Pegasys (peginterferon alfa-2a)

Pegasys is a prescription medicine that is:

• used with other hepatitis C virus (HCV) antiviral medicines to treat adults who have chronic (lasting a long time) hepatitis C infection and compensated liver disease.
• used alone to treat adults with chronic hepatitis C (CHC) and compensated liver disease, and who are not able to take other HCV antiviral medicines.
• used with Ribavirin to treat children 5 years of age and older who have CHC and compensated liver disease.

WARNING

RISK OF SERIOUS DISORDERS

Risk of Serious Disorders

Alpha interferons, including Pegasys (peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping Pegasys therapy.

Pegasys can cause serious side effects including:

• Blood problems. Pegasys can affect your bone marrow and cause low red blood cell, low white blood cell and low platelet counts. These blood counts may fall to dangerously low levels. If your blood cell counts become very low, you can get anemia, infections or have problems with bleeding and bruising.
• Thyroid problems. Symptoms of thyroid changes include feeling cold or hot all the time, a change in your weight, and changes to your skin, trouble concentrating.
• Blood sugar problems. Pegasys may cause low blood sugar (hypoglycemia), high blood sugar (hyperglycemia) or diabetes. If you have high blood sugar or diabetes before starting Pegasys, talk to your healthcare provider before you take Pegasys. If you develop high blood sugar or diabetes during treatment with Pegasys, your healthcare provider may tell you to stop Pegasys and prescribe a different medicine for you.

Symptoms of low blood sugar may include:

• feeling faint
• anxiousness
• headaches
• confusion
• sweating
• weakness

Symptoms of high blood sugar or diabetes may include:

• increased thirst
• increased appetite
• tiredness
• weight loss
• urinating more often than normal
• your breath smells like fruit
• Serious eye problems. Pegasys may cause eye problems that may lead to vision loss or blindness. You should have an eye exam before you start taking Pegasys. If you have eye problems or have had them in the past, you may need eye exams during treatment with Pegasys. Tell your healthcare provider or eye doctor right away if you have any vision changes during treatment with Pegasys.
• Serious liver problems, worsening of liver problems including liver failure and death. Symptoms may include:
  • nausea
  • bleeding more easily than normal
  • loss of appetite
  • swelling of your stomach area (abdomen)
  • tiredness
  • confusion
  • diarrhea
  • sleepiness
  • yellowing of your skin or the white part of your eyes
  • you cannot be awakened (coma)
• Lung problems, including:
  • trouble breathing
  • new or worse high blood pressure of the lungs (pulmonary hypertension). This can be severe andmay lead to death.
  • pneumonia
  • inflammation of lung tissue

  You may need to have a chest X-ray or other tests if you develop fever, cough, shortness of breath or other symptoms of a lung problem during treatment with Pegasys.

• Inflammation of your intestines (colitis). Symptoms of inflammation of your intestines (colitis) may include:
  • severe stomach area (abdomen) pain
  • bloody diarrhea or blood bowel movements
  • fever
• Inflammation of your pancreas (pancreatitis). Symptoms of inflammation of your pancreas (pancreatitis) may include:
  • severe stomach (abdomen) pain
  • vomiting
  • severe back pain
  • fever
  • nausea
• Serious allergic reactions and skin reactions. Get medical help right away if you get any of the following symptoms:
  • itching
  • chest pain
  • swelling of your face, eyes, lips, tongue, or throat
  • feeling faint
  • trouble breathing
  • skin rash, hives, sores in your mouth, or your skin blisters and peels
• Effect on growth in children. Children can experience a delay in weight gain and height increase during treatment with Pegasys. In children with hepatitis C, catch-up in growth happens after treatment stops, but some children may not reach the height that they were expected to have before treatment. In children with hepatitis B, it is not yet known if catch-up in growth happens after treatment stops. Talk to your healthcare provider if you are concerned about your child’s growth during treatment with Pegasys.
• Nerve problems. People who take Pegasys or other alfa interferon products with telbivudine (Tyzeka) for hepatitis B can develop nerve problems such as continuing numbness, tingling, or burning sensation in the arms or legs (peripheral neuropathy). Call your healthcare provider if you have any of these symptoms.

