Infergen

Dosage Forms And Strengths

INFERGEN is provided in single-use vials containing:

• 9 mcg/0.3 mL INFERGEN in sterile, clear, colorless, preservative-free liquid
• 15 mcg/0.5 mL INFERGEN in sterile, clear, colorless, preservative-free liquid

Storage And Handling

Use only one vial per dose; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.

Single-use, preservative-free vials containing 9 mcg (0.3 mL) of interferon alfacon-1 are available in dispensing packs of 6 vials (NDC 66435-202-09).

Single-use, preservative-free vials containing 15 mcg (0.5 mL) of interferon alfacon-1 are available in dispensing packs of 6 vials (NDC 66435-201-15).

INFERGEN should be stored in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. Avoid vigorous shaking and exposure to direct sunlight.

Manufactured by: Boehringer Ingelheim Pharma GmbH & Co. Biberach, Germany. Manufactured for: Kadmon Pharmaceuticals, LLC Warrendale, PA 15086, USA (877) 377-7862. Revised: May 2013

Chronic Hepatitis C

INFERGEN® (interferon alfacon-1) is indicated for treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease. This indication is based on clinical trials conducted using INFERGEN as monotherapy prior to the time that combination treatment was the standard of care and on a single trial evaluating INFERGEN in combination with ribavirin in patients who failed to respond to previous treatment with a pegylated interferon and ribavirin.

The following points should be considered when initiating treatment with INFERGEN:

• Use of monotherapy with an interferon such as INFERGEN for the treatment of hepatitis C is not recommended unless a patient is unable to take ribavirin.
• The safety and efficacy of the combination of INFERGEN/ribavirin in treatment-naïve patients or in patients co-infected with HBV or HIV-1 have not been evaluated.
• Patients with the following characteristics are less likely to benefit from retreatment with combination therapy: response of < 1 log₁₀ drop HCV RNA on previous treatment, Genotype 1, high viral load ( ≥ 850,000 IU/mL), African American race, and/or presence of cirrhosis.
• No safety and efficacy data are available for treatment of longer than one year.

INFERGEN Monotherapy Dosing

The recommended dose of INFERGEN monotherapy for the initial treatment of chronic HCV infection is 9 mcg administered three times a week as a single subcutaneous injection for 24 weeks.

The recommended dose of INFERGEN monotherapy for patients who tolerated previous interferon therapy and did not respond or relapsed following its discontinuation is 15 mcg administered three times a week as a single subcutaneous injection for up to 48 weeks. Patients who do not tolerate initial standard interferon therapy should not be treated with INFERGEN therapy 15 mcg three times a week.

Combination Treatment with INFERGEN/Ribavirin Dosing

The recommended dose of INFERGEN is 15 mcg daily administered as a single subcutaneous injection in combination with weight-based ribavirin at 1,000 mg -1,200 mg ( < 75 kg and ≥ 75 kg) orally in two divided doses for up to 48 weeks..

Ribavirin should be taken with food. INFERGEN/ribavirin should not be used in patients with creatinine clearance < 50 mL/min.

Dose Modifications

If a serious adverse reaction develops during the course of treatment discontinue or modify the dosage of INFERGEN and/or ribavirin until the adverse event abates or decreases in severity. If persistent or recurrent serious adverse events develop despite adequate dosage adjustment, discontinue treatment. Upon resolution or improvement of the adverse reaction, resuming INFERGEN and/or ribavirin may be considered.

INFERGEN Monotherapy Dose Modifications

Dose reduction to 7.5 mcg may be necessary following a serious adverse reaction. If serious adverse events continue to occur, dosing should be interrupted or discontinued as the efficacy of lower doses has not been established.

INFERGEN/Ribavirin Combination Therapy Dose Modifications

Stepwise dose reduction from 15 mcg to 9 mcg and from 9 mcg to 6 mcg may be necessary for serious adverse reactions.

Guidelines for INFERGEN/Ribavirin Dose Modifications

Tables 1, 2, and 3 provide guidelines for dose modifications and discontinuation of INFERGEN and/or ribavirin based on depression or laboratory parameters.

Table 1: Guidelines for Dose Modification or Discontinuation of INFERGEN and for Scheduling Visits for Patients with Depression

Table 2: Guidelines for Dose Modification or Discontinuation of INFERGEN for Hematologic Toxicities

Table 3: Guidelines for Dose Modification or Discontinuation of INFERGEN/Ribavirin for the Management of Anemia*

Renal Function

INFERGEN/ribavirin should not be used in patients with creatinine clearance < 50 mL/min..

