ReciGen®


(Interferon Beta-1a)

HIGH DOSE, HIGH EFFICACY


INDICATIONS AND USAGE

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.

DOSAGE AND ADMINISTRATION

Dosing Information

The recommended dose of RECIGEN is either 22 mcg or 44 mcg injected subcutaneously three times per week. RECIGEN should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week.

Generally, patients should be started at 20% of the prescribed dose three times per week and increased over a 4-week period to the targeted dose, either 22 mcg three times per week (see Table 1) or 44 mcg three times per week (see Table 2). Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for titration.

 

Table 1: Titration Schedule for a 22 mcg Prescribed Dose*

Week of Use Dose Syringe to Use Amount of syringe

Week1

Titration

4.4 mcg 8.8 mcg syringe Use half of syringe

Week2

Titration 

4.4 mcg 8.8 mcg syringe Use half of syringe

Week3  

Titration

11 mcg 22 mcg syringe Use half of syringe

Week4 

Titration 

11 mcg 22 mcg syringe Use half of syringe

Week5

 Titration

22 mcg 22 mcg syringe or Use full syringe or
  • Use only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose

Table 2: Titration Schedule for a 44 mcg Prescribed Dose*

Week of Use Dose Syringe to Use Amount of syringe

Week1

Titration

8.8 mcg 8.8 mcg syringe Use full syringe

Week2

Titration

8.8 mcg 8.8 mcg syringe Use full syringe

Week3

Titration

22 mcg 22 mcg syringe  Use full syringe

Week4

Titration

22 mcg 22 mcg syringe Use full syringe

Week5

and after

44 mcg 44 mcg syringe Use full syringe

 

  • Prefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose

Decreased peripheral blood counts or elevated liver function tests may necessitate dose reduction or discontinuation of RECIGEN administration until toxicity is resolved.

Important Administration Instructions

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 or injection device approved for use with RECIGEN.

The initial injection should be performed under the supervision of an appropriately qualified health care provider.

Appropriate instruction for self-injection or injection by another person should be provided to the patient or their caregiver, including careful review of the RECIGEN Medication Guide. Users should demonstrate competency in all aspects of the injection prior to independent use. If a patient is to self-administer RECIGEN, the physical and cognitive ability of that patient to self-administer and properly dispose of prefilled syringes should be assessed. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver.

Advise patients and caregivers to:

  • visually inspect RECIGEN for particulate matter and discoloration prior to administration use aseptic technique when administering RECIGEN
  • rotate site of injection with each dose to minimize the likelihood of severe injection site reactions or necrosis
  • use a puncture-resistant container for safe disposal of used needles, prefilled syringes
  • do not re-use needles  or syringes

Premedication for Flu-like Symptoms

Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms associated with RECIGEN use on treatment days.

DOSAGE FORMS AND STRENGTHS

Injection: 44 mcg per 0.5 mL in a graduated, single-dose RECIGEN prefilled syringe

CONTRAINDICATIONS

RECIGEN is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation.

WARNINGS AND PRECAUTIONS

Depression and Suicide

RECIGEN (interferon beta-1a) should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including RECIGEN. In addition, there have been postmarketing reports of suicide in patients treated with RECIGEN. Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to the prescribing physician. If a patient develops depression, cessation of treatment with RECIGEN should be considered.

Hepatic Injury

Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking RECIGEN. Symptoms of liver dysfunction began from one to six months following the initiation of RECIGEN. If jaundice or other symptoms of liver dysfunction appear, treatment with RECIGEN should be discontinued immediately due to the potential for rapid progression to liver failure. Asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon therapy. RECIGEN should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum SGPT (> 2.5 times ULN), or a history of significant liver disease. Also, the potential risk of RECIGEN used in combination with known hepatotoxic products should be considered prior to RECIGEN administration, or when adding new agents to the regimen of patients already on RECIGEN. Reduction of RECIGEN dose should be considered if SGPT rises above 5 times the upper limit of normal. The dose may be gradually re-escalated when enzyme levels have normalized.

Anaphylaxis and Other Allergic Reactions

Anaphylaxis has been reported as a rare complication of RECIGEN use. Other allergic reactions have included skin rash and urticaria, and have ranged from mild to severe without a clear relationship to dose or duration of exposure. Several allergic reactions, some severe, have occurred after prolonged use. Discontinue RECIGEN if anaphylaxis occurs.

Injection Site Reactions including Necrosis

In controlled clinical trials, injection site reactions occurred more frequently in RECIGEN-treated patients (92% in the 44 mcg group and 89% in the 22 mcg group) than in placebo-treated patients (39%) and at a higher frequency in RECIGEN treated patients (83%) than in CINNOVEX-treated patients (28%). Injection site necrosis also occurred more frequently in RECIGEN-treated patients (3% in the 44 mcg group and 1% in the 22 mcg group) than in placebo-treated patients (0) during the two years of therapy. All events resolved with conservative management.

