Cinnomer®


(Glatiramer Acetate)

Safe as Cinnomer


INDICATIONS AND USAGE

CINNOMER is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

DOSAGE AND ADMINISTRATION

Recommended Dose

CINNOMER is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are:

CINNOMER 40 mg per mL: administer three times per week and at least 48 hours apart

CINNOMER 20 mg per mL and CINNOMER 40 mg per mL are not interchangeable.

Instructions for Use

Remove one blister-packaged prefilled syringe from the refrigerated carton. Let the prefilled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Visually inspect the syringe for particulate matter and discoloration prior to administration. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the syringe.

Areas for subcutaneous self-injection include arms, abdomen, hips, and thighs. The prefilled syringe is for single use only. Discard unused portions.

DOSAGE FORMS AND STRENGTHS

Injection: 20 mg per mL in a single-dose. For subcutaneous use only.

Injection: 40 mg per mL in a single-dose. For subcutaneous use only.

CONTRAINDICATIONS

CINNOMER is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.

WARNINGS AND PRECAUTIONS

Immediate Post-Injection Reaction

Approximately 16% of patients exposed to CINNOMER 20 mg per mL in the 5 placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to CINNOMER 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms immediately after injection that included at least two of the following: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a specific syndrome is uncertain. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown.

Chest Pain

Approximately 13% of CINNOMER 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to CINNOMER 40 mg per mL in a placebo-controlled trial compared to 1% of placebo patients, experienced at least one episode of transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least 1 month after the initiation of treatment. The pathogenesis of this symptom is unknown.

Lipoatrophy and Skin Necrosis

At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy occurred in approximately 2% of patients exposed to CINNOMER 20 mg per mL in the 5 placebocontrolled trials compared to none on placebo, and 0.5% of patients exposed to CINNOMER 40 mg per mL in a single placebo-controlled trial and none on placebo. Skin necrosis has only been observed in the post-marketing setting. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection.

Potential Effects on Immune Response

Because CINNOMER can modify immune response, it may interfere with immune functions. For example, treatment with CINNOMER may interfere with the recognition of foreign antigens in a way that would undermine the body's tumor surveillance and its defenses against infection. There is no evidence that CINNOMER does this, but there has not been a systematic evaluation of this risk. Because CINNOMER is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken.

Although CINNOMER is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with CINNOMER may result in untoward effects.

Glatiramer acetate-reactive antibodies are formed in most patients receiving glatiramer acetate. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of 125 RRMS patients given CINNOMER 20 mg per mL, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the IgG subtype and predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded.

ADVERSE REACTIONS

>10%:

Cardiovascular: Vasodilatation (3% to 20%), chest pain (2% to 13%)

Central nervous system: Pain (20%), anxiety (13%)

Dermatologic: Skin rash (2% to 19%), diaphoresis (15%)

Gastrointestinal: Nausea (2% to 15%)

Hypersensitivity: Immediate hypersensitivity (2% to 16%; postinjection, including flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and/or urticaria)

Immunologic: Development of IgG antibodies (3 months: ≥3 x baseline: 80%; 12 months: 90%; ≥3 x baseline: 30%)

Infection: Infection (30%)

Local: Inflammation at injection site (2% to 49%), erythema at injection site (22% to 43%), pain at injection site (10% to 40%), itching at injection site (6% to 27%), residual mass at injection site (6% to 27%), swelling (1% to 19%)

Neuromuscular & skeletal: Weakness (22%), back pain (12%)

Respiratory: Dyspnea (3% to 14%), flu-like symptoms (3% to 14%), nasopharyngitis (11%)

1% to 10%:

Cardiovascular: Palpitations (7% to 9%), edema (8%), tachycardia (5%), facial edema (3%), peripheral edema (3%), syncope (3%), hypertension (1%)

Central nervous system: Migraine (4%), chills (2% to 3%), nervousness (2%), speech disturbance (2%), abnormal dreams (1%), emotional lability (1%), stupor (1%)

Dermatologic: Hyperhidrosis (7%), pruritus (5%), erythema (2% to 4%), urticaria (3%), skin atrophy (≥1%), warts (≥1%), eczema (1%), pustular rash (1%)

Endocrine & metabolic: Weight gain (3%), amenorrhea (1%), hypermenorrhea (1%)

Gastrointestinal: Vomiting (7%), gastroenteritis (6%), dysphagia (2%), aphthous stomatitis (≥1%), bowel urgency (≥1%), dental caries (≥1%), enlargement of salivary glands (≥1%), oral candidiasis (≥1%)

Genitourinary: Urinary urgency (5%), volvovaginal candidiasis (4%), abnormal Pap smear (≥1%), hematuria (≥1%), vaginal hemorrhage (≥1%), impotence (1%)

Hematologic & oncologic: Bruise (8%), lymphadenopathy (7%), benign skin neoplasm (2%)

Hypersensitivity: Hypersensitivity (3%)

Infection: Abscess (≥1%), herpes zoster (≥1%)

Local: Bleeding at injection site (5%), hypersensitivity reaction at injection site (4%), fibrosis at injection site (2%), lipoatrophy at injection site (≤2%), abscess at injection site (1%)

Neuromuscular & skeletal: Neck pain (8%), tremor (4%), laryngospasm (2%)

Ophthalmic: Diplopia (3%), visual field defect (1%)

