PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 1
`
`LABELING
`
`PEG-IntronTM
`(Peginterferon alfa-2b)
`Powder For Injection
`
`Alpha interferons, including PEG-Intron, may cause or aggravate fatal or life-
`threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.
`Patients should be monitored closely with periodic clinical and laboratory
`evaluations. Patients with persistently severe or worsening signs or symptoms of
`these conditions should be withdrawn from therapy. In many but not all cases
`these disorders resolve after stopping PEG-Intron therapy. See WARNINGS,
`ADVERSE REACTIONS.
`
`Use with Ribavirin. Ribavirin may cause birth defects and/or death of the unborn
`child. Extreme care must be taken to avoid pregnancy in female patients and in
`female partners of male patients. Ribavirin causes hemolytic anemia. The anemia
`associated with REBETOL therapy may result in a worsening of cardiac disease.
`Ribavirin is genotoxic and mutagenic and should be considered a potential
`carcinogen. (See REBETOL package insert for additional information and other
`warnings).
`
`DESCRIPTION
`PEG-IntronTM, peginterferon alfa-2b, Powder for Injection is a covalent conjugate of
`recombinant alfa-2b interferon with monomethoxy polyethylene glycol (PEG). The
`average molecular weight of the PEG portion of the molecule is 12,000 daltons. The
`average molecular weight of the PEG-Intron molecule is approximately 31,000
`daltons. The specific activity of peginterferon alfa-2b is approximately 0.7 x 108
`IU/mg protein.
`
`Interferon alfa-2b, is a water-soluble protein with a molecular weight of 19,271
`daltons produced by recombinant DNA techniques. It is obtained from the bacterial
`fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid
`containing an interferon gene from human leukocytes.
`
`PEG-Intron is a white to off-white lyophilized powder supplied in 2-mL vials for
`subcutaneous use. Each vial contains either 74 m g, 118.4 m g, 177.6 m g or 222 m g of
`
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`Ex. 1033 - Page 1 of 28
`
`AMGEN INC.
`Exhibit 1033
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 2
`
`LABELING
`
`PEG-Intron, and 1.11 mg dibasic sodium phosphate anhydrous, 1.11 mg monobasic
`sodium phosphate dihydrate, 59.2 mg sucrose and 0.074 mg polysorbate 80.
`Following reconstitution with 0.7 mL of the supplied diluent (Sterile Water for
`Injection, USP), each vial contains PEG-Intron at strengths of either 50 m g per 0.5
`mL, 80 m g per 0.5 mL, 120 m g per 0.5 mL, or 150 m g per 0.5 mL.
`
`CLINICAL PHARMACOLOGY-
`General: The biological activity of PEG-Intron is derived from its interferon alfa-2b
`moiety. Interferons exert their cellular activities by binding to specific membrane
`receptors on the cell surface and initiate a complex sequence of intracellular events.
`These include the induction of certain enzymes, suppression of cell proliferation,
`immunomodulating activities such as enhancement of the phagocytic activity of
`macrophages and augmentation of the specific cytotoxicity of lymphocytes for target
`cells, and inhibition of virus replication in virus-infected cells. Interferon alfa
`upregulates the Th1 T-helper cell subset in in vitro studies. The clinical relevance of
`these findings is not known.
`
`Pharmacodynamics: PEG-Intron raises concentrations of effector proteins such as
`serum neopterin and 2’5’ oligoadenylate synthetase, raises body temperature, and
`causes reversible decreases in leukocyte and platelet counts. The correlation
`between the in vitro and in vivo pharmacologic and pharmacodynamic and clinical
`effects is unknown.
`
`Pharmacokinetics: Following a single subcutaneous (SC) dose of PEG-Intron, the
`mean absorption half-life (t ½ ka) was 4.6 hours. Maximal serum concentrations
`(Cmax) occur between 15-44 hours post-dose, and are sustained for up to 48-72
`hours. The Cmax and AUC measurements of PEG-Intron increase in a dose-related
`manner. After multiple dosing, there is an increase in bioavailability of PEG-Intron.
`Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately
`3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416).
