PEG-IntronTM, peginterferon alfa-2b, Powder for Injection, is a covalent conjugate of recombinant alfa interferon with monomethoxy polyethylene glycol (PEG). The 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 pegylated interferon 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 µg, 118.4 µg, 177.6 µg, or 222 µg of 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 µg per 0.5 mL, 80 µg per 0.5 mL, 120 µg per 0.5 mL, or 150 µg 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 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 µg/kg dose suggest the clearance of peginterferon alfa-2b is reduced by approximately half in patients 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 µg/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 Cmax and 50-fold greater AUC than interferon alfa-2b. The pharmacokinetics of geriatric patients (> 65 years of age) treated with a single subcutaneous dose of 1.0 µg/kg of PEG-Intron were similar in Cmax, AUC, clearance, or elimination half-life as compared to younger subjects (28 to 44 years in 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 µg/kg PEG-Intron did not inhibit CYP1A2, 2C8/9, 2D6, 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 µg/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% 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 µg/kg PEG-Intron doses were similar (approximately 24%) to each other and were both higher than response rates to INTRON A (12%). (See Table 1)
Table 1. Rates of Response to Treatment-Study 1
aSerum HCV RNA is measured by a research-based quantitative polymerase chain reaction by a central laboratory.
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 compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of non-Caucasians studied (9% 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 naďve patients were treated for 48 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 1.5µg/kg plus ribavirin 800mg dose was higher than the response rate to Intron A/REBETOL (See Table 2). The response rate to PEG-Intron 1.5®0.5µg/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
1Serum HCV RNA is measured with a research-based quantitative polymerase chain reaction assay by a central
laboratory. Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-Intron (1.5 µg/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. 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:
PEG-Intron/REBETOL combination therapy is additionally contraindicated in:
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. Endocrine disorders PEG-Intron causes or aggravates hypothyroidism and hyperthyroidism. 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 Cardiovascular events, which include hypotension, arrhythmia, tachycardia, 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 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 Development or exacerbation of autoimmune disorders (e.g. thyroiditis, 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 Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with PEG-Intron, discontinue 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
Patients with renal failure: Patients with impairment of renal function should be closely monitored for signs and symptoms of interferon toxicity and doses of 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. Immunogenicity: Approximately 2% of patients receiving PEG-Intron (32/1759) or INTRON A (11/728) with or without REBETOL developed low-titer (£160) 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 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. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with PEG-Intron/REBETOL. 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). 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, 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 µg/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 µg/m2 (approximately 21 times the 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 Use: 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 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 psychiatric, systemic (e.g. fatigue, headache), or gastrointestinal adverse events. In the combination therapy trial, dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-Intron (1.5 µg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of patients (57%) weighing 60 kg or less receiving Peg-Intron (1.5 µg/kg)/REBETOL required dose reduction. Reduction of interferon was dose related (PEG-Intron 1.5 µg/kg > PEG-Intron 0.5 µg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three groups, 33-35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%). (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In the PEG-Intron/REBETOL combination trial the most common adverse events were psychiatric which occurred among 77% of patients and included most commonly depression, irritability, and insomnia, each reported by approximately 30-40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all patients during treatment or during follow-up after treatment cessation (see WARNINGS). PEG-Intron induced fatigue or headache in approximately two-thirds of patients, and induced fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (e.g. fever and headache) tended to decrease as treatment continues. The incidence tends to be higher with PEG-Intron than with Intron A therapy alone or in combination with REBETOL. Application site inflammation and reaction (e.g. bruise, itchiness, irritation) occurred at approximately twice the incidence with PEG-Intron therapies (in up to 75% of patients) compared with INTRON A. However injection site pain was infrequent (2-3%) in all groups. Other common adverse events in the PEG-Intron/REBETOL group included myalgia (56%), arthralgia (34%) nausea (43%), anorexia (32%), weight loss (29%), alopecia (36%), and pruritus (29%). In the PEG-Intron monotherapy trial the incidence of severe adverse events was 13% in the INTRON A group and 17% in the PEG-Intron groups. In the PEG-Intron/REBETOL combination therapy trial the incidence of severe adverse events was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-Intron/REBETOL groups. The incidence of life-threatening adverse events was < 1% across all groups in the monotherapy and combination therapy trials. Adverse events that occurred in the clinical trial at >5% incidence are provided in Table 3 by treatment group. Due to potential differences in ascertainment procedures, adverse event rate comparisons across studies should not be made. Table 3. Adverse Events Occurring in > 5% of Patients
*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.
