ReciGen®


(Interferon Beta-1a)

HIGH DOSE, HIGH EFFICACY


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® 44 mcg contains approximately 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 44 mcg of interferon beta-1a, 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.

Dosage Forms and Strengths

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

Injection: 44 mcg per 0.5 mL in a single-dose prefilled ReciGen® Physioject™

Indication 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 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 44 mcg three times per week (see Table 1).

Table 1: 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 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 Physioject™ 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.

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.

Warning and Precautions

Depression and Suicide

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. In addition, there have been postmarketing reports of suicide in patients treated with interferon beta-1a. 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 Interferon beta-1a should be considered.

Hepatic Injury

Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking Interferon beta-1a. Symptoms of liver dysfunction began from one to six months following the initiation of interferon beta-1a. If jaundice or other symptoms of liver dysfunction appear, treatment with interferon beta-1a 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. Interferon beta-1a 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 interferon beta-1a used in combination with known hepatotoxic products should be considered prior to interferon beta-1a administration, or when adding new agents to the regimen of patients already on interferon beta-1a. Reduction of interferon beta-1a 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 interferon beta-1a 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 interferon beta-1a if anaphylaxis occurs.

Injection Site Reactions including Necrosis

In controlled clinical trials, injection site reactions occurred more frequently in interferon beta-1a -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 interferon beta-1a treated patients (83%) than in Avonex-treated patients (28%). Injection site necrosis also occurred more frequently in interferon beta-1a -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 interferon beta-1a . 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 interferon beta-1a -treated patients. In controlled clinical trials, leukopenia occurred at a higher frequency in interferon beta-1a -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 interferon beta-1a -treated patients (6%) compared to the Avonex-treated patients (<1%). Thrombocytopenia and anemia occurred more frequently in 44 mcg interferon beta-1a -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 interferon beta-1a 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 interferon beta-1a 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 interferon beta-1a to patients with pre-existing seizure disorders. Seizures have been temporally associated with the use of beta interferons, 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 the introduction of interferon beta-1a 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 interferon beta-1a . Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated.

Adverse Reactions / Side Effects

>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

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

Drug Interactions

Theophylline Derivatives: Interferons may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy

Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Risk C: Monitor therapy

Use in Specific Populations

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of interferon beta-1a 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.

Pregnancy and Lactation

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Interferon beta-1a 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 interferon beta-1a is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when interferon beta-1a is administered to a nursing woman.

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 gender-related effects on pharmacodynamic parameters have been observed.

Pharmacokinetics

The pharmacokinetics of 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.

Non-Clinical 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.

Clinical Studies

In 2008, a randomized, phase III clinical trial was conducted to compare efficacy and safety of CinnaGen recombinant interferon beta1-a (ReciGen) to the innovator product (Rebif®, Biogen) for patients with Relapsing-remitting Multiple Sclerosis (RRMS). A total of 77 RRMS patients with EDSS scores of 0-5.5 were randomly assigned to receive 44µg subcutaneous injections of ReciGen® of Rebif® three times a week for 24 months. Primary efficacy outcomes included annualized relapse rate (ARR), proportions of relapse-free patients, and EDSS mean difference. Safety and MRI end-points including total volume of plaques, number of active plaques and new T2 lesions were the secondary outcomes in this study. Fifty patients completed the 24-month study period. Patients in ReciGen® and Rebif® arms showed no significant difference in terms of ARR (p=0.34), proportions of relapse-free patients (p=0.21), and EDSS mean difference (p=0.4). In addition, no statistically significant differences were noted in MRI and safety outcome measures between groups. Based on the findings, ReciGen® has similar efficacy and safety profile to the reference product in patients with RRMS.

How Supplied / Storage and Handling

 ReciGen® is supplied as a sterile solution containing no preservative available in the following package presentations:

Prefilled Syringes:

 ReciGen® (interferon beta -1a) 44 mcg Prefilled syringe

  • Twelve interferons beta-1a 44 mcg prefilled syringes

ReciGen® Physioject™ (interferon beta-1a) 44 mcg Autoinjector

  • Twelve ReciGen® Physioject™

ReciGen® should be stored refrigerated between 36°F to 46°F (2°C to 8°C). DO NOT FREEZE.

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