`The mean PEG-Intron elimination half-life is approximately 40 hours (range 22 to 60
`
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`Ex. 1033 - Page 2 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 3
`
`LABELING
`
`hours) in patients with HCV infection. The apparent clearance of PEG-Intron is
`estimated to be approximately 22.0 mL/hr·kg. Renal elimination accounts for 30% of
`the clearance. Single dose peginterferon alfa-2b pharmacokinetics following a
`subcutaneous 1.0 m g/kg dose suggest the clearance of peginterferon alfa-2b is
`reduced by approximately half in subjects with impaired renal function (creatinine
`clearance <50 mL/minute).
`
`Pegylation of interferon alfa-2b produces a product (PEG-Intron) whose clearance is
`lower than that of non-pegylated interferon alfa-2b. When compared to INTRON A,
`PEG-Intron (1.0 m g/kg) has approximately a seven-fold lower mean apparent
`clearance and a five-fold greater mean half-life permitting a reduced dosing
`frequency. At effective therapeutic doses, PEG-Intron has approximately ten-fold
`greater C max and 50-fold greater AUC than interferon alfa-2b.
`
`The pharmacokinetics of geriatric subjects (> 65 years of age) treated with a single
`subcutaneous dose of 1.0 m g/kg of PEG-Intron were similar in Cmax, AUC, clearance,
`or elimination half-life as compared to younger subjects (28 to 44 years of age).
`
`During the 48 week treatment period with PEG-Intron no differences in the
`pharmacokinetic profiles were observed between male and female patients with
`chronic hepatitis C infection.
`
`Effect of Food on Absorption of Ribavirin Both AUCtf and Cmax increased by
`70% when REBETOL Capsules were administered with a high-fat meal (841 kcal,
`53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic
`study. (See DOSAGE AND ADMINISTRATION).
`
`Drug Interactions: It is not known if PEG-Intron therapy causes clinically significant
`drug-drug interactions with drugs metabolized by the liver in patients with hepatitis
`C. In 12 healthy subjects known to be CYP2D6 extensive metabolizers, a single
`subcutaneous dose of 1 m g/kg PEG-Intron did not inhibit CYP1A2, 2C8/9, 2D6,
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`Ex. 1033 - Page 3 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 4
`
`LABELING
`
`hepatic 3A4 or N-acetyltransferase; the effects of PEG-Intron on CYP2C19 were not
`assessed.
`
`CLINICAL STUDIES
`
`PEG-Intron Monotherapy-Study 1
`A randomized study compared treatment with PEG-Intron (0.5, 1.0, or 1.5 m g/kg
`once weekly SC) to treatment with INTRON A, (3 million units three times weekly
`SC) in 1219 adults with chronic hepatitis from HCV infection. The patients were not
`previously treated with interferon alfa, had compensated liver disease, detectable
`HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.
`Patients were treated for 48 weeks and were followed for 24 weeks post-treatment.
`Seventy percent of all patients were infected with HCV genotype 1, and 74 percent
`of all patients had high baseline levels of HCV RNA (more than 2 million copies per
`mL of serum), two factors known to predict poor response to treatment.
`
`Response to treatment was defined as undetectable HCV RNA and normalization of
`ALT at 24 weeks post-treatment. The response rates to the 1.0 and 1.5 m g/kg PEG-
`Intron doses were similar (approximately 24%) to each other and were both higher
`than the response rate to INTRON A (12%). (See Table 1)
`
`Table 1.
`
`Rates of Response to Treatment-Study 1
`A
`B
`C
`PEG-Intron
`PEG-Intron
`INTRON A
`0.5 m g/kg
`1.0 m g/kg
`3 MIU TIW
`(N=307)
`(N=315)
`(N=298)
`
`B - C (95% CI)
` Difference between
`PEG-Intron 1.0 m g/kg
`and INTRON A
`
`Treatment Response
`(Combined Virologic Response
`and ALT Normalization)
` Virologic Responsea
`
`17%
`
`18%
`
`24%
`
`25%
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`12%
`
`12%
`
`11 (5, 18)
`
`12 (6,19)
`
`18%
`29%
`24%
` ALT Normalization
`Serum HCV is measured by a research-based quantitative polymerase chain reaction assay by a central
`laboratory.