Injection site reactions including injection site pain, erythema, edema, cellulitis, abscess, and necrosis have been reported in the postmarketing setting. Some occurred more than 2 years after initiation of RECIGEN. Necrosis occurred at single and at multiple injection sites. Some cases of injection site necrosis required treatment with intravenous antibiotics and surgical intervention (debridement and skin grafting). Patient understanding and use of aseptic self-injection techniques and procedures should be periodically evaluated, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating sites of injection with each dose and not reusing syringes. Patients should be advised against injecting an area which is inflamed, edematous, erythematous, ecchymotic, or has any other signs of infection. These signs should be reported to a healthcare professional immediately.

Decreased Peripheral Blood Counts

Decreased peripheral blood counts in all cell lines, including pancytopenia, have been reported in RECIGEN-treated patients. In controlled clinical trials, leukopenia occurred at a higher frequency in RECIGEN-treated patients (36% in 44 mcg group and 28% in 22 mcg group) than in placebo-treated patients (14%) and at a higher frequency in RECIGEN-treated patients (6%) compared to the CINNOVEX-treated patients (<1%). Thrombocytopenia and anemia occurred more frequently in 44 mcg RECIGEN-treated patients (8% and 5%, respectively) than in placebo-treated patients (2% and 3%, respectively). In a pooled analysis of 7 placebo controlled trials with RECIGEN doses of 22 mcg or 44 mcg, the rate of pancytopenia (in subjects with normal baseline values who developed laboratory values less than the lower limit of normal for all 3 hematology parameters simultaneously) was higher in the total RECIGEN group (5.5 per 1000 subject-year) than in the placebo group (1.2 per 1000 subject-year). Patients should be monitored for symptoms or signs of decreased blood counts. Monitoring of complete blood and differential white blood cell counts is also recommended.

Seizures

Caution should be exercised when administering RECIGEN to patients with pre-existing seizure disorders. Seizures have been temporally associated with the use of beta interferons, including RECIGEN, in clinical trials and in postmarketing reports.

Laboratory Tests

In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, blood cell counts and liver function tests are recommended at regular intervals (1, 3, and 6 months) following introduction of RECIGEN therapy and then periodically thereafter in the absence of clinical symptoms. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. New or worsening thyroid abnormalities have developed in some patients treated with RECIGEN. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated.

ADVERSE REACTIONS

>10%:

Central nervous system: Headache (58% to 70%), fatigue (33% to 41%), depression (18% to 25%), pain (23%), chills (19%), dizziness (14%)

Gastrointestinal: Nausea (23%), abdominal pain (8% to 22%)

Genitourinary: Urinary tract infection (17%)

Hematologic & oncologic: Leukopenia (28% to 36%), lymphadenopathy (11% to 12%)

Hepatic: Increased serum ALT (20% to 27%), increased serum AST (10% to 17%)

Immunologic: Antibody development (neutralizing; significance not known; ReciGen: 24% to 31%; CinnoVex: 5%)

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%)

Ophthalmic: Visual disturbance (7% to 13%)

Respiratory: Flu-like symptoms (49% to 59%), sinusitis (14%), upper respiratory tract infection (14%)

Miscellaneous: Fever (20% to 28%)

1% to 10%:

Cardiovascular: Chest pain (5% to 8%), vasodilation (2%)

Central nervous system: Hypertonia (6% to 7%), migraine (5%), ataxia (4% to 5%), drowsiness (4% to 5%), malaise (4% to 5%), seizure (1% to 5%), suicidal tendencies (4%)

Dermatologic: Erythematous rash (5% to 7%), maculopapular rash (4% to 5%), alopecia (4%), urticaria

Endocrine & metabolic: Thyroid disease (4% to 6%)

Gastrointestinal: Xerostomia (1% to 5%), toothache (3%)

Genitourinary: Urinary frequency (2% to 7%), urinary incontinence (2% to 4%), urine abnormality (3%)

Hematologic & oncologic: Thrombocytopenia (2% to 8%), anemia (3% to 5%)

Hepatic: Hyperbilirubinemia (2% to 3%)

Infection: Infection (7%)

Local: Pain at injection site (8%), bruising at injection site (6%), inflammation at injection site (6%), tissue necrosis at injection site (1% to 3%)

Neuromuscular & skeletal: Arthralgia (9%)

Ophthalmic: Eye disease (4%), xerophthalmia (1% to 3%)

Respiratory: Bronchitis (8%)