Discontinuation of Treatment

Patients who fail to achieve at least a 2 log₁₀ drop at 12 weeks or undetectable HCV-RNA at week 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Ribavirin should be discontinued in any patient who temporarily or permanently discontinues INFERGEN.

Preparation and Administration

Just prior to injection, INFERGEN may be allowed to reach room temperature.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration; if particulates or discoloration are observed, the vial should not be used.

If home use is determined to be desirable by the physician, instructions on appropriate use should be given by a healthcare professional. After administration of INFERGEN, it is essential to follow the procedure for proper disposal of syringes and needles..

INFERGEN is contraindicated in patients with:

• hepatic decompensation (Child-Pugh score > 6 [class B and C])
• autoimmune hepatitis
• known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis to interferon alphas or to any component of the product

Additionally, ribavirin is contraindicated in:

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Treatment with INFERGEN and combination treatment with INFERGEN/ribavirin should be administered under the guidance of a qualified physician, and may lead to moderate-to-severe adverse reactions requiring dose reduction, temporary dose cessation, or discontinuation of further therapy.

Use with Ribavirin

Pregnancy

Ribavirin may cause birth defects and death of the unborn child. Ribavirin 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. Pregnancy should be avoided for at least six months after discontinuation of ribavirin.

Anemia

Ribavirin caused hemolytic anemia in 30% of INFERGEN/ribavirin-treated subjects. 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 ribavirin therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of ribavirin may be necessary.

Neuropsychiatric Disorders

Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferon alphas, including INFERGEN. Depression, suicidal ideation, suicide attempt, suicide, and homicidal ideation may occur. Other prominent psychiatric adverse reactions including psychosis, aggressive behavior, nervousness, anxiety, emotional lability, abnormal thinking, agitation, apathy and relapse of drug addiction may occur. INFERGEN should be used with extreme caution in patients who report a history of depression. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Prior to initiation of INFERGEN therapy, physicians should inform patients of the possible development of depression and patients should be advised to report any sign or symptom of depression and/or suicidal ideation immediately. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others are identified, it is recommended that treatment with INFERGEN be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, INFERGEN should be stopped immediately and psychiatric intervention instituted.

Cardiovascular Events

Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with INFERGEN. INFERGEN should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require INFERGEN therapy should be closely monitored. Patients with a history of significant or unstable cardiac disease should not be treated with INFERGEN/ribavirin combination therapy.

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 interferon alpha therapy, including INFERGEN. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with INFERGEN. Recurrence of respiratory failure has been observed with interferon rechallenge. INFERGEN treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.

Hepatic Failure

Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when treated with interferon alphas, including INFERGEN. During treatment, patients' clinical status and hepatic function should be closely monitored, and INFERGEN treatment should be immediately discontinued if symptoms of hepatic decompensation, such as jaundice, ascites, coagulopathy, or decreased serum albumin are observed.

Renal Insufficiency

Increases in serum creatinine levels, including renal failure, have been observed in patients receiving INFERGEN. INFERGEN has not been studied in patients with renal insufficiency. It is recommended that renal function be evaluated in all patients starting INFERGEN alone or with ribavirin therapy. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine. Combination treatment with INFERGEN/ribavirin should not be used in patients with creatinine clearance < 50 mL/min..

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha-based therapies, including INFERGEN. 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 alpha-based therapies and these events is difficult to establish.

Bone Marrow Toxicity

Interferon alphas suppress bone marrow function and may result in severe cytopenias including aplastic anemia. It is advised that complete blood counts be obtained pretreatment and monitored routinely during therapy. INFERGEN therapy should be discontinued in patients who develop severe decreases in neutrophil ( < 0.5 x 10⁹/L) or platelet counts ( < 25 x 10⁹/L). INFERGEN should be used cautiously in patients with abnormally low peripheral blood cell counts or who are receiving agents that are known to cause myelosuppression. Transplantation patients or other chronically immunosuppressed patients should be treated with interferon alpha therapy with caution.

The use of ribavirin may result in a worsening of INFERGEN-induced neutropenia. Therefore combination treatment with INFERGEN/ribavirin should be used with caution in patients with low baseline neutrophil counts ( < 1500 cells/mm³) and may require that therapy be discontinued in the event of a severe decrease in neutrophil count.

