Copaxone

Copaxone

glatiramer acetate

Manufacturer:

Norton Healthcare

Distributor:

DKLL

Marketer:

Teva Pharma
Full Prescribing Info
Contents
Glatiramer acetate.
Description
1 ml of solution for injection (1 pre-filled pen) contains 40 mg glatiramer acetate*, equivalent to 36 mg of glatiramer.
*Glatiramer acetate is the acetate salt of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine and L-lysine, in molar fraction ranges of 0.129-0.153, 0.392-0.462, 0.086-0.100 and 0.300-0.374, respectively. The average molecular weight of glatiramer acetate is in the range of 5,000-9,000 daltons. Due to its compositional complexity, no specific polypeptide can be fully characterized, including in terms of amino acid sequence, although the final glatiramer acetate composition is not entirely random.
The solution for injection has a pH of 5.5 - 7.0 and an osmolarity of about 300 mOsmol/L.
Excipients/Inactive Ingredients: Mannitol, Water for Injections.
Action
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other immunostimulants. ATC code: L03AX13.
Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism(s) by which glatiramer acetate exerts its therapeutic effects in relapsing forms of MS is not fully elucidated, but is presumed to involve modulation of immune processes. Studies in animals and MS patients suggest glatiramer acetate acts on innate immune cells, including monocytes, dendritic cells and B cells, which in turn modulate adaptive functions B and T cells inducing anti-inflammatory and regulatory cytokine secretion. Whether the therapeutic effect is mediated by the cellular effects described as previously mentioned is not known because the pathophysiology of MS is only partially understood.
Clinical efficacy and safety: Relapsing-Remitting Multiple Sclerosis: Evidence supporting the effectiveness of glatiramer acetate 40 mg/ml injection administered subcutaneously three times a week in decreasing the frequency of relapses derives from one 12-month placebo-controlled study.
In the pivotal clinical trial Relapsing-Remitting Multiple Sclerosis was characterized by either at least one documented relapse in the last 12 months, or at least two documented relapses in the last 24 months, or one documented relapse between the last 12 and 24 months with at least one documented T1-gadolinium enhancing lesion on magnetic resonance imaging performed the last 12 months.
The primary outcome measure was the total number of confirmed relapses. Secondary MRI outcomes included the cumulative number of new/enlarging T2 lesions and the cumulative number of enhancing lesions on T1-weighted images, both measured at months 6 and 12.
A total of 1404 patients were randomized in a 2:1 ratio to receive either glatiramer acetate 40 mg/ml (n=943) or placebo (n=461). Both treatment groups were comparable with respect to baseline demographics, MS disease characteristics and magnetic resonance imaging (MRI) parameters. Patients had a median of 2.0 relapses in the 2 years prior to screening.
Compared to placebo, patients treated with glatiramer acetate 40 mg/ml three times per week had meaningful and statistically significant reductions in the primary and secondary outcome measures which are consistent with the treatment effect of glatiramer acetate 20 mg/ml administered daily.
The following table presents the values for the primary and secondary outcome measures for the intent-to-treat population: (See Table 1.)

Click on icon to see table/diagram/image

A direct comparison of the efficacy and safety between glatiramer acetate 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed.
Glatiramer acetate 40 mg/ml: The proportion of patients with 3-month confirmed disability progression (CDP) was an exploratory endpoint in a 12-month placebo-controlled study (GALA). Three-month CDP was experienced by 3% and 3.5% placebo- and glatiramer acetate-treated patients, respectively (odds ratio, OR [95% CI]: 1.182 [0.661, 2.117] (p=0.5726). Including the open-label extension of the study (up to 7 years), time to 6-month CDP was an exploratory endpoint. The hazard ratio (HR) [95% CI] for the intent to treat cohort, comparing the early start glatiramer acetate group to the delayed start group was 0.892 [0.688, 1.157] (p=0.3898).
There is currently no evidence for the use of glatiramer acetate in patients with primary or secondary progressive disease.
Pharmacokinetics: Pharmacokinetic studies in patients have not been performed. In vitro data and limited data from healthy volunteers indicate that with subcutaneous administration of glatiramer acetate, the active substance is readