacerbations

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including Pegasys. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study 7 [see Clinical Studies (14.3)], among 129 CHC/HIV cirrhotic subjects receiving HAART, 14 (11%) of these subjects across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 subjects were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs for the associated risk. During treatment, patients' clinical status and hepatic function should be closely monitored, and Pegasys/ribavirin treatment should be immediately discontinued in patients with hepatic decompensation [see Contraindications (4)].

Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation greater than 10-fold higher than the upper limit of normal) during Pegasys treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive subjects, respectively. Marked transaminase flares while on Pegasys therapy have been accompanied by other liver test abnormalities. Patients experiencing ALT flares should receive more frequent monitoring of liver function. Pegasys dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of Pegasys dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, Pegasys should be immediately discontinued [see Adverse Reactions (6.1) and Dosage and Administration (2.5)].

Pulmonary Disorders

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

Infections

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, or fungal), some fatal, have been reported during treatment with alpha interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered [see Boxed Warning].

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. Pegasys should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.

Pancreatitis

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

Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with Pegasys/ribavirin should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving Pegasys with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].

Impact on Growth in Pediatric Patients

During combination therapy for up to 48 weeks with Pegasys plus ribavirin growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.

The available longer term data on subjects who were followed up to 6 years post-treatment is too limited to determine the risk of reduced adult height in some patients [see Clinical Trials Experience (6.1)].

Peripheral Neuropathy

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and Pegasys as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated.

Laboratory Tests

Before beginning Pegasys or Pegasys combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Pegasys/ribavirin.

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 adult 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 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In a pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. 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 Pegasys may be considered as a guideline to acceptable baseline values for initiation of treatment:

• Platelet count greater than or equal to 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV subjects with cirrhosis or 70,000 cells/mm3 in subjects with CHC and HIV)
• Absolute neutrophil count (ANC) greater than or equal to 1,500 cells/mm3
• Serum creatinine concentration less than 1.5 × upper limit of normal
• TSH and T4 within normal limits or adequately controlled thyroid function
• CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5,000 copies/mL in subjects coinfected with HIV
• Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected subjects
• Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in subjects with CHC and HIV

Drugs Metabolized by Cytochrome P450

There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

Treatment with Pegasys once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC.

Theophylline

Treatment with Pegasys once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and Pegasys.

Methadone

In a PK study of HCV subjects concomitantly receiving methadone, treatment with Pegasys once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity.

The pharmacokinetics of concomitant administration of methadone and Pegasys were evaluated in 24 Pegasys naïve chronic hepatitis C (CHC) subjects (15 male, 9 female) who received 180 mcg Pegasys subcutaneously weekly. All subjects were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving Pegasys. Mean methadone PK parameters were 10% to 15% higher after 4 weeks of Pegasys treatment as compared to baseline. Methadone did not significantly alter the PK of Pegasys as compared to a PK study of 6 chronic hepatitis C subjects not receiving methadone.

Nucleoside Analogues

NRTIs

In Study 7 among the CHC/HIV coinfected cirrhotic subjects receiving NRTIs cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.9)].

Patients receiving Pegasys/ribavirin in combination with other HCV antiviral drugs and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for other HCV antiviral drugs and the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of Pegasys, ribavirin or both, should also be considered if worsening toxicities are observed [see Warnings and Precautions (5.3, 5.9) and Dosage and Administration (2.5)].

Zidovudine

In Study 7, subjects who were administered zidovudine in combination with Pegasys/COPEGUS developed severe neutropenia (ANC less than 500 cells/mm3) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar subjects not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of Pegasys, ribavirin or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).

Refer to the prescribing information for specific HCV antiviral drugs used in combination with Pegasys for information on drug interaction potential.

Pegasys® (PEG-ah-sis)

(peginterferon alfa-2a)

ProClick™ Autoinjector

First read the Medication Guide that comes with Pegasys for the most important information you need to know about Pegasys. Be sure that you read, understand and follow these Instructions for Use before injecting Pegasys. Your healthcare provider should show you how to prepare and use your Pegasys ProClick™ autoinjector properly before you use it for the first time. Ask your healthcare provider if you have any questions.