Many patients continued to experience adverse events several months after discontinuation of therapy. By the end of the 6-month follow-up period the incidence of ongoing adverse events by body class in the PEG-Intron 1.5 µg/kg/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10-15% of patients weight loss, fatigue and headache had not resolved. Individual serious adverse events occurred at a frequency £1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis; urticaria, injection-site necrosis, vasculitis, phototoxicity. Laboratory Values Changes in selected laboratory values during treatment with PEG-Intron alone or incombination with REBETOL treatment are described below. Decreases in hemoglobin, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy. (See DOSAGE AND ADMINISTRATION- Dose Reduction) Hemoglobin. REBETOL induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to <11g/dl in about 30% of patients. Severe anemia (<8 g/dl) occurred in < 1% of patients. Dose modification was required in 9 and 13% of patients in the PEG-Intron/REBETOL and INTRON A /REBETOL groups. Hemoglobin levels become stable by treatment week 4-6 on average. Hemoglobin levels return to baseline between 4 and 12 weeks post-treatment. In the PEG-Intron monotherapy trial hemoglobin decreases were generally mild and dose modifications were rarely necessary. (See DOSAGE AND ADMINISTRATION: Dose Modification). Neutrophils. Decreases in neutrophil counts were observed in a majority of patients treated with PEG-Intron alone (70%) or as combination therapy with REBETOL (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (<0.5 x 109/L) occurred in 1% of patients treated with PEG-Intron monotherapy, 2% of patients treated with INTRON A/REBETOL and in 4% of patients treated with PEG-Intron/REBETOL. Two percent of patients receiving PEG-Intron monotherapy and 18% of patients receiving PEG-Intron /REBETOL required modification of interferon dosage. Few patients (£ 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels within 4 weeks of cessation of therapy. (See DOSAGE AND ADMINISTRATION: Dose Modification). Platelets. Platelet counts decrease in approximately 20% of patients treated with PEG-Intron alone or with REBETOL and in 6% of patients treated with INTRON A/REBETOL. Severe decreases in platelet counts (<50,000/mm3) occur in <1% of patients. Patients may require discontinuation or dose modification as a result of platelet decreases. (See DOSAGE AND ADMINISTRATION: Dose Modification). In the PEG-Intron/REBETOL combination therapy trial 1% or 3% of patients required dose modification of INTRON A or PEG-Intron respectively. Platelet counts generally returned to pretreatment levels within 4 weeks of the cessation of therapy. Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. Clinically apparent thyroid disorders occur among patients treated with either Intron A or PEG-Intron (with or without REBETOL) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still had abnormal TSH values. Bilirubin and uric acid. In the PEG-Intron/REBETOL trial 10-14% of patients developed hyperbilirubinemia and 33-38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout. OVERDOSAGE There is limited experience with overdosage. In the clinical studies, a few patients accidentally received a dose greater than that prescribed. There were no instances in which a participant in the monotherapy or combination therapy trials received more than 10.5 times the intended dose of PEG-Intron. The maximum dose received by any patient was 3.45 µg/kg weekly over a period of approximately 12 weeks. The maximum known overdosage of REBETOL was an intentional ingestion of 10 g (fifty 200 mg capsules). There were no serious reactions attributed to these overdosages. In cases of overdosing, symptomatic treatment and close observation of the patient are recommended. DOSAGE AND ADMINISTRATION There are no safety and efficacy data on treatment for longer than one year. A patient should self-inject PEG-Intron only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and training in proper injection technique has been given to him/her. (See illustrated MEDICATION GUIDE for instructions.) It is recommended that patients receiving PEG-Intron, alone or in combination with ribavirin, be discontinued from therapy if HCV viral levels remain high after 6 months of therapy. PEG-Intron Monotherapy The recommended dose of PEG-Intron regimen is 1.0 mcg/kg/week for one year. The volume of PEG-Intron to be injected depends on the vial strength used and the patient weight (see Table 4 below). Table 4 Recommended PEG-Intron Monotherapy Dosing
* When reconstituted as directed
PEG-Intron/REBETOL Combination Therapy When administered in combination with REBETOL, the recommended dose of PEG-Intron is 1.5 micrograms/kg/week. The volume of PEG-Intron to be injected depends on the vial strength of PEG-Intron and patient’s body weight. (See Table 5 below). TABLE 5. Recommended PEG-Intron Combination Therapy Dosing
The recommended dose of REBETOL is 800 mg/day in 2 divided doses: two capsules (400 mg) with breakfast and two capsules (400 mg) with dinner. REBETOL should not be used in patients with creatinine clearance <50 mL/min. Dose Reduction If a serious adverse reaction develops during the course of treatment (See WARNINGS) discontinue or modify the dosage of PEG-Intron and/or REBETOL until the adverse event abates or decreases in severity. If persistent or recurrent serious adverse events develop despite adequate dosage adjustment, discontinue treatment. For guidelines for dose modifications and discontinuation based on laboratory parameters, see Tables 6 and 7. In the combination therapy trial dose reductions occurred among 42% of patients receiving PEG-Intron 1.5 µg/kg/REBETOL 800 mg daily including 57% of those patients weighing 60 kg or less (see ADVERSE REACTIONS).