Colitis

Hemorrhagic/ischemic colitis, sometimes fatal, has been observed within 12 weeks of interferon alpha therapies and has been reported in patients treated with INFERGEN. INFERGEN treatment should be discontinued immediately in patients who develop signs and symptoms of colitis.

Pancreatitis

Pancreatitis, sometimes fatal, has been observed in patients treated with interferon alphas, including INFERGEN. INFERGEN should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.

Hypersensitivity

Serious acute hypersensitivity reactions have been reported following treatment with interferon alphas. If hypersensitivity reactions occur (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis), INFERGEN should be discontinued immediately and appropriate medical treatment instituted.

Autoimmune Disorders

Development or exacerbation of autoimmune disorders (e.g., autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, thyroiditis, interstitial nephritis, systemic lupus erythematosus (SLE)) have been reported in patients receiving interferon alpha therapies, including INFERGEN. INFERGEN should not be used in patients with autoimmune hepatitis. Therefore, these laboratory parameters should be monitored closely.

Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with INFERGEN/ribavirin.

Patient Counseling Information

Information for Patients

Patients should be instructed on appropriate use by a health care professional. Patients receiving INFERGEN alone or in combination treatment with INFERGEN/ribavirin must be instructed as to the proper dosage and administration, and informed of the benefits and risks associated with treatment. Information included in the Medication Guide should be reviewed fully with the patient; it is not a disclosure of all or possible adverse reactions.

Patients must be informed that 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 during combination treatment with INFERGEN/ribavirin therapy and for 6 months post-therapy. Combination treatment with INFERGEN/ribavirin 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.

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

The most common adverse reactions occurring with INFERGEN and combination treatment with INFERGEN/ribavirin are flu-like symptoms including fatigue, fever, nausea, headache, arthralgia, myalgia, rigors, and increased sweating. Non-narcotic analgesics and bedtime administration of INFERGEN may be used to prevent or lessen some of these symptoms. Other common adverse reactions are neutropenia, insomnia, leukopenia, and depression.

While fever may be related to the flu-like symptoms reported in patients treated with INFERGEN, when fever occurs, other possible causes of persistent fever should be ruled out.

Patients must be thoroughly instructed in the importance of proper disposal procedures and cautioned against the reuse of needles, syringes, or re-entry of the vial. A puncture-resistant container for the disposal of used syringes and needles should be used by the patient and should be disposed of according to the directions provided by the health care provider .

Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity data for INFERGEN are available in animals or humans.

Mutagenesis

INFERGEN was not mutagenic when tested in several in vitro assays, including the Ames bacterial mutagenicity assay and an in vitro cytogenetic assay in human lymphocytes, either in the presence or absence of metabolic activation.

Use with Ribavirin

See ribavirin labeling for additional warnings relevant to INFERGEN therapy in combination with ribavirin.

Impairment of Fertility

INFERGEN at doses as high as 100 mcg/kg did not selectively affect reproductive performance or the development of the offspring when administered subcutaneous injection to male and female golden Syrian hamsters for 70 and 14 days before mating, respectively, and then through mating and to day 7 of pregnancy.

Use In Specific Populations

Pregnancy

INFERGEN Monotherapy - Pregnancy Category C

INFERGEN has been shown to have embryo lethal or abortifacient effects in golden Syrian hamsters when given at doses > 150 mcg/kg/day (135 times the human dose) and in cynomolgus and rhesus monkeys when given at doses of 3 mcg/kg/day and 10 mcg/kg/day (9 to 81 times the human dose), respectively, based on body surface area, the human dose. There are no adequate and well-controlled studies in pregnant women. INFERGEN should not be used during pregnancy. If a woman becomes pregnant or plans to become pregnant while taking INFERGEN, she should be informed of the potential hazards to the fetus. Males and females treated with INFERGEN should be advised to use effective contraception.

Combination Treatment with INFERGEN/Ribavirin - Pregnancy Category X

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

Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Nursing Mothers

It is not known whether INFERGEN or ribavirin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if INFERGEN is administered to a nursing woman. The effect on the nursing neonate of orally ingested INFERGEN in breast milk has not been evaluated. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue ribavirin.

