interferon alfacon-1
Dosage Form: injection
FULL PRESCRIBING INFORMATION
Alpha interferons, including Infergen, 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 Patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping interferon alfacon-1 therapy. [see WARNINGS AND PRECAUTIONS (5) and ADVERSE REACTIONS (6.1)].
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 ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. [see WARNINGS AND PRECAUTIONS (5); and Ribavirin Full Prescribing Information].
Indications and Usage for Infergen
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 Dosage and Administration
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 [see Clinical Studies (14.1), Medication Guide for instructions].
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 [see Clinical Studies (14.2), Medication Guide for instructions]. 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. [see Clinical Studies (14.3), Medication Guide for instructions].
Ribavirin should be taken with food. Infergen/ribavirin should not be used in patients with creatinine clearance < 50 mL/min [see CONTRAINDICATIONS (4)].
Dose Modifications
If a serious adverse reaction develops during the course of treatment [see WARNINGS AND PRECAUTIONS (5)] 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.
| * See DSM-IV for definitions. | |||||
| Depression Severity* | Initial Management (4–8 Weeks) | Depression | |||
| Dose Modification | Visit Schedule | Remains Stable | Improves | Worsens | |
| Mild | No change to Infergen dose or ribavirin dose. | Evaluate once weekly by visit and/or phone. | Continue weekly visit schedule. | Resume normal visit schedule. | (See moderate or severe depression) |
| Moderate | Decrease Infergen dose from 15 mcg to 9 mcg; or from 9 mcg to 6 mcg, no change to ribavirin dose. | Evaluate once weekly (office visit at least every other week). | Consider psychiatric consultation. Continue reduced dosing. | If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced Infergen dosing or return to normal Infergen dose. | (See severe depression) |
| Severe | Discontinue Infergen and ribavirin permanently. | Not applicable. | Psychiatric therapy necessary. | Not applicable. | Not applicable. |
| Laboratory Values | Action |
| ANC < 0.75 × 109/L | Reduce Infergen dose from 15 mcg to 9 mcg, or from 9 mcg to 6 mcg; maintain ribavirin dose at 1200 mg or 1000 mg. |
| ANC < 0.50 × 109/L | Infergen and ribavirin treatment should be suspended until ANC values return to more than 1000/mm3. |
| Platelet Count < 50 × 109/L | Reduce Infergen dose from 15 mcg to 9 mcg or from 9 mcg to 6 mcg; maintain ribavirin dose at 1200 mg or 1000 mg. |
| Platelet Count < 25 × 109/L | Infergen and ribavirin treatment should be discontinued. |
| * For adult patients with a history of stable cardiac disease receiving Infergen in combination with ribavirin, the Infergen dose should be reduced from 15 mcg to 9 mcg or 9 mcg to 6 mcg and the ribavirin dose by 200 mg/day if a >2 g/dL decrease in hemoglobin is observed during any 4-week period. Both Infergen and ribavirin should be permanently discontinued if patients have hemoglobin levels <12 g/dL after this ribavirin dose reduction. ** 1st dose reduction of ribavirin is by 200 mg/day. 2nd dose reduction of ribavirin (if needed) is by an additional 200 mg/day. | ||
| Condition | Infergen | Ribavirin |
| Hgb <10 g/dL | History of Cardiac or Cerebrovascular Disease, reduce dose of Infergen | Adjust dose** |
| Hgb <8.5 g/dL | Permanently discontinue | Permanently discontinue |
Renal Function: Infergen/ribavirin should not be used in patients with creatinine clearance <50 mL/min. [See CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5) and ribavirin Full Prescribing Information].
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 [See Clinical Studies (14)].
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. [see Medication Guide for detailed instructions].
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
Contraindications
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 and 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 [see BOXED WARNING, CONTRAINDICATIONS (4), Use in Specific Populations (8.1), Patient Counseling Information (17) and ribavirin Full Prescribing Information].
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 [see Dosage and Administration (2.3) and Ribavirin Full Prescribing Information].
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 is 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 [see DOSAGE AND ADMINISTRATION: Dose Modifications (2.3)].
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 [see WARNINGS and PRECAUTIONS (5)]. Patients with a history of significant or unstable cardiac disease should not be treated with Infergen/ribavirin combination therapy [see Ribavirin Full Prescribing Information].
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 [see CONTRAINDICATIONS (4)].
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. [see CONTRAINDICATIONS (4) and ribavirin Full Prescribing Information].
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 (< 50 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 [see DOSAGE AND ADMINISTRATION: Dose Modifications (2.3) and WARNINGS AND PRECAUTIONS: Laboratory Tests (5.16)].
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 [see CONTRAINDICATIONS (4)] and should be used with caution in patients with other autoimmune disorders.
Ophthalmologic Disorders
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by treatment with Infergen or other interferons alpha. 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. Infergen therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Peripheral Neuropathy
Peripheral neuropathy has been reported when interferon alphas were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated.
