ReciGen(IFNβ1a) 1

Transcription

1 ReciGen(IFNβ1a) 1

2 Interferon beta-1a is a purified 166 amino acid glycoprotein with a molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of ReciGen is identical to that of natural fibroblast derived human interferon beta. Using a reference standard calibrated against the World Health Organization natural interferon beta standard Third International Standard for Interferon, Human Fibroblast (NIBSC-00/572), ReciGen has a specific activity of approximately more than 200 million international units (MIU) of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using lung carcinoma cells (A549) and Encephalomyocarditis virus (EMC). Clinical Pharmacology Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons possess immunomodulatory, antiviral and antiproliferative biological activities. They exert their biological effects by binding to specific receptors on the surface of cells. Three major groups of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I interferons and interferon gamma is a Type II interferon. Type I interferons have considerably overlapping but also distinct biological activities. Interferon beta is produced naturally by various cell types including fibroblasts and macrophages. Binding of interferon beta to its receptors initiates a complex cascade of intracellular events that leads to the expression of numerous interferoninduced gene products and markers, including 2, 5 -oligoadenylate synthetase, beta 2- microglobulin and neopterin, which may mediate some of the biological activities. The specific interferon-induced proteins and mechanisms by which interferon beta-1a exerts its effects in multiple sclerosis have not been fully defined. Pharmacodynamics/ Kinetics Onset of action: 12 hours (based on biological response markers) Peak biological response marker levels are typically observed 48 hours after dosing. Duration: 4 days (based on biological response markers) Time to peak, serum: 16 hours Half-life elimination: 69 hours Use: ReciGen (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Efficacy of ReciGen in chronic progressive multiple sclerosis has not been established. 2

3 Dosing: The recommended dosage of ReciGen is 12 Million IU (44 mcg) injected SC 3 times per week. Administration ReciGen is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train patients in the proper technique for self-administering subcutaneous injections using the prefilled syringe. Remove syringe from the refrigerator at least 30 minutes prior to use and let it adjust to room temperature. After removing the ReciGen syringe from the plastic packaging, keep the needle capped. It should be inspected visually for particulate matter and discoloration prior to administration. Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days. ReciGen should be administered at the same time (preferably in the late afternoon/ evening) on the same three days (for example Monday, Wednesday, and Friday) at least 48 hours apart each week. The best sites for injection are those areas with a layer of fat between the skin and muscle, like thigh, the outer surface of upper arm, stomach or buttocks. Rotate injection site. Patients should be started at 20% of the prescribed dose 3 times per week and increased over a 4-week period to the targeted dose 3 times per week. Following the administration of each dose, any residual product remaining in the syringe should be discarded in a safe and proper manner. Never reuse syringes. Target dose 44 mcg 3 times/week: Initial (20% of final dose): 8.8 mcg (0.1 ml) 3 times/week for 2 weeks Titration (50% of final dose): 22 mcg (0.25 ml) 3 times/week for 2 weeks Final dose: 44 mcg (0.5 ml) 3 times/week If liver function tests increase or in case of leucopenia, decrease dose 20% to 50% or discontinue of administration until toxicity resolves. Adverse Reactions >10%: Central nervous system: Headache (58% to 70%), fatigue (33% to 41%), fever (20% to 28%), pain (23%), chills (19%), depression (18% to 25%), dizziness (14%) Gastrointestinal: Nausea (23%), abdominal pain (8% to 22%) Genitourinary: Urinary tract infection (17%) 3

4 Hematologic: Leukopenia (28% to 36%) Hepatic: ALT increased (20% to 27%), AST increased (10% to 17%) Local: Injection site reaction (3% to 92%) Neuromuscular & skeletal: Myalgia (25% to 29%), back pain (23% to 25%), weakness (24%), skeletal pain (10% to 15%), rigors (6% to 13%) Ocular: Vision abnormal (7% to 13%) Respiratory: Sinusitis (14%), upper respiratory tract infection (14%) Miscellaneous: Flu-like syndrome (49% to 59%), neutralizing antibodies (24%), lymphadenopathy (11% to 12%) 1% to 10%: Cardiovascular: Chest pain (5% to 6%), vasodilation (2%) Central nervous system: Migraine (5%), somnolence (4% to 5%), malaise (4% to 5%), seizure (1% to 5%) Dermatologic: Erythematous rash (5% to 7%), maculopapular rash (4% to 5%), alopecia (4%), urticaria Endocrine & metabolic: Thyroid disorder (4% to 6%) Gastrointestinal: Xerostomia (1% to 5%), toothache (3%) Genitourinary: Micturition frequency (2% to 7%), urinary incontinence (2% to 4%) Hematologic: Thrombocytopenia (2% to 8%), anemia (3% to 5%) Hepatic: Bilirubinemia (2% to 3%) Local: Injection site pain (8%), injection site bruising (6%), injection site necrosis (1% to 3%), injection site inflammation Neuromuscular & skeletal: Arthralgia (9%), hypertonia (6% to 7%), coordination abnormal (4% to 5%) Ocular: Eye disorder (4%), xerophthalmia (1% to 3%) Respiratory: Bronchitis (8%) Miscellaneous: Infection (7%) <1% (Limited to important and life-threatening): Anaphylaxis, autoimmune hepatitis, cardiomyopathy, CHF, hepatic failure, hepatitis, hyper-/hypothyroidism, idiopathic thrombocytopenia, injection site abscess/cellulitis, menorrhagia, metrorrhagia, pancytopenia, psychiatric disorders (new or worsening; including suicidal ideation), vesicular rash Contraindications Hypersensitivity to natural or recombinant interferons, human albumin, or any other component of the formulation 4

