DESCRIPTION

COPAXONE® is the brand name for glatiramer acetate (formerly known as copolymer-1). Glatiramer acetate, a member of the Glatiramoid family of compounds and the active ingredient of COPAXONE®, 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 L-tyrosine, acetate (salt). Its structural formula is:

COPAXONE® Injection is a clear, colorless to slightly yellow, sterile, non-pyrogenic solution for subcutaneous injection. Each 1.0 mL of solution contains 20 mg of glatiramer acetate and 40 mg of mannitol, USP. The pH range of the solution is approximately 5.5 to 7.0. The biological activity of COPAXONE® is determined by its ability to block the induction of EAE in mice.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism(s) by which glatiramer acetate exerts its effects in patients with Multiple Sclerosis (MS) is (are) not fully elucidated. However, it is thought to act by modifying immune processes that are currently 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 allergic encephalomyelitis (EAE), a condition induced in several animal species 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. Results of a limited battery of tests designed to eva luate this risk produced no finding of concern; nevertheless, there is no logical way to absolutely exclude this possibility (see PRECAUTIONS).

Pharmacokinetics

Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support the assumption that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Nevertheless, larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive 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.

Clinical Trials

Evidence supporting the effectiveness of glatiramer acetate in decreasing the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RR MS) derives from two placebo-controlled trials, both of which used a glatiramer acetate dose of 20 mg/day. (No other dose or dosing regimen has been studied in placebo-controlled trials of RR MS.)

One trial was performed at a single center. It enrolled 50 patients who were randomized to receive daily doses of either glatiramer acetate, 20 mg subcutaneously, or placebo (glatiramer acetate, n=25; placebo, n=25). Patients were diagnosed with RR MS by standard criteria, and had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging from 0–Normal to 10–Death due to MS. A score of 6 is defined as one at which a patient is still ambulatory with assistance; a score of 7 means the patient must use a wheelchair.

Patients were examined every 3 months for 2 years, as well as within several days of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours).

The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the 2 years of the trial, but two other important outcomes were also specified as endpoints: 1) the frequency of attacks during the trial, and 2) the change in the number of attacks compared with the number which occurred during the previous 2 years.

Table 1 presents the values of the three outcomes described above, as well as several protocol specified secondary measures. These values are based on the intent-to-treat population (i.e., all patients who received at least 1 dose of treatment and who had at least 1 on-treatment assessment):

The second trial was a multicenter trial of similar design which was performed in 11 US centers. A total of 251 patients (glatiramer acetate, 125; placebo, 126) were enrolled. The primary outcome measure was the Mean 2-Year Relapse Rate. The table below presents the values of this outcome for the intent-to-treat population, as well as several secondary measures:

In both studies glatiramer acetate exhibited a clear beneficial effect on relapse rate, and it is based on this evidence that glatiramer acetate is considered effective.

A third study was a multi-national study in which MRI parameters were used both as primary and secondary endpoints. A total of 239 patients with RR MS (119 on glatiramer acetate and 120 on placebo) were randomized. Inclusion criteria were similar to those in the second study with the additional criterion that patients had to have at least one Gd-enhancing lesion on the screening MRI. The patients were treated in a double-blind manner for nine months, during which they underwent monthly MRI scanning. The primary endpoint for the double-blind phase was the total cumulative number of T1 Gd-enhancing lesions over the nine months. Table 3 summarizes the results for the primary outcome measure monitored during the trial for the intent-to-treat cohort.

The following figure displays the results of the primary outcome on a monthly basis.

Figure 1: Median Cumulative Number of Gd-Enhancing Lesions

p= 0.0030 for the difference between the placebo-treated (n=120) and glatiramer acetate-treated (n=119) groups

INDICATIONS AND USAGE

COPAXONE® Injection is indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis.

CONTRAINDICATIONS

COPAXONE® Injection is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.