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`11 (5,18)
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`Ex. 1033 - Page 4 of 28
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`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 5
`
`LABELING
`
`Patients with both viral genotype 1 and high serum levels of HCV RNA at baseline
`were less likely to respond to treatment with PEG-Intron. Among patients with the
`two unfavorable prognostic variables, 8% (12/157) responded to PEG-Intron
`treatment and 2% (4/169) responded to INTRON A. Doses of PEG-Intron higher
`than the recommended dose did not result in higher response rates in these
`patients.
`
`Patients receiving PEG-Intron with viral genotype 1 had a response rate of 14%
`(28/199) while patients with other viral genotypes had a 45% (43/96) response rate.
`
`Ninety-six percent of the responders in the PEG-Intron groups and 100% of
`responders in the INTRON A group first cleared their viral RNA by week-24 of
`treatment. See DOSAGE AND ADMINISTRATION.
`
`The treatment response rates were similar in men and women. Response rates
`were lower in African American and Hispanic patients and higher in Asians
`compares to Caucasians. Although African Americans had a higher proportion of
`poor prognostic factors compared to Caucasians the number of Non-Caucasians
`studied (9 percent of the total) was insufficient to allow meaningful conclusions
`about differences in response rates after adjusting for prognostic factors.
`
`Liver biopsies were obtained before and after treatment in 60% of patients. A
`modest reduction in inflammation compared to baseline that was similar in all four
`treatment groups was observed.
`
`PEG-Intron/REBETOL Combination Therapy-Study 2
`A randomized study compared treatment with two PEG-Intron/REBETOL regimens
`[PEG-Intron 1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided
`doses) ; PEG-Intron 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44
`weeks/REBETOL 1000/1200 mg PO daily (in divided doses)] with INTRON A (3 MIU
`SC thrice weekly (TIW)/REBETOL 1000/1200 mg PO daily (in divided doses) in
`1530 adults with chronic hepatitis C. Interferon naïve patients were treated for 48
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`Ex. 1033 - Page 5 of 28
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`

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`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 6
`
`LABELING
`
`weeks and followed for 24 weeks post-treatment. Eligible patients had compensated
`liver disease, detectable HCV RNA, elevated ALT, and liver histopathology
`consistent with chronic hepatitis.
`
`Response to treatment was defined as undetectable HCV RNA at 24 weeks post-
`treatment. The response rate to the PEG-Intron 1.5m g/kg plus ribavirin 800mg dose
`was higher than the response rate to Intron A/REBETOL (See Table 2). The
`response rate to PEG-Intron 1.5fi 0.5m g/kg/REBETOL was essentially the same as
`the response to INTRON A/REBETOL (data not shown).
`
`Table 2. Rates of Response to Treatment. Study 2
`
`PEG-Intron 1.5m g/kg
`QW
`REBETOL 800 mg QD
`
`INTRON A 3 MIU TIW
`REBETOL 1000/1200mg
` QD
`
`Overall 1,2
`response
`
`52% (264/511)
`
`46% (231/505)
`
`Genotype 1
`
`41% (141/348)
`
`33% (112/343)
`
`Genotype 2-6
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`75%(123/163)
`
`73% (119/162)
`
`1Serum HCV RNA is measured with a research-based quantitative polymerase chain reaction assay by a central
`laboratory.
`2 Difference in overall treatment response (Peg-Intron/REBETOL vs. Intron A/REBETOL) is 6% with 95%
`confidence interval of ( 0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline.
`
`Patients with viral genotype 1, regardless of viral load, had a lower response rate to
`PEG-Intron (1.5 m g/kg)/REBETOL compared to patients with other viral genotypes.
`Patients with both poor prognostic factors (genotype 1 and high viral load) had a
`response rate of 30% (78/256) compared to a response rate of 29% (71/247) with
`INTRON A/REBETOL.
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`Ex. 1033 - Page 6 of 28
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`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 7
`
`LABELING
`
`Patients with lower body weight tended to have higher adverse event rates (see
`ADVERSE REACTIONS) and higher response rates than patients with higher body
`weights. Differences in response rates between treatment arms did not substantially
`vary with body weight.
`
`Treatment response rates with PEG-Intron/REBETOL were 49% in men and 56% in
`women. Response rates were lower in African American and Hispanic patients and
`higher in Asians compared to Caucasians. Although African Americans had a higher
`proportion of poor prognostic factors compared to Caucasians the number of non-
`Caucasians studied (11% of the total) was insufficient to allow meaningful
`conclusions about differences in response rates after adjusting for prognostic
`factors.