Tell your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects of Pegasys include:

• flu-like symptoms. Symptoms may include tiredness, weakness, fever, chills, muscle aches, joint pain, and headaches. Some of these symptoms may be decreased by injecting your Pegasys dose in the evening. Talk to your healthcare provider about which over-the-counter medicines you can take to help prevent or decrease some of the symptoms.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the side effects of Pegasys.

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

You may also report side effects to Genentech at 1-888-835-2555.

Dosage Overview

Administer Pegasys by subcutaneous injection once weekly in the abdomen or thigh for the treatment of:

• Adult patients with CHC without or with HIV coinfection [see Recommended Dosage for Adult Patients with CHC ];
• Pediatric patients with CHC [see Recommended Dosage for Pediatric Patients with CHC];
• Adult patients with CHB [see Recommended Dosage for Adults with CHB]; and
• Pediatric patients with CHB [see Recommended Dosage for Pediatrics Patients with CHB].

For treatment of CHC, use Pegasys in combination with other HCV antiviral drugs. For information about the recommended dosage and administration and the safe and effective use of these other HCV antiviral drugs, refer to their prescribing information. Pegasys monotherapy is only indicated in the treatment of CHC if there are contraindications to or significant intolerance to other HCV antiviral drugs.

For dosage modifications in patients with CHC or CHB:

• Due to neutropenia, thrombocytopenia, ALT elevation, and depression [see Dosage Modifications].
• In patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and in patients with creatinine clearance between 30 and 50 mL/minute [see Dosage Modifications].

For important administration instructions for all the Pegasys injection presentations (i.e., vial, prefilled syringe, autoinjector) [see Dosage Modifications].

Recommended Dosage For Adults with CHC

Dosage In Adults With CHC Without HIV Coinfection

Table 1 displays the recommended dosage and duration of Pegasys and other HCV antiviral drugs in adults with CHC (without HIV coinfection) based on HCV genotype.

For treatment of HCV genotype 1 with Pegasys in combination with ribavirin or alone, discontinuation of treatment is recommended if at least a 2 log₁₀ reduction from baseline in HCV RNA has not been demonstrated by 12 weeks of therapy or if undetectable HCV RNA has not been achieved after 24 weeks of therapy. Refer to the prescribing information for specific HCV antiviral drugs used in combination with Pegasys for information on stopping therapy based on treatment response.

Immediately discontinue Pegasys for hepatic decompensation (Child-Pugh score greater than 6 [class B and C]).

Table 1 : Recommended Dosage for Pegasys for Adults with CHC Infection¹

If Pegasys monotherapy is used for treatment of CHC, the recommended Pegasys dosage is 180 mcg via subcutaneous injection in thigh or abdomen once weekly for 48 weeks.

Dosage In Adults With CHC With HIV Coinfection

The recommended Pegasys dosage in adults with CHC and HIV coinfection is 180 mcg subcutaneously once weekly in the thigh or abdomen. If Pegasys is used in combination with other antiviral drugs, refer to the prescribing information of the other HCV antiviral drugs for the recommended dosage of the other HCV antiviral drugs and duration of the entire treatment regimen (including Pegasys). If Pegasys and ribavirin are used without other HCV antiviral drugs, the recommended duration of therapy is 48 weeks (regardless of HCV genotype).

Recommended Dosage For Pediatric Patients With CHC

Pegasys is administered as 180 mcg/1.73 m² x BSA subcutaneously once weekly, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for pediatric patients with HCV genotype 2 or 3 is 24 weeks and for other HCV genotypes is 48 weeks. Patients who initiate treatment prior to their 18th birthday should maintain the recommended pediatric dosage (not the adult dosage) through the completion of therapy. Refer to the prescribing information of ribavirin for the recommended dosage and duration.