Pediatric Use

The safety and effectiveness of INFERGEN have not been established in patients below the age of 18 years. INFERGEN therapy is not recommended in pediatric patients.

Geriatric Use

Clinical studies of INFERGEN alone or in combination with ribavirin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, treatment with interferons, including INFERGEN, is associated with psychiatric, cardiac, and systemic (flu-like) adverse reactions. Since decreased hepatic, renal or cardiac function, concomitant disease, and the use of other drug therapies in elderly patients may produce adverse reactions of greater severity, caution should be exercised in the use of INFERGEN and INFERGEN/ribavirin in this population. Ribavirin should not be used in patients with creatinine clearance < 50 mL/min.

Hepatic Impairment

The safety and efficacy of INFERGEN, alone or in combination with ribavirin, for the treatment of chronic HCV infection in patients with hepatic impairment has not been studied. The use of INFERGEN in patients with hepatic decompensation (Child-Pugh score > 6 [class B and C]) is contraindicated.

Renal Impairment

The safety and efficacy of INFERGEN, alone or in combination with ribavirin, for the treatment of chronic HCV infection in patients with renal impairment has not been studied. In patients with impaired renal function, signs and symptoms of interferon toxicity should be closely monitored and INFERGEN dose should be adjusted as recommended in Tables 1-3. INFERGEN/ribavirin should not be administered to patients with creatinine clearance < 50 mL/min and Ribavirin Labeling].

Organ Transplant Recipients

The safety and efficacy of INFERGEN, alone or in combination with ribavirin, for the treatment of chronic HCV infection in liver or other organ transplant recipients have not been evaluated.

HIV or HBV Coinfection

The safety and efficacy of INFERGEN, alone or in combination with ribavirin, for the treatment of chronic HCV infection in patients coinfected with HIV or HBV have not been determined.

SIDE EFFECTS

INFERGEN alone or in combination with ribavirin causes a broad range of serious adverse reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development, more than 560 subjects were exposed to 9 mcg or 15 mcg of INFERGEN monotherapy administered three times per week over a range of 24 to 48 weeks, and more than 480 subjects were exposed to 9 mcg or 15 mcg of INFERGEN, in combination with ribavirin, administered daily up to 48 weeks.

INFERGEN Monotherapy Clinical Trials

Adverse reactions that were reported, regardless of attribution to treatment, in ≥ 10% of subjects in INFERGEN monotherapy studies are presented in Table 4.

Flu-like symptoms (i.e., headache, fatigue, fever, rigors, myalgia, arthralgia, and sweating increased) were the most frequently reported treatment-related adverse reactions. In most cases, these events could be treated symptomatically.

Depression of any severity was reported in 26% of subjects who received 9 mcg INFERGEN monotherapy and was the most common adverse reaction resulting in study drug discontinuation.

INFERGEN 15 mcg three times a week monotherapy as subsequent treatment was associated with a greater incidence of leukopenia and granulocytopenia. One or more dose reductions for any causes were required in up to 36% of subjects.

Table 4: Treatment Emergent Adverse Reactions Occurring in ≥ 10% of Subjects in INFERGEN Monotherapy Trials

Combination Treatment with INFERGEN/Ribavirin Clinical Trials

The most common adverse reactions in the combination treatment with INFERGEN/ribavirin trial are listed in Table 5 and included fatigue (76%), nausea (45%), flu-like symptoms (40%), headache (42%), arthralgia (31%), and myalgia (29%), neutropenia (40%), leukopenia (29%), insomnia (39%), and depression (26%).

Adverse reactions led to early study discontinuation in 104 (21%) of subjects; more subjects discontinued from the 15 mcg INFERGEN group (64 versus 40). Fatigue, anemia, and depression were the most common adverse reactions resulting in study drug discontinuation. A higher proportion of subjects who received the recommended starting dose of 15 mcg (52%) than the 9 mcg dose group (40%) required INFERGEN dose modifications due to adverse reactions, primarily due to neutropenia/leukopenia, thrombocytopenia, and fatigue/weakness. A total of 14% of subjects experienced serious adverse reactions, the most common of which were neutropenia (2%), suicidal ideation (1%), and hyperuricemia (1%).