`
`Liver biopsies were obtained before and after treatment in 68% of patients.
`Compared to baseline approximately 2/3 of patients in all treatment groups were
`observed to have a modest reduction in inflammation.
`
` INDICATIONS AND USAGE
`
`PEG-Intron, peginterferon alfa-2b, is indicated for use alone or in combination with
`REBETOL (ribavirin, USP) for the treatment of chronic hepatitis C in patients with
`compensated liver disease who have not been previously treated with interferon
`alpha and are at least 18 years of age.
`
`CONTRAINDICATIONS
`
`PEG-Intron is contraindicated in patients with:
`• hypersensitivity to PEG-Intron or any other component of the product
`• autoimmune hepatitis
`• decompensated liver disease
`
`PEG-Intron/REBETOL combination therapy is additionally contraindicated in:
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`Ex. 1033 - Page 7 of 28
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`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 8
`
`LABELING
`
`• patients with hypersensitivity to ribavirin or any other component of the
`product
`• women who are pregnant
`• men whose female partners are pregnant
`• patients with hemoglobinopathies (e.g.,
`anemia)
`
`thalassemia major, sickle-cell
`
`WARNINGS
`Patients should be monitored for the following serious conditions, some of which
`may become life threatening. Patients with persistently severe or worsening signs or
`symptoms should be withdrawn from therapy.
`
`Neuropsychiatric events
`Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and
`homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive
`behavior have occurred in patients with and without a previous psychiatric disorder
`during PEG-Intron treatment and follow-up. Psychoses, hallucinations, bipolar
`disorders, and mania have been observed in patients treated with alpha interferons.
`PEG-Intron should be used with extreme caution in patients with a history of
`psychiatric disorders. Patients should be advised to report immediately any
`symptoms of depression and/or suicidal ideation to their prescribing physicians.
`Physicians should monitor all patients for evidence of depression and other
`psychiatric symptoms. In severe cases, PEG-Intron should be stopped immediately
`and psychiatric intervention instituted. (See DOSAGE AND ADMINISTRATION:
`Dose Reduction)
`
`Bone marrow toxicity
`
`PEG-Intron suppresses bone marrow function, sometimes resulting in severe
`cytopenias. PEG-Intron should be discontinued in patients who develop severe
`decreases in neutrophil or platelet counts. (See DOSAGE AND ADMINISTRATION:
`Dose Reduction). Ribavirin may potentiate the neutropenia induced by interferon
`alpha. Very rarely alpha interferons may be associated with aplastic anemia.
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`Ex. 1033 - Page 8 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 9
`
`LABELING
`
`Endocrine disorders
`
`causes or aggravates hypothyroidism and hyperthyroidism.
`PEG-Intron
`Hyperglycemia has been observed in patients treated with PEG-Intron. Diabetes
`mellitus has been observed in patients treated with alpha interferons. Patients with
`these conditions who cannot be effectively treated by medication should not begin
`PEG-Intron therapy. Patients who develop these conditions during treatment and
`cannot be controlled with medication should not continue PEG-Intron therapy.
`
`Cardiovascular events
`tachycardia,
`include hypotension, arrhythmia,
`Cardiovascular events, which
`cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in
`patients treated with PEG-Intron. PEG-Intron should be used cautiously in patients
`with cardiovascular disease. Patients with a history of myocardial infarction and
`arrhythmic disorder who require PEG-Intron therapy should be closely monitored
`(see Laboratory Tests). Patients with a history of significant or unstable cardiac
`disease should not be treated with PEG-Intron/REBETOL combination therapy. [See
`REBETOL package insert.]
`
`Pulmonary disorders
`Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial
`pneumonitis and sarcoidosis some resulting in respiratory failure and/or patient
`deaths, may be induced or aggravated by PEG-Intron or alpha interferon therapy.
`Recurrence of respiratory failure has been observed with interferon rechallenge.
`PEG-Intron combination treatment should be suspended in patients who develop
`pulmonary infiltrates or pulmonary function impairment. Patients who resume
`interferon treatment should be closely monitored.
`
`Colitis
`Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed
`within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody
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`Ex. 1033 - Page 9 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 10
`
`LABELING
`
`diarrhea, and fever are the typical manifestations. PEG-Intron treatment should be
`discontinued immediately in patients who develop these symptoms and signs. The
`colitis usually resolves within 1-3 weeks of discontinuation of alpha interferons.