Recommended Dosage For Adults With CHB

The recommended Pegasys dosage in adults with CHB is 180 mcg subcutaneously once weekly in the thigh or abdomen for 48 weeks.

Recommended Dosage For Pediatrics Patients With CHB

The recommended Pegasys dosage in pediatric patients for HBeAg-positive CHB is 180 mcg/1.73 m² x BSA subcutaneously once weekly to a maximum dose of 180 mcg. The recommended duration of therapy is 48 weeks.

Maintain the recommended pediatric dosage through the entire duration of therapy in patients who turn 18 years of age during therapy.

Dosage Modifications

Pegasys Dosage Modifications Due to Adverse Reactions, Neutropenia or Thrombocytopenia in Adults

Table 2 displays the recommended Pegasys dosage modifications due to adverse reactions, or due to neutropenia, or thrombocytopenia in adults. Following improvement of the adverse reaction, neutropenia or thrombocytopenia, consider re-escalation of the dosage back to the previous dosage.

Table 2 : Recommended Pegasys Dosage Modifications in Adults Due to Adverse Reactions, Neutropenia or Thrombocytopenia

Pegasys Dosage Modifications Due To ALT Elevation In Adults

If ALT increases are progressive despite dose reduction or accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be immediately discontinued. In CHC patients with progressive ALT increases above baseline values, the dosage of Pegasys should be reduced to 135 mcg and more frequent monitoring of liver function should be performed. After Pegasys dosage reduction or withholding, therapy can be resumed after ALT flares subside.

In CHB patients with elevations in ALT (greater than 5 x ULN), more frequent monitoring of liver function should be performed and consideration should be given to either reducing the dosage of Pegasys to 135 mcg or temporarily discontinuing treatment. After Pegasys dosage reduction or withholding, therapy can be resumed after ALT flares subside.

In adult patients with persistent, severe (ALT greater than 10 times above the upper limit of normal) hepatitis B flares, consideration should be given to discontinuation of treatment.

Pegasys Dosage Modifications Due To Depression In Adults And In Pediatric Patients

Table 3 displays the recommended Pegasys dosage modifications in adult and pediatric patients who develop interferon-related depression or whose underlying depression worsens. Table 3 also includes recommended frequency of psychiatric visits.

Table 3 : Recommended Pegasys Dosage Modifications and Psychiatric Visits Due to Depression in Adult & Pediatric Patients

Pegasys Dosage Modifications Due To Adverse Reactions Or Laboratory Abnormalities In Pediatric Patients

Table 4 displays the recommended Pegasys dosage modifications due to adverse reactions, neutropenia, thrombocytopenia, or elevated ALT in pediatric patients.

Table 4 : Recommended Pegasys Dosage Modifications for Neutropenia, Thrombocytopenia, and Elevated ALT in Pediatric Patients

Pegasys Dosage Modifications For Adults With Renal Impairment

Prior to administering Pegasys, evaluate renal function. Table 5 displays the recommended dosage modifications for adults with creatinine clearance less than 30 mL/minute, including patients with end-stage renal disease requiring hemodialysis.

Refer to the respective prescribing information of other HCV antiviral drugs regarding use in patients with renal impairment.

Table 5 : Pegasys Dosage Modification for Adults with Renal Impairment

Pegasys Dosage Modifications For Pediatric Patients With Renal Impairment

Dosage recommendations for pediatric patients with renal impairment are not available.

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 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.
• 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.

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.

• A Ribavirin Pregnancy Registry has been established to monitor maternal and fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during pregnancy or who become pregnant within 6 months following cessation of treatment with ribavirin.
• Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.
• There is no information regarding the presence of peginterferon alfa-2a in human milk, the effects on the breastfed infant, or the effects on milk production.
• Because of the potential for adverse reactions from the drugs in nursing infants, a decision must be made whether to discontinue nursing or discontinue Pegasys.
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Pegasys and any potential adverse effects on the breastfed child from Pegasys or from the underlying maternal condition.