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.
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.
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