Pegasys ProClick™ Autoinjectors come either in a box that contains 1 single use autoinjector or in a Monthly Convenience Pack that contains 4 single use autoinjectors. Before starting, collect all of the supplies that you will need to inject a dose of Pegasys. You will need the following supplies:

• 1 Pegasys ProClick™ single use autoinjector
• 1 alcohol pad
• You will also need a puncture-resistant disposable container to throw away your used autoinjector as soon as you finish your injection. See the section "How should I dispose of the used Pegasys ProClick Autoinjector?"

Important information:

• Use your autoinjector exactly as your healthcare provider tells you.
• Never reuse the same autoinjector.
• Your healthcare provider should show you or your caregiver how to use your autoinjector correctly before you use it the first time.
• Do not try to open the autoinjector or take it apart.
• Do not use your autoinjector to inject through clothing covering your skin.
• Do not use your autoinjector if it looks damaged.
• Do not shake your autoinjector. If shaken, Pegasys may not work properly.
• Do not remove the blue cap until you are ready to inject.
• Do not move or handle the red needle-shield before, during or after use. This is a safety device.

Pegasys ProClick™ Autoinjector parts (see Figure "A")

Figure "A"

Step 1. Prepare a dose of Pegasys with your Pegasys ProClick™ Autoinjector

• Find a well-lit, clean flat surface such as a table.
• Look at your autoinjector:
  • Take a carton containing your autoinjector out of the refrigerator and take your autoinjector out of the carton. Keep the blue cap on your autoinjector until Step 3. Allow the autoinjector to come to room temperature for about 20 minutes to warm up. Do not warm up the autoinjector in any other way.
  • Check the expiration date on the carton and autoinjector to make sure that it has not passed (expired). Do not use the autoinjector if the expiration date has passed (see Figure "B").
    Figure "B"
  • Look at the autoinjector to make sure that it is not damaged in any way. Do not use the autoinjector if it looks damaged.
  • Then, look at the medicine inside of the autoinjector by looking through the viewing window. The medicine in the autoinjector should be clear and colorless to light yellow.
  • Do not shake the autoinjector. If there is foam in the medicine, put the autoinjector back in the refrigerator and use it at a later time.
  • Do not use the autoinjector if the medicine in it:
    • is cloudy
    • contains particles
    Use a different autoinjector and contact your healthcare provider or pharmacist, or call Genentech at 1-877-436-3683 for assistance.
• Wash your hands with soap and water.

Step 2. Choose and prepare an injection site

• Choose an injection site on your stomach or thigh (see Figure "C"). Avoid the 2 inch area around your belly button (navel) and your waistline. Use a different place each time you give yourself an injection.
  Figure "C"
  
• Clean the injection site using the alcohol pad (see Figure "D"). Let the skin dry for 10 seconds. Be sure not to touch the cleaned area before injecting.
  Figure "D"
  

Step 3. Remove blue cap from autoinjector

• Hold the autoinjector firmly with one hand and pull off the blue cap with the other hand (see Figure "E").

After the blue cap is removed, set it aside. The blue cap contains a loose-fitting metal tube. Never reattach the blue cap after it has been removed.

Figure "E"

Step 4. Injecting Pegasys

• Hold the autoinjector comfortably in your hand. Pinch and hold a fold of skin at the injection site with your other hand, so that the red needle-shield can rest on the skin-fold firmly and safely (see Figure "F").

  Figure "F"

• Place the autoinjector straight up and down on your skin at a right angle (90°) on the injection site (see Figure "G").
• Do not press the blue activation button yet. Press the autoinjector firmly against your skin until the red needle-shield is completely pushed in (see Figure "G"). The autoinjector is now unlocked and ready for injection.
  Figure "G"
  
• While holding the autoinjector firmly in place, press the blue activation button with your thumb and release the blue button right away (see Figure "H"). Make sure to take your thumb off the blue activation button and do not press it again.
  • You should hear a "click" sound, telling you that the injection has started.
  • The red indicator should move down in the viewing window during the injection (see Figure "I").