<1% (Limited to important and life-threatening): Abnormal healing, abscess, abscess at injection site, amnesia, anaphylaxis, arteritis, arthritis, bloody stools, breast fibroadenosis, cardiac arrest, cardiac failure, cellulitis at injection site, conjunctivitis, depersonalization, dermal ulcer, diverticulitis, drug dependence, emphysema, epididymitis, erythema multiforme, facial paralysis, fibrosis at injection site, furunculosis, gallbladder disease, gastritis, gastrointestinal hemorrhage, gingivitis, gynecomastia, hemolytic uremic syndrome, hemorrhage, hepatic failure, hepatic neoplasm, hepatitis, hepatomegaly, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hernia, hypersensitivity reaction at injection site, hyperthyroidism, hypoglycemia, hypokalemia, hypomagnesemia, hypotension, hypothyroidism, immune thrombocytopenia, intestinal obstruction, intestinal perforation, lipoma, lupus erythematosus, menopause, neoplasm, nephrolithiasis, neurological signs and symptoms (transient; may mimic multiple sclerosis exacerbations), nevus, orthostatic hypotension, osteonecrosis, pancytopenia, pelvic inflammatory disease, pericarditis, periodontitis, peripheral vascular disease, Peyronie's disease, pneumonia, postmenopausal bleeding, proctitis, psychiatric disorders (new or worsening; including suicidal ideation), psychoneurosis, pulmonary embolism, pyelonephritis, retinal vascular disease, sepsis, severe weakness (transient), skin photosensitivity, Stevens-Johnson syndrome, synovitis, tachycardia, telangiectasia, testicular disease, thromboembolism, thrombotic thrombocytopenic purpura, uterine fibroids, vaginal hemorrhage, vascular disease, vesicular eruption

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. RECIGEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a study in pregnant cynomolgus monkeys, interferon beta was administered daily (intramuscular doses approximately 1, 2, and 7 times the maximum recommended cumulative weekly human dose, based on body surface area) either throughout the period of organogenesis or later in pregnancy (gestation day 90 to term). No adverse effects on embryofetal development were observed; however, the possibility of adverse effects cannot be ruled out because of the small number of animals tested (six per dose group at each developmental period).

Nursing Mothers

It is not known whether RECIGEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECIGEN is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of RECIGEN 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.

DESCRIPTION

RECIGEN (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. Natural interferon beta and interferon beta-1a (RECIGEN) are glycosylated with each containing a single N-linked complex carbohydrate moiety.

Using a reference standard calibrated against the World Health Organization natural interferon beta standard (Second International Standard for Interferon, Human Fibroblast GB 23 902 531), RECIGEN has a specific activity of approximately 270 million international units (MIU) of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using WISH cells and Vesicular Stomatitis virus. RECIGEN 8.8 mcg, 22 mcg and 44 mcg contains approximately 2.4 million international units, 6 million international units or 12 million international units, respectively, of antiviral activity using this method.

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 either 22 mcg or 44 mcg of interferon beta-1a, 2 mg or 4 mg albumin (human), 27.3 mg mannitol, 0.4 mg sodium acetate, and water for injection. Each 0.2 mL (0.2 cc) of RECIGEN contains 8.8 mcg of interferon beta-1a, 0.8 mg albumin (human), 10.9 mg mannitol, 0.16 mg sodium acetate, and water for injection.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism(s) by which RECIGEN (interferon beta-1a) exerts its therapeutic effects in patients with multiple sclerosis is unknown.

Pharmacodynamics

The relationships between serum interferon beta-1a levels and measurable pharmacodynamic activities to the mechanism(s) by which INTERFERON BETA-1A exerts its effects in multiple sclerosis are unknown. No genderrelated effects on pharmacodynamic parameters have been observed.

Pharmacokinetics

The pharmacokinetics of INTERFERON BETA-1A (interferon beta-1a) in people with multiple sclerosis have not been evaluated. In healthy subjects, a single subcutaneous (sc) injection of 60 mcg of INTERFERON BETA-1A (liquid formulation) resulted in a peak serum concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum concentration (Tmax) of 16 hours. The serum elimination half-life (t1/2) was 69 ± 37 hours, and the area under the serum concentration versus time curve (AUC) from zero to 96 hours was 294 ± 81 IU h/mL. Following every other day sc injections in healthy subjects, an increase in AUC of approximately 240% was observed, suggesting that accumulation of interferon beta-1a occurs after repeat administration. Total clearance is approximately 33-55 L/hour. There have been no observed gender-related effects on pharmacokinetic parameters. Pharmacokinetics of INTERFERON BETA-1A in pediatric and geriatric patients or patients with renal or hepatic insufficiency have not been established.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: INTERFERON BETA-1A has not been tested for carcinogenic potential in animals. 

Mutagenesis: Interferon beta was negative in an in vitro bacterial reverse mutation (Ames) assay and an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation.

Impairment of Fertility: In studies in normally cycling female cynomolgus monkeys given daily subcutaneous injections of interferon beta for six months at doses of up to 9 times the recommended weekly human dose (based on body surface area), no effects were observed on either menstrual cycling or serum estradiol levels. In male monkeys, the same doses of interferon beta had no demonstrable adverse effects on sperm count, motility, morphology, or function.

HOW SUPPLIED/STORAGE AND HANDLING

INTERFERON BETA-1A is supplied as a sterile solution containing no preservative available in the following package presentations:

Prefilled Syringes:

INTERFERON BETA-1A (interferon beta -1a) 44 mcg Prefilled syringe

Twelve INTERFERON BETA-1A 44 mcg prefilled syringes

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