Table 6: Guidelines for Modification or Discontinuation of PEG-Intron
1 See DSM-IV for definitions
Table 7. Guidelines for Dose Modification and Discontinuation of PEG-Intron
* For patients with a history of stable cardiac disease receiving PEG-Intron in combination with ribavirin, the PEG-Intron dose should be reduced by half and the ribavirin dose by 200mg/day if a > 2g/dL decrease in hemoglobin is observed during any 4 week period. Both PEG-Intron and ribavirin should be permanently discontinued if patients have hemoglobin levels <12 g/dL after this ribavirin dose reduction.
Preparation and Administration Two B-D Safety LokTM syringes are provided in the package; one syringe is for the reconstitution steps and one for the patient injection. There is a plastic safety sleeve to be pulled over the needle after use. The syringe locks with an audible click when the green stripe on the safety sleeve covers the red stripe on the needle. Brief instructions for the preparation and administration of PEG-Intron Powder for Injection are provided below. Please refer to the Medication Guide for detailed, step-by-step instructions. Reconstitute the PEG-Intron lyophilized product with only 0.7 mL of supplied diluent (Sterile Water for Injection, USP). The diluent vial is for single use only. The remaining diluent should be discarded. No other medications should be added to solutions containing PEG-Intron, and PEG-Intron should not be reconstituted with other diluents. Swirl gently to hasten complete dissolution of the powder. The reconstituted solution should be clear and colorless. Visually inspect the solution for particulate matter and discoloration prior to administration. The solution should not be used if discolored or cloudy, or if particulates are present (see MEDICATION GUIDE for detailed instructions). The reconstituted solution should be used immediately and cannot be stored for more than 24 hours at 2-80 C (See Storage). The appropriate PEG-Intron dose should be withdrawn and injected subcutaneously. (See MEDICATION GUIDE for detailed instructions). The PEG-Intron vial is a single use vial and does not contain a preservative. DO NOT REENTER VIAL. DISCARD UNUSED PORTION. Once the dose from a single dose vial has been withdrawn, the sterility of any remaining product can no longer be guaranteed. Pooling of unused portions of some medications has been linked to bacterial contamination and morbidity. After preparation and administration of the PEG-Intron injection, it is essential to follow the procedure for proper disposal of syringes and needles. A puncture-resistant container should be used for disposal of syringes. Patients should be instructed in the technique and importance of proper syringe disposal and be cautioned against reuse of these items (See MEDICATION GUIDE for detailed instructions.) Storage PEG-Intron, should be stored at 25oC (77oF): excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature]. After reconstitution with supplied Diluent the solution should be used immediately, but may be stored up to 24 hours at 2o to 8oC (36o to 46oF). The reconstituted solution contains no preservative, is clear and colorless. Do not freeze. HOW SUPPLIED PEG-Intron is a white to off-white lyophilized powder supplied in 2-mL vials. The PEG-Intron Powder for Injection should be reconstituted with 0.7 mL of the supplied Diluent (Sterile Water for Injection, USP) prior to use.
Schering Corporation Kenilworth, NJ 07033 USA Revision: DATE Copyright©, 2001 Schering Corporation, All rights reserved.
Last Updated: 10/3/2001 Date created: September 26, 2003
|
|
|  | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
