2.1 Recommended Dose

COPAXONE is for subcutaneous use only. Do not administer intravenously. The recommended dose of COPAXONE is 20 mg/day.

2.2 Instructions for Use

Remove one blister that contains the syringe from the COPAXONE prefilled syringes package. Since this product should be refrigerated, let the prefilled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Inspect the COPAXONE syringe visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the COPAXONE syringe.

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

5.1 Immediate Post-Injection Reaction

Approximately 16% of patients exposed to COPAXONE in the 5 placebo-controlled trials compared to 4% of those 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. The symptoms were generally transient and self-limited and did not require treatment. 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. During the postmarketing period, 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.

5.2 Chest Pain

Approximately 13% of COPAXONE patients in the 5 placebo-controlled studies compared to 6% of placebo patients experienced at least one episode of what was described as 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 of COPAXONE was not always known. The pain was transient (usually lasting only a few minutes), 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.

5.3 Lipoatrophy and Skin Necrosis

At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis have been reported during the postmarketing experience. 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 daily.

5.4 Potential Effects on Immune Response

Because COPAXONE can modify immune response, it may interfere with immune functions. For example, treatment with COPAXONE 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 COPAXONE does this, but there has not been a systematic eva luation of this risk. Because COPAXONE 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 COPAXONE is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with COPAXONE may result in untoward effects.

Glatiramer acetate-reactive antibodies are formed in most patients exposed to daily treatment with the recommended dose. 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 COPAXONE, 20 mg, 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 lgG subtype and predominantly of the lgG-1 subtype. No lgE 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.