`
`Pancreatitis
`Fatal and nonfatal pancreatitis has been observed in patients treated with alpha
`interferon. PEG-Intron therapy should be suspended in patients with signs and
`symptoms suggestive of pancreatitis and discontinued in patients diagnosed with
`pancreatitis.
`
`Autoimmune disorders
`thyroiditis,
`(e.g.
`Development or exacerbation of autoimmune disorders
`thrombocytopenia,
`rheumatoid arthritis,
`interstitial nephritis, systemic
`lupus
`erythematosus, psoriasis) have been observed in patients receiving PEG-Intron.
`PEG-Intron should be used with caution in patients with autoimmune disorders.
`
`Ophthalmologic disorders
`
`Decrease or loss of vision, retinal artery or vein thrombosis, retinal hemorrhages and
`cotton wool spots, optic neuritis, and papilledema are induced or aggravated by
`treatment with PEG-Intron 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. PEG-interferon
`treatment should be discontinued in patients who develop new or worsening
`ophthalmologic disorders.
`
`Hypersensitivity
`angioedema,
`urticaria,
`(e.g.,
`reactions
`hypersensitivity
`Serious,
`acute
`bronchoconstriction, anaphylaxis) have been rarely observed during alpha interferon
`therapy. If such a reaction develops during treatment with PEG-Intron, discontinue
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`Ex. 1033 - Page 10 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 11
`
`LABELING
`
`treatment and institute appropriate medical therapy immediately. Transient rashes
`do not necessitate interruption of treatment.
`
`Use with Ribavirin—(See also REBETOL Package Insert)
`
`REBETOL may cause birth defects and/or death of the unborn child.
`REBETOL therapy should not be started until a report of a negative pregnancy
`test has been obtained immediately prior to planned initiation of therapy.
`Patients should use at least two forms of contraception and have monthly
`pregnancy
`tests
`(See BOXED WARNING, CONTRAINDICATIONS and
`PRECAUTIONS: Information for Patients and REBETOL package insert).
`
`Anemia
`Ribavirin caused hemolytic anemia in 10% of PEG-Intron/REBETOL treated patients
`within 1-4 weeks of initiation of therapy. Complete blood counts should be obtained
`pretreatment and at week 2 and week 4 of therapy or more frequently if clinically
`indicated. Anemia associated with REBETOL therapy may result in a worsening of
`cardiac disease. Decrease in dosage or discontinuation of REBETOL may be
`necessary. (See DOSAGE AND ADMINISTRATION: Dose Reduction)
`
`PRECAUTIONS
`• PEG-Intron alone or in combination with REBETOL has not been studied in
`patients who have failed other alpha interferon treatments.
`
`• The safety and efficacy of PEG-Intron alone or in combination with REBETOL for
`the treatment of hepatitis C in liver or other organ transplant recipients have not
`been studied.
`
`• The safety and efficacy of PEG-Intron/REBETOL for the treatment of patients
`with HCV co-infected with HIV or HBV have not been established.
`
`Patients with renal failure: Patients with impairment of renal function should be
`closely monitored for signs and symptoms of interferon toxicity and doses of
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`Ex. 1033 - Page 11 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 12
`
`LABELING
`
`PEG-Intron should be adjusted accordingly. PEG-Intron should be used with caution
`in patients with creatinine clearance <50 mL/min. See DOSAGE AND
`ADMINISTRATION: Dose Modification.
`
`Immunogenicity: Approximately 2% of patients receiving PEG-Intron (32/1759) or
`low-titer (£ 160)
`INTRON A (11/728) with or without REBETOL developed
`neutralizing antibodies to PEG-Intron or INTRON A. The clinical and pathological
`significance of the appearance of serum neutralizing antibodies is unknown. No
`apparent correlation of antibody development to clinical response or adverse events
`was observed. The incidence of post-treatment binding antibody ranged from 8 to
`15 percent. The data reflect the percentage of patients whose test results were
`considered positive for antibodies to PEG-Intron in a Biacore assay that is used to
`measure binding antibodies, and in an antiviral neutralization assay, which
`measures serum-neutralizing antibodies. The percentage of patients whose test
`results were considered positive for antibodies is highly dependent on the sensitivity
`and specificity of the assays. Additionally the observed incidence of antibody
`positivity in these assays may be influenced by several factors including sample
`timing and handling, concomitant medications, and underlying disease. For these
`reasons, comparison of the incidence of antibodies to PEG-Intron with the incidence
`of antibodies to other products may be misleading.
`
`Laboratory Tests: PEG-Intron alone or in combination with ribavirin may cause
`severe decreases in neutrophil and platelet counts, and hematologic, endocrine
`(e.g.TSH) and hepatic abnormalities. Transient elevations in ALT (2-5 fold above
`baseline) were observed in 10% of patients treated with PEG-Intron, and was not
`associated with deterioration of other liver functions.
`
`Patients on PEG-Intron or PEG-Intron/REBETOL combination therapy should have
`hematology and blood chemistry testing before the start of treatment and then
`periodically thereafter. In the clinical trial CBC (including hemoglobin, neutrophil and
`platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were
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`Ex. 1033 - Page 12 of 28
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`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 13
`
`LABELING
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`measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week
`intervals or more frequently if abnormalities developed. TSH levels were measured
`every 12 weeks during the treatment period.
`
`HCV RNA should be measured at 6 months of treatment. PEG-Intron or PEG-
`Intron/REBETOL combination therapy should be discontinued in patients with
`persistent high viral levels.
`
`should
`abnormalities
`cardiac
`pre-existing
`have
`Patients who
`electrocardiograms administered before treatment with PEG-Intron/REBETOL.
`
`have
`
`Information for Patients: Patients receiving PEG-Intron alone or in combination
`with REBETOL should be directed in its appropriate use, informed of the benefits
`and risks associated with treatment, and referred to the MEDICATION GUIDES for
`PEG-Intron and, if applicable, REBETOL (ribavirin, USP).
`
`Patients must be informed that REBETOL may cause birth defects and/or death of
`the unborn child. Extreme care must be taken to avoid pregnancy in female patients
`and in female partners of male patients taking combination PEG-Intron/REBETOL
`therapy. Combination PEG-Intron/REBETOL therapy should not be initiated until a
`report of a negative pregnancy test has been obtained immediately prior to initiation
`of therapy. It is recommended that patients undergo monthly pregnancy tests during
`therapy and for 6 months post-therapy. (See CONTRAINIDICATIONS and
`REBETOL package insert).
`
`A puncture-resistant container for the disposal of used syringes and needles should
`be supplied to the patient for at home use. Patients should be thoroughly instructed
`in the importance of proper disposal and cautioned against any reuse of needles and
`syringes. The full container should be disposed of according to the directions
`provided by the physician (see MEDICATION GUIDE).
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`Ex. 1033 - Page 13 of 28
`
`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 14
`
`LABELING
`
`Patients should be informed that there are no data regarding whether PEG-Intron
`therapy will prevent transmission of HCV infection to others. Also, it is not known if
`treatment with PEG-Intron will cure hepatitis C or prevent cirrhosis, liver failure, or
`liver cancer that may be the result of infection with the hepatitis C virus.
`
`Patients should be advised that laboratory evaluations are required before starting
`therapy and periodically thereafter (see Laboratory Tests). It is advised that
`patients be well-hydrated, especially during the initial stages of treatment. “Flu-like”
`symptoms associated with administration of PEG-Intron may be minimized by
`bedtime administration of PEG-Intron or by use of antipyretics.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`Carcinogenesis and Mutagenesis: PEG-Intron has not been tested for its
`carcinogenic potential. Neither PEG-Intron, nor its components interferon or
`methoxypolyethylene glycol caused damage to DNA when tested in the standard
`battery of mutagenesis assays, in the presence and absence of metabolic activation.
`
`Use with Ribavirin: Ribavirin is genotoxic and mutagenic and should be
`considered a potential carcinogen. See REBETOL package insert for additional
`warnings relevant to PEG-Intron therapy in combination with ribavirin.