Table 5: Treatment Emergent Adverse Reactions Occurring in the > 10% of Subjects in Combination Treatment with INFERGEN/Ribavirin Phase 3 Trial

Laboratory Values

Hemoglobin and Hematocrit: Treatment with INFERGEN alone and in combination with ribavirin is associated with decreases in mean values for hemoglobin and hematocrit. In the INFERGEN monotherapy trials, 4% and 5% of subjects had decreases in hemoglobin and hematocrit levels. Decreases from baseline of 20% or more in hemoglobin or hematocrit were seen in ≤ 1% of subjects.

In the combination INFERGEN/ribavirin trial, 88% of subjects had decreases in hemoglobin levels of ≥ 2 g/dL from baseline. Of these, 27% had hemoglobin levels decrease to ≤ 10 g/dL, and underwent dose reductions of ribavirin. Anemia or hemolytic anemia led to study drug discontinuation in 10 subjects.

White Blood Cells: INFERGEN treatment is associated with decreases in mean values for both total white blood cell (WBC) count and ANC. By the end of initial monotherapy treatment, mean decreases from baseline of 19% for WBCs and 23% for ANC were observed. These effects reversed during the post treatment observation period. In two INFERGEN-monotherapy treated subjects ANC levels decreased to below 500 × 10⁶ cells/L. In both cases, the ANC values returned to clinically acceptable levels with INFERGEN dose reductions and were not associated with infections.

Mean decreases from baseline up to 23% for WBCs and up to 27% for ANC were observed for subjects subsequently retreated with INFERGEN monotherapy. Two subjects experienced reversible reductions in ANC to less than 500 × 10⁶ cells/L.

In the combination INFERGEN/ribavirin trial, leukopenia was reported in 24% and 34% of 9 mcg and 15 mcg treated subjects, respectively. More subjects treated with 15 mcg experienced lymphopenia than did those treated with 9 mcg: 14% versus 7%. ANC levels < 0.75 x 10⁹/L were observed in 21% of subjects treated with 9 mcg and 27% of those treated with 15 mcg; no subjects experienced significant infections associated with low ANC levels.

Platelets: INFERGEN treatment is associated with alterations in platelet count. Decreases in mean platelet count of 16% compared to baseline were seen by the end of INFERGEN monotherapy treatment. These decreases were reversed during the post treatment observation period. Three percent of subjects had platelets decrease to less than 50 × 10⁹ cells/L, which necessitated dose reduction.

More subjects treated with 15 mcg in the INFERGEN/ribavirin combination trial experienced a decrease in platelet counts < 40 × 10⁹/L, 3% versus 1% in the 9 mcg dose group. None of the subjects had platelet counts < 25 × 10⁹/L. One subject in the 15 mcg group had Grade 4 thrombocytopenia 127 days after the start of treatment, was hospitalized for this event, and treatment with both study drugs was discontinued; the event resolved 8 days later.

Triglycerides: Mean values for serum triglyceride increased shortly after the start of administration of INFERGEN monotherapy, with increases of 41%, compared with baseline, at the end of the treatment period. Seven percent of the subjects developed values which were at least 3 times above pretreatment levels during treatment. This effect was reversed after discontinuation of treatment.

In the INFERGEN/ribavirin combination trial, 7% of subjects in the 15 mcg dose group experienced increases in triglyceride levels over baseline levels at week 48 compared to 2% in the 9 mcg dose group. There were no differences in the proportion of subjects who had ≥ Grade 3 triglyceride elevations: 2% in both dose groups.

Thyroid Function: INFERGEN monotherapy treatment was associated with biochemical changes consistent with hypothyroidism including increases in TSH and decreases in T4 mean values. Increases in TSH to greater than 7 mU/L were seen in 10% of 9 mcg INFERGEN-treated subjects either during the treatment period or the 24-week post treatment observation period. Thyroid supplements were instituted in approximately one-third of these subjects.

In the combination INFERGEN/Ribavirin trial, mean increases in TSH levels from baseline were greater for the 15 mcg group compared with the 9 mcg group; 14% and 3%, respectively, at Week 12 and 54% and 0% at Week 48. No serious adverse events, discontinuations or dose modifications were related to abnormalities in thyroid function.

Uric Acid: Grade 4 ( > 10 mg/dL) uric acid levels were commonly observed in both INFERGEN/ribavirin treatment groups: 23 in the 9 mcg and 26 in the 15 mcg group. One subject in the 9 mcg group and three in the 15 mcg group experienced serious adverse events related to elevated uric acid levels. Four subjects in the 15 mcg had INFERGEN/ribavirin temporarily interrupted due to elevated uric acid levels.