    Figure "H"	Figure "I"

• Continue to hold the autoinjector pressed firmly against your skin. Slowly count to 10 to be sure that your injection is complete (see Figure "J").
  • You may hear a second click as the blue activation button pops back up.
  • The viewing window should now be completely red.
    Figure "J"
• After you slowly count to 10, lift the autoinjector straight up (90° angle) from your skin. The red needle-shield will automatically move out and lock to prevent needle stick injuries (see Figure "K").
  Figure "K"

If the viewing window is not completely filled by the red indicator,

• the red needle-shield may not have locked.
  • Do not touch the tip of the autoinjector, because a needle-stick injury may happen.
• you may not have received your full dose of Pegasys.
  • Do not try to reuse the autoinjector
  • Do not repeat the injection with another autoinjector
  • Call your healthcare provider for instructions

If you see leakage around the injection site, you may not have received your full dose of Pegasys.

• Do not try to reuse the autoinjector
• Do not repeat the injection with another autoinjector
• Call your healthcare provider for instructions

Step 5. After the injection:

Throw away your used autoinjector and blue cap right away as described below in the section "How should I dispose of the used Pegasys ProClick™ Autoinjector?" (see Figure "L").

Figure "L"

• Wipe the injection site with the alcohol pad (see Figure "M").
  Figure "M"
• Wash your hands with soap and water.

How should I dispose of the used Pegasys ProClick™ Autoinjector?

• Do not try to re-cap your autoinjector.
• Throw away used autoinjectors in a puncture-resistant container or sharps container. Ask your healthcare provider or pharmacist for information about where you can get a "sharps" container or what other types of puncture-resistant containers you can use to safely dispose of your used autoinjectors if you do not have one.
• Check with your healthcare provider for instructions about the right way to throw away used autoinjectors. There may be local or state laws about how to throw away used autoinjectors.
• Do not throw away used autoinjectors or the puncture-resistant container in household trash and do not recycle them.
• Dispose of the full container as instructed by your healthcare provider or pharmacist.
• Always keep the puncture-resistant container out of the reach of children.

How should I store the Pegasys ProClick™ Autoinjector?

• Store Pegasys in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not leave Pegasys out of the refrigerator for more than 24 hours.
• Do not freeze or shake Pegasys.
• Protect Pegasys from light.

Keep Pegasys and all medicines out of the reach of children.

If you have any concerns or questions about your autoinjector, contact your healthcare provider or pharmacist, or call Genentech at 1-877-436-3683 for assistance.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 09 2014

Pegasys® is a registered trademark of Hoffmann-La Roche Inc.

Manufactured by:
Hoffmann-La Roche, Inc.
c/o Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

© 2015 Genentech, Inc. All rights reserved.

NDC 0004-0350-09

Pegasys®
(peginterferon alfa-2a)

180 µg/1 mL

For Subcutaneous Use
For Single Use
Sterile

ATTENTION PHARMACIST: Each
patient is required to receive
the enclosed Medication Guide.

Refrigerate Immediately

Vial contains: 180 µg/1 mL

Rx only

Genentech

PRINCIPAL DISPLAY PANEL - 0.5 mL 4 Syringe Monthly Convenience Pack (with Alcohol Swabs)

NDC 0004-0352-39

ATTENTION PHARMACIST: Each patient is required
to receive the enclosed Medication Guide.

Refrigerate Immediately

Pegasys®
(peginterferon alfa-2a)

Rx only

180 µg/0.5 mL

For Subcutaneous Injection Only
Sterile
Prefilled Syringes Monthly Convenience Pack Package Contains:
4 Single-Use Prefilled Syringes Pegasys® 180 µg/0.5 mL, NDC 0004-0352-30
4 Needles (27-gauge, 1/2-inch)
4 Alcohol Swabs

Each Prefilled Syringe Contains:
180 µg/0.5 mL

Genentech

Use your dose of Pegasys as soon as you remember the missed dose, then go back to your regular schedule on the day your next dose is due. If you are more than 2 days late in using your injection, call your doctor for instructions. Do not use extra medicine to make up a missed dose.