`
`Impairment of Fertility: PEG-Intron may impair human fertility. Irregular menstrual
`cycles were observed in female cynomolgus monkeys given subcutaneous injections
`of 4239 m g/m2 PEG-Intron alone every other day for one month, (approximately 345
`times the recommended weekly human dose based upon body surface area). These
`effects included transiently decreased serum levels of estradiol and progesterone,
`suggestive of anovulation. Normal menstrual cycles and serum hormone levels
`resumed in these animals 2 to 3 months following cessation of PEG-Intron
`treatment. Every other day dosing with 262 m g/m2 (approximately 21 times the
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`Ex. 1033 - Page 14 of 28
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`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 15
`
`LABELING
`
`weekly human dose) had no effects on cycle duration or reproductive hormone
`status. The effects of PEG-Intron on male fertility have not been studied.
`
`Pregnancy Category C: PEG-Intron monotherapy: Non-pegylated Interferon alfa-
`2b, has been shown to have abortifacient effects in Macaca mulatta (rhesus
`monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million
`IU/kg, based on body surface area adjustment for a 60 kg adult). PEG-Intron should
`be assumed to also have abortifacient potential. There are no adequate and well-
`controlled studies in pregnant women. PEG-Intron therapy is to be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`Therefore, PEG-Intron is recommended for use in fertile women only when they are
`using effective contraception during the treatment period.
`Pregnancy Category X : Use with Ribavirin
`Significant teratogenic and/or embryocidal effects have been demonstrated in
`all animal species exposed to ribavirin. REBETOL therapy is contraindicated
`in women who are pregnant and in the male partners of women who are
`pregnant. See CONTRAINDICATIONS and the REBETOL Package Insert.
`
`If pregnancy occurs in a patient or partner of a patient during treatment with PEG-
`Intron and REBETOL during the 6 months after treatment cessation, physicians
`should report such cases by calling (800) 727-7064.
`
`Pediatric. Safety and effectiveness in pediatric patients below the age of 18 years
`have not been established.
`
`Geriatric . In general, younger patients tend to respond better than older patients to
`interferon-based therapies. Clinical studies of PEG-Intron alone or in combination
`with REBETOL did not include sufficient numbers of subjects aged 65 and over,
`however, to determine whether they respond differently than younger subjects.
`Treatment with alpha
`interferons,
`including PEG-Intron,
`is associated with
`neuropsychiatric, cardiac, pulmonary, GI and systemic (flu-like) adverse effects.
`Because these adverse reactions may be more severe in the elderly, caution should
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`Ex. 1033 - Page 15 of 28
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`

`

`PEG-INTRON/RIBAVIRIN
`SECTION 2.
`
`PAGE 16
`
`LABELING
`
`be exercised in use of PEG-Intron in this population. This drug is known to be
`substantially excreted by the kidney. Because elderly patients are more likely to
`have decreased renal function, the risk of toxic reactions to this drug may be greater
`in patients with impaired renal function. REBETOL should not be used in patients
`with creatinine clearance <50 mL/min. When using PEG-Intron/REBETOL therapy,
`refer also to the REBETOL Medication Guide.
`
`ADVERSE REACTIONS
`Nearly all study patients in clinical trials experienced one or more adverse events. In
`the PEG monotherapy trial the incidence of serious adverse events was similar
`(about 12%) in all treatment groups. In the PEG-Intron/REBETOL combination trial
`the incidence of serious adverse events was 17% in the PEG-Intron/REBETOL
`groups compared to 14% in the INTRON A/REBETOL group.
`
`In many but not all cases, adverse events resolved after dose reduction or
`discontinuation of therapy. Some patients experienced ongoing or new serious
`adverse events during the 6-month follow-up period. In the PEG-Intron/REBETOL
`trial 13 patients experienced life-threatening psychiatric events (suicidal ideation or
`attempt) and one patient accomplished suicide.
`
`There have been five patient deaths which occurred in clinical trials: one suicide in a
`patient receiving PEG-Intron monotherapy and one suicide in a patient receiving
`PEG-Intron/REBETOL combination therapy; two deaths among patients receiving
`INTRON A monotherapy (1 murder/suicide and 1 sudden death) and one patient
`death in the INTRON A/REBETOL group (motor vehicle accident).
`
`Overall 10-14% of patients receiving PEG-Intron, alone or in combination with
`REBETOL, discontinued therapy compared with 6% treated with INTRON A alone
`and 13% treated with INTRON A in combination with REBETOL. The most common
`reasons for discontinuation of therapy were related to ps