Immunogenicity

The number of subjects developing positive binding antibody responses was similar in the 9 mcg INFERGEN (11%) and 3 MIU IFN α-2b groups (15%) in monotherapy studies. The titer of neutralizing antibodies to interferon was not measured. Following cessation of interferon therapy, the number of subjects with a positive antibody response declined.

In the INFERGEN/ribavirin combination study, approximately 13% of subjects in the 15 mcg and 18% in the 9 mcg arms developed low-titer neutralizing antibodies to INFERGEN. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response was observed. The incidence of binding antibody was approximately 31%.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies for INFERGEN with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of INFERGEN. Because these reactions are reported voluntarily and from a population of uncertain size, it is not possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Application site

injection site reaction, including injection site necrosis ulcer, and bruising

Ear and Labyrinth

hearing loss, hearing impairment

Gastrointestinal

abdominal distention, gastrointestinal bleeding, gastritis

Hepatobiliary

hepatic enzyme elevations, including ALT and AST elevation, abnormal hepatic function, hyperbilirubinemia, jaundice, ascites, hepatic encephalopathy

Infections

sepsis

Metabolism and Nutritional

dehydration

Musculoskeletal

rhabdomyolysis, arthritis, bone pain

Nervous

speech disorder, ataxia, gait abnormal, convulsions, loss of consciousness, memory impairment, tremors, visual field defect

Psychiatric

delusions, hallucinations

Skin and Subcutaneous

bruising, pyoderma gangrenosum, toxic epidermal necrolysis

Vascular Disorders

Hemorrhage

DRUG INTERACTIONS

INFERGEN

No formal drug interaction studies have been conducted with INFERGEN. INFERGEN should be used cautiously in patients who are receiving agents that are known to cause myelosuppression.

Combination Use with Ribavirin

Please refer to ribavirin labeling for details on ribavirin's drug interaction potential.

INFERGEN Monotherapy - Pregnancy Category C

INFERGEN has been shown to have embryo lethal or abortifacient effects in golden Syrian hamsters when given at doses > 150 mcg/kg/day (135 times the human dose) and in cynomolgus and rhesus monkeys when given at doses of 3 mcg/kg/day and 10 mcg/kg/day (9 to 81 times the human dose), respectively, based on body surface area, the human dose. There are no adequate and well-controlled studies in pregnant women. INFERGEN should not be used during pregnancy. If a woman becomes pregnant or plans to become pregnant while taking INFERGEN, she should be informed of the potential hazards to the fetus. Males and females treated with INFERGEN should be advised to use effective contraception.

Combination Treatment with INFERGEN/Ribavirin - Pregnancy Category X

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

Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

INFERGEN alone or in combination with ribavirin causes a broad range of serious adverse reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development, more than 560 subjects were exposed to 9 mcg or 15 mcg of INFERGEN monotherapy administered three times per week over a range of 24 to 48 weeks, and more than 480 subjects were exposed to 9 mcg or 15 mcg of INFERGEN, in combination with ribavirin, administered daily up to 48 weeks.

INFERGEN Monotherapy Clinical Trials

Adverse reactions that were reported, regardless of attribution to treatment, in ≥ 10% of subjects in INFERGEN monotherapy studies are presented in Table 4.

Flu-like symptoms (i.e., headache, fatigue, fever, rigors, myalgia, arthralgia, and sweating increased) were the most frequently reported treatment-related adverse reactions. In most cases, these events could be treated symptomatically.

Depression of any severity was reported in 26% of subjects who received 9 mcg INFERGEN monotherapy and was the most common adverse reaction resulting in study drug discontinuation.

INFERGEN 15 mcg three times a week monotherapy as subsequent treatment was associated with a greater incidence of leukopenia and granulocytopenia. One or more dose reductions for any causes were required in up to 36% of subjects.

Table 4: Treatment Emergent Adverse Reactions Occurring in ≥ 10% of Subjects in INFERGEN Monotherapy Trials

Combination Treatment with INFERGEN/Ribavirin Clinical Trials

The most common adverse reactions in the combination treatment with INFERGEN/ribavirin trial are listed in Table 5 and included fatigue (76%), nausea (45%), flu-like symptoms (40%), headache (42%), arthralgia (31%), and myalgia (29%), neutropenia (40%), leukopenia (29%), insomnia (39%), and depression (26%).