Endocrine Disorders
Infergen should be administered with caution to patients with a history of endocrine disorders. Occurrence or aggravation of hyperthyroidism or hypothyroidism have been reported with Infergen. Hyperglycemia and diabetes mellitus have also been observed in patients treated with Infergen. Patients who develop these conditions during treatment that cannot be controlled with medication should not continue Infergen therapy.
Laboratory Tests
Laboratory tests are recommended for all patients on Infergen therapy, as follows: prior to beginning treatment (baseline), 2 weeks after initiation of therapy, and periodically thereafter during the 24 or 48 weeks of therapy at the discretion of the physician. Following completion of Infergen therapy, any abnormal test values should be monitored periodically. The entrance criteria that were used for the clinical study of Infergen may be considered as a guideline to acceptable baseline values for initiation of treatment:
- Platelet count ≥ 75 × 109/L
- Hemoglobin concentration ≥ 10 g/dL
- ANC ≥ 1500 × 106/L
- Serum creatinine concentration < 180 µmol/L (< 2.0 mg/dL) or creatinine clearance > 0.83 mL/second (> 50 mL/minute)
- Serum albumin concentration ≥ 25 g/L
- Bilirubin ≤ 1.4 mg/dL (with the exception of patients with Gilbert’s syndrome)
- TSH and T4 within normal limits
Neutropenia, thrombocytopenia, hypertriglyceridemia and thyroid disorders have been reported with administration of Infergen [see ADVERSE REACTIONS]. Therefore, these laboratory parameters should be monitored closely.
Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Infergen/ribavirin.
Adverse Reactions
Infergen alone or in combination with ribavirin causes a broad range of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5)].
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.
| Initial Treatment | Subsequent Treatment | |||
| Infergen 9 mcg (n = 231) | IFN α-2b (n = 236) | Infergen 15 mcg 24 wks (n = 165) | Infergen 15 mcg 48 wks (n = 168) | |
Body System/Preferred Term (COSTART) | % of Subjects | % of Subjects | ||
| APPLICATION SITE | ||||
| Injection Site Erythema | 23 | 15 | 17 | 22 |
| BODY AS A WHOLE | ||||
| Fatigue | 69 | 67 | 65 | 71 |
| Fever | 61 | 45 | 58 | 55 |
| Rigors | 57 | 45 | 62 | 66 |
| Body Pain | 54 | 45 | 39 | 51 |
| Influenza-like Symptoms | 15 | 11 | 8 | 8 |
| Chest Pain | 13 | 14 | 5 | 9 |
| Hot Flushes | 13 | 7 | 7 | 4 |
| Malaise | 11 | 10 | 2 | 5 |
| Asthenia | 9 | 11 | 10 | 7 |
| CNS/PNS | ||||
| Headache | 82 | 83 | 78 | 80 |
| Insomnia | 39 | 30 | 24 | 28 |
| Dizziness | 22 | 25 | 18 | 25 |
| Paresthesia | 13 | 10 | 9 | 9 |
| Hypoesthesia | 10 | 8 | 8 | 10 |
| Amnesia | 10 | 6 | 2 | 5 |
| GASTROINTESTINAL | ||||
| Abdominal Pain | 41 | 40 | 24 | 32 |
| Nausea | 40 | 36 | 30 | 36 |
| Diarrhea | 29 | 24 | 24 | 22 |
| Anorexia | 24 | 17 | 21 | 14 |
| Dyspepsia | 21 | 18 | 12 | 10 |
| Vomiting | 12 | 11 | 13 | 11 |
| MUSCULO-SKELETAL | ||||
| Myalgia | 58 | 56 | 51 | 55 |
| Arthralgia | 51 | 44 | 43 | 46 |
| Back Pain | 42 | 37 | 29 | 23 |
| Limb Pain | 26 | 25 | 13 | 23 |
| Skeletal Pain | 14 | 14 | 10 | 12 |
| Neck Pain | 14 | 13 | 8 | 5 |
| PSYCHIATRIC DISORDER | ||||
| Nervousness | 31 | 29 | 16 | 22 |
| Depression | 26 | 25 | 18 | 19 |
| Anxiety | 19 | 18 | 9 | 14 |
| Emotional Lability | 12 | 11 | 6 | 3 |
| Thinking Abnormal | 8 | 12 | 10 | 20 |
| RESPIRATORY | ||||
| Pharyngitis | 34 | 31 | 17 | 21 |
| Cough | 22 | 17 | 12 | 11 |
| Sinusitis | 17 | 22 | 12 | 16 |
| Dyspnea | 7 | 12 | 8 | 7 |
| SKIN AND APPENDAGES | ||||
| Alopecia | 14 | 25 | 10 | 13 |
| Pruritus | 14 | 14 | 11 | 10 |
| Rash | 13 | 15 | 13 | 10 |
| Sweating Increased | 12 | 11 | 13 | 11 |
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%).
| Retreatment | ||
Infergen 9 mcg/RBV 48 wks (n = 244) | Infergen 15 mcg/RBV 48 wks (n = 242) | |
| Body System/Preferred Term (MedDRA) | % of Subjects | |
| GASTROINTESTINAL DISORDERS | ||
| Abdominal pain | 15 | 14 |
| Constipation | 9 | 10 |