5 Warnings/Precautions Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: Allergic reactions, including anaphylaxis, have been reported. Autoimmune disorders: Autoimmune disorders including idiopathic thrombocytopenia, hyper- and hypothyroidism and rarely autoimmune hepatitis have been reported. Bone marrow suppression: Pancytopenia (rare) and thrombocytopenia have been reported; use with caution in patients with bone marrow suppression. Flu-like symptoms: Associated with a high incidence of flu-like adverse effects; use of analgesics and/or antipyretics on treatment days may be helpful. Hepatic effects: Rare cases of severe hepatic injury, including hepatic failure, have been reported in patients receiving interferon beta-1a; risk may be increased by ethanol use or concurrent therapy with hepatotoxic drugs. Treatment should be suspended if jaundice or symptoms of hepatic dysfunction occur. Some reports indicate symptoms began after 1-6 months of treatment. Transaminase elevations may be asymptomatic, so monitoring is important. Neuropsychiatric disorders: Interferons have been associated with severe psychiatric adverse events (psychosis, mania, depression, suicidal behavior/ideation) in patients with and without previous psychiatric symptoms, avoid use in severe psychiatric disorders and use caution in patients with a history of depression; patients exhibiting symptoms of depression should be closely monitored and discontinuation of therapy should be considered. Disease-related concerns: Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease,including angina, HF, and/or arrythmia. Rare cases of new-onset cardiomyopathy and/or HF have been reported. Hepatic impairment: Use with caution in patients with hepatic impairment or in those who abuse alco-hol. Dosage adjustment may be necessary. Seizure disorder: Use with caution in patients with a history of seizure disorder. Special populations: Chronic progressive MS: Safety and efficacy have not been established for this use. Pediatrics: Safety and efficacy have not been established in children. Geriatric: Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. 5

6 Dosage form specific issues: Albumin: Some formulations contain albumin, which may carry a remote risk of transmitting CreutzfeldtJakob or other viral diseases. Interferon beta-1a is contraindicated in albumin-sensitive patients. Drug Interactions Theophylline Derivatives: Interferons may decrease the metabolism of Theophylline Derivatives. Monitor therapy Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Monitor therapy Due to its potential to cause neutropenia and lymphopenia, proper monitoring of patients is required if ReciGen is given in combination with myelosuppressive agents. The potential for hepatic injury should be considered when ReciGen is used in combination with other products associated with hepatic injury, or when new agents are added to the regimen of patients already on ReciGen. Pregnancy Risk Factor C Pregnancy Implications There are no adequate and well-controlled studies in pregnant women. Consideration should be given to discontinue treatment if a woman becomes pregnant, or plans to become pregnant during therapy. A doserelated abortifacient activity was reported in Rhesus monkeys. Lactation Excretion in breast milk unknown/not recommended Breast-Feeding Considerations Potential for serious adverse reactions. Because its use has not been evaluated during lactation, a decision should be made to either discontinue breast-feeding or discontinue the drug. Monitoring Parameters Thyroid function tests, CBC with differential, transaminase levels, symptoms of autoimmune disorders, signs/symptoms of psychiatric disorder (including depression and/or suicidal ideation), signs/symptoms of new onset/worsening cardiovascular disease CBC and liver function testing at 1-, 3-, and 6 months, then periodically thereafter. Thyroid function every 6 months (in patients with pre-existing abnormalities and/or clinical indications) 6

7 Dosage Forms ReciGen (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe intended for subcutaneous (sc) injection. Each 0.5 ml (0.5 cc) of ReciGen contains 44 mcg (12 Million IU) of interferon beta-1a, albumin (human), mannitol, sodium acetate, Water for Injection. ReciGen are available in the following package configuration: 12 prefilled syringes for subcutaneous injection. Stability and Storage ReciGen should be stored refrigerated between 2-8 C. Do not freeze. Do not use beyond the expiration date printed on cartons. ReciGen contains no preservatives. Each syringe is intended for single use. Unused portions should be discarded. 7