Adverse reactions led to early study discontinuation in 104 (21%) of subjects; more subjects discontinued from the 15 mcg INFERGEN group (64 versus 40). Fatigue, anemia, and depression were the most common adverse reactions resulting in study drug discontinuation. A higher proportion of subjects who received the recommended starting dose of 15 mcg (52%) than the 9 mcg dose group (40%) required INFERGEN dose modifications due to adverse reactions, primarily due to neutropenia/leukopenia, thrombocytopenia, and fatigue/weakness. A total of 14% of subjects experienced serious adverse reactions, the most common of which were neutropenia (2%), suicidal ideation (1%), and hyperuricemia (1%).

Table 5: Treatment Emergent Adverse Reactions Occurring in the > 10% of Subjects in Combination Treatment with INFERGEN/Ribavirin Phase 3 Trial

Laboratory Values

Hemoglobin and Hematocrit: Treatment with INFERGEN alone and in combination with ribavirin is associated with decreases in mean values for hemoglobin and hematocrit. In the INFERGEN monotherapy trials, 4% and 5% of subjects had decreases in hemoglobin and hematocrit levels. Decreases from baseline of 20% or more in hemoglobin or hematocrit were seen in ≤ 1% of subjects.

In the combination INFERGEN/ribavirin trial, 88% of subjects had decreases in hemoglobin levels of ≥ 2 g/dL from baseline. Of these, 27% had hemoglobin levels decrease to ≤ 10 g/dL, and underwent dose reductions of ribavirin. Anemia or hemolytic anemia led to study drug discontinuation in 10 subjects.

White Blood Cells: INFERGEN treatment is associated with decreases in mean values for both total white blood cell (WBC) count and ANC. By the end of initial monotherapy treatment, mean decreases from baseline of 19% for WBCs and 23% for ANC were observed. These effects reversed during the post treatment observation period. In two INFERGEN-monotherapy treated subjects ANC levels decreased to below 500 × 10⁶ cells/L. In both cases, the ANC values returned to clinically acceptable levels with INFERGEN dose reductions and were not associated with infections.

Mean decreases from baseline up to 23% for WBCs and up to 27% for ANC were observed for subjects subsequently retreated with INFERGEN monotherapy. Two subjects experienced reversible reductions in ANC to less than 500 × 10⁶ cells/L.

In the combination INFERGEN/ribavirin trial, leukopenia was reported in 24% and 34% of 9 mcg and 15 mcg treated subjects, respectively. More subjects treated with 15 mcg experienced lymphopenia than did those treated with 9 mcg: 14% versus 7%. ANC levels < 0.75 x 10⁹/L were observed in 21% of subjects treated with 9 mcg and 27% of those treated with 15 mcg; no subjects experienced significant infections associated with low ANC levels.

Platelets: INFERGEN treatment is associated with alterations in platelet count. Decreases in mean platelet count of 16% compared to baseline were seen by the end of INFERGEN monotherapy treatment. These decreases were reversed during the post treatment observation period. Three percent of subjects had platelets decrease to less than 50 × 10⁹ cells/L, which necessitated dose reduction.

More subjects treated with 15 mcg in the INFERGEN/ribavirin combination trial experienced a decrease in platelet counts < 40 × 10⁹/L, 3% versus 1% in the 9 mcg dose group. None of the subjects had platelet counts < 25 × 10⁹/L. One subject in the 15 mcg group had Grade 4 thrombocytopenia 127 days after the start of treatment, was hospitalized for this event, and treatment with both study drugs was discontinued; the event resolved 8 days later.

Triglycerides: Mean values for serum triglyceride increased shortly after the start of administration of INFERGEN monotherapy, with increases of 41%, compared with baseline, at the end of the treatment period. Seven percent of the subjects developed values which were at least 3 times above pretreatment levels during treatment. This effect was reversed after discontinuation of treatment.

In the INFERGEN/ribavirin combination trial, 7% of subjects in the 15 mcg dose group experienced increases in triglyceride levels over baseline levels at week 48 compared to 2% in the 9 mcg dose group. There were no differences in the proportion of subjects who had ≥ Grade 3 triglyceride elevations: 2% in both dose groups.