Respiratory: Rhinitis (7%), bronchitis (6%), cough (6%), laryngismus (5%), viral respiratory tract infection (3%), hyperventilation (1%)

Miscellaneous: Fever (3% to 6%)

<1% (Limited to important or life-threatening): Amyotrophy, anaphylactoid reaction, anemia, angina pectoris, angioedema, aphasia, arthritis, asthma, ataxia, atrial fibrillation, blepharoptosis, blindness, bradycardia, bursitis, carcinoma (breast, bladder, lung, ovarian), cardiac arrhythmia, cardiac failure, cardiomegaly, cardiomyopathy, cataract, cerebral edema, cerebrovascular accident, cholecystitis, cholelithiasis, CNS neoplasm, colitis, coma, corneal ulcer, coronary occlusion, Cushing's syndrome, cyanosis, decreased libido, deep vein thrombophlebitis, depersonalization, dermatitis, dry eye syndrome, duodenal ulcer, eosinophilia, erythema nodosum, esophageal ulcer, esophagitis, facial paralysis, fibrocystic breast disease, fourth heart sound, fungal dermatitis, furunculosis, gastrointestinal carcinoma, gastrointestinal hemorrhage, gastrointestinal ulcer, genitourinary neoplasm, glaucoma, gout, hallucination, hematemesis, hepatic cirrhosis, hepatitis, hepatomegaly, hernia, hydrocephalus, hypercholesterolemia, hyperthyroidism, hypokinesia, hypotension, hypothyroidism, hypoventilation, increased appetite, leukemia, leukopenia, lupus erythematosus, lymphedema, maculopapular rash, malignant neoplasm of cervix, malignant neoplasm of skin, mania, memory impairment, meningitis, mitral valve prolapse syndrome, moon face, muscle spasm, mydriasis, myelitis, myocardial infarction, myoclonus, nephrolithiasis, nephrosis, neuralgia, optic neuritis, oral mucosa ulcer, orthostatic hypotension, osteomyelitis, otitis externa, ovarian cyst, pancreatitis, pancytopenia, paraplegia, pericardial effusion, peripheral vascular disease, photophobia, pneumonia, priapism, pseudolymphoma, psoriasis, psychotic depression, pulmonary embolism, pyelonephritis, rectal hemorrhage, renal failure, seizures, sepsis, serum sickness, skin hypertrophy, skin photosensitivity, skin pigmentation, splenomegaly, stomatitis, suicidal tendencies, systemic lupus erythematosus, systolic heart murmur, tenosynovitis, thrombocytopenia, thrombophlebitis, thrombosis, tissue necrosis at injection site, urethritis, vesicobullous rash, weight loss, xeroderma

DRUG INTERACTIONS

Interactions between CINNOMER and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of CINNOMER with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. CINNOMER has not been formally evaluated in combination with interferon beta.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B.

Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on offspring development. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CINNOMER should be used during pregnancy only if clearly needed.

In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on a mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed.

Labor and Delivery

The effects of CINNOMER on labor and delivery in pregnant women are unknown.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of CINNOMER have not been established in patients under 18 years of age.

Geriatric Use

CINNOMER has not been studied in elderly patients.

Use in Patients with Impaired Renal Function

The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined.

DESCRIPTION

Glatiramer acetate, the active ingredient of CINNOMER, consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000 – 9,000 daltons. Glatiramer acetate is identified by specific antibodies.

Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and Ltyrosine, acetate (salt). Its structural formula is:

(Glu, Ala, Lys, Tyr)xxCH3COOH

(C5H9NO4●C3H7NO2●C6H14N2O2●C9H11NO3)xxC2H4O2

CINNOMER is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 1 mL of CINNOMER solution contains 20 mg or 40 mg of glatiramer acetate and the following inactive ingredient: 40 mg of mannitol. The pH of the solutions is approximately 5.5 to 7.0. The biological activity of glatiramer acetate is determined by its ability to block the induction of experimental autoimmune encephalomyelitis (EAE) in mice.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS are not fully understood. However, glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis, a condition induced in animals through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.

Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally-occurring immune responses. There is no evidence that glatiramer acetate does this, but this has not been systematically evaluated.

Pharmacokinetics

Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer acetate can be recognized by glatiramer acetatereactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose of 20 mg/day on a mg/m2 basis). No increase in systemic neoplasms was observed. In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over a limited skin area.

In a 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on a mg/m2 basis). No increase in neoplasms was observed.

Glatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk) assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes but not clastogenic in an in vivo mouse bone marrow micronucleus assay.

When glatiramer acetate was administered by subcutaneous injection prior to and during mating (males and females) and throughout gestation and lactation (females) at doses up to 36 mg/kg/day (18 times the human therapeutic dose on a mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters.

HOW SUPPLIED/STORAGE AND HANDLING

CINNOMER (glatiramer acetate injection) is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution supplied as:

20 mg per mL in a single-dose, prefilled syringe

40 mg per mL in a single-dose, prefilled syringe

Store CINNOMER refrigerated at 2°C to 8°C (36°F to 46°F). If needed, the patient may store CINNOMER at room temperature, 15°C to 30°C (59°F to 86°F), for up to one month, but refrigeration is preferred. Avoid exposure to higher temperatures or intense light. Do not freeze CINNOMER. If a CINNOMER syringe freezes, it should be discarded.

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