WARNINGS

The only recommended route of administration of COPAXONE® Injection is the subcutaneous route. COPAXONE® Injection should not be administered by the intravenous route.

PRECAUTIONS

General

Patients should be instructed in self-injection techniques to assure the safe administration of COPAXONE® Injection (see PRECAUTIONS: Information for Patients and the COPAXONE® INJECTION PATIENT INFORMATION Leaflet). Current data indicate that no special caution is required for patients operating an automobile or using complex machinery.

Considerations Regarding the Use of a Product Capable of Modifying Immune Responses

Because glatiramer acetate can modify immune response, it could possibly interfere with useful immune functions. For example, treatment with glatiramer acetate might, in theory, 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 glatiramer acetate does this, but there has as yet been no systematic eva luation of this risk. Because glatiramer acetate 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 glatiramer acetate is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with glatiramer acetate might result in untoward effects.

Glatiramer acetate-reactive antibodies are formed in practically all 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 RR MS patients given glatiramer acetate, 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.

Information for Patients

To assure safe and effective use of COPAXONE® Injection, the following information and instructions should be given to patients:

1. Inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while taking this medication.
2. Inform your physician if you are nursing.
3. Do not change the dose or dosing schedule without consulting your physician.
4. Do not stop taking the drug without consulting your physician.

Patients should be instructed in the use of aseptic techniques when administering COPAXONE® Injection. Appropriate instructions for the self-injection of COPAXONE® Injection should be given, including a careful review of the COPAXONE® INJECTION PATIENT INFORMATION Leaflet. The first injection should be performed under the supervision of an appropriately qualified health care professional. Patient understanding and use of aseptic self-injection techniques and procedures should be periodically reeva luated. Patients should be cautioned against the reuse of needles or syringes and instructed in safe disposal procedures. They should use a puncture-resistant container for disposal of used needles and syringes. Patients should be instructed on the safe disposal of full containers according to local laws.

Awareness of Adverse Reactions: Physicians are advised to counsel patients about adverse reactions associated with the use of COPAXONE® Injection (see ADVERSE REACTIONS section). In addition, patients should be advised to read the COPAXONE® INJECTION PATIENT INFORMATIONLeaflet and resolve any questions regarding it prior to beginning COPAXONE® Injection therapy.

Laboratory Tests

Data collected during premarketing development do not suggest the need for routine laboratory monitoring.

Drug Interactions

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

Drug/Laboratory Test Interactions

None are known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a two-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 on a mg/m2 basis). No increase in systemic neoplasms was observed. In males of the high dose group (60 mg/kg/day), but not in females, 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 two-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 systemic neoplasms was observed.

Mutagenesis

Glatiramer acetate was not mutagenic in four strains of Salmonella typhimurium and two strains of Escherichia coli (Ames test) or in the in vitro mouse lymphoma assay in L5178Y cells. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes; it was not clastogenic in an in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

In a multigeneration reproduction and fertility study in rats, glatiramer acetate at subcutaneous doses of up to 36 mg/kg (18 times the human therapeutic dose on a mg/m2 basis) had no adverse effects on reproductive parameters.

Pregnancy

Pregnancy Category B. No adverse effects on embryofetal development occurred in reproduction studies in rats and rabbits receiving subcutaneous doses of up to 37.5 mg/kg of glatiramer acetate during the period of organogenesis (18 and 36 times the therapeutic human dose on a mg/m2 basis, respectively). In a prenatal and postnatal study in which rats received 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.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, glatiramer acetate should be used during pregnancy only if clearly needed.

Labor and Delivery

In a prenatal and postnatal study, in which rats received subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery were observed. The relevance of these findings to humans is unknown.

Nursing Mothers

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

Pediatric Use

The safety and efficacy of COPAXONE® Injection have not been established in individuals under 18 years of age.

Use in the Elderly

COPAXONE® Injection has not been studied specifically in elderly patients.

Use in Patients with Impaired Renal Function

The pharmacokinetics of