Thyroid Function: INFERGEN monotherapy treatment was associated with biochemical changes consistent with hypothyroidism including increases in TSH and decreases in T4 mean values. Increases in TSH to greater than 7 mU/L were seen in 10% of 9 mcg INFERGEN-treated subjects either during the treatment period or the 24-week post treatment observation period. Thyroid supplements were instituted in approximately one-third of these subjects.

In the combination INFERGEN/Ribavirin trial, mean increases in TSH levels from baseline were greater for the 15 mcg group compared with the 9 mcg group; 14% and 3%, respectively, at Week 12 and 54% and 0% at Week 48. No serious adverse events, discontinuations or dose modifications were related to abnormalities in thyroid function.

Uric Acid: Grade 4 ( > 10 mg/dL) uric acid levels were commonly observed in both INFERGEN/ribavirin treatment groups: 23 in the 9 mcg and 26 in the 15 mcg group. One subject in the 9 mcg group and three in the 15 mcg group experienced serious adverse events related to elevated uric acid levels. Four subjects in the 15 mcg had INFERGEN/ribavirin temporarily interrupted due to elevated uric acid levels.

Immunogenicity

The number of subjects developing positive binding antibody responses was similar in the 9 mcg INFERGEN (11%) and 3 MIU IFN α-2b groups (15%) in monotherapy studies. The titer of neutralizing antibodies to interferon was not measured. Following cessation of interferon therapy, the number of subjects with a positive antibody response declined.

In the INFERGEN/ribavirin combination study, approximately 13% of subjects in the 15 mcg and 18% in the 9 mcg arms developed low-titer neutralizing antibodies to INFERGEN. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response was observed. The incidence of binding antibody was approximately 31%.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies for INFERGEN with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of INFERGEN. Because these reactions are reported voluntarily and from a population of uncertain size, it is not possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Application site

injection site reaction, including injection site necrosis ulcer, and bruising

Ear and Labyrinth

hearing loss, hearing impairment

Gastrointestinal

abdominal distention, gastrointestinal bleeding, gastritis

Hepatobiliary

hepatic enzyme elevations, including ALT and AST elevation, abnormal hepatic function, hyperbilirubinemia, jaundice, ascites, hepatic encephalopathy

Infections

sepsis

Metabolism and Nutritional

dehydration

Musculoskeletal

rhabdomyolysis, arthritis, bone pain

Nervous

speech disorder, ataxia, gait abnormal, convulsions, loss of consciousness, memory impairment, tremors, visual field defect

Psychiatric

delusions, hallucinations

Skin and Subcutaneous

bruising, pyoderma gangrenosum, toxic epidermal necrolysis

Vascular Disorders

Hemorrhage

In INFERGEN trials, the maximum overdose reported was a dose of 150 mcg INFERGEN administered subcutaneously in a subject enrolled in a phase 1 advanced malignancy trial. The subject received 10 times the prescribed dosage for three days and experienced a mild increase in anorexia, chills, fever, and myalgia. Increases in ALT (15 IU/L to 127 IU/L), aspartate transaminase (AST) (15 to 164 IU/L), and lactic dehydrogenase (LDH) (183 IU/L to 281 IU/L) were reported. These laboratory values returned to normal or to the subjects baseline values within 30 days.

Interferons induce pleiotropic biologic responses which include antiviral, antiproliferative, and immunomodulatory effects, regulation of cell surface major histocompatibility antigen (HLA class I and class II) expression and regulation of cytokine expression.

Analysis of INFERGEN-induced cellular products (induction of 2'5' OAS and ß-2 microglobulin) after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC) for the levels of 2'5' OAS or ß-2 microglobulin induced over time. Concentrations of 2'5' OAS were maximal at 24 hours after dosing, while serum levels of ß-2 microglobulin appeared to reach a maximum 24 to 36 hours after dosing. The dose-response relationships observed for 2'5' OAS and ß-2 microglobulin were indicative of biological activity after subcutaneous injection administration of 1 mcg to 9 mcg INFERGEN.

The pharmacokinetic properties of INFERGEN have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after subcutaneous injection of 1 mcg, 3 mcg, or 9 mcg INFERGEN. Plasma levels of INFERGEN after subcutaneous injection administration of any dose were too low to be detected by either enzyme-linked immunosorbent assay (ELISA) or by inhibition of viral cytopathic effect.

Renal Dysfunction

Patients with creatinine clearance < 50 mL/min should not be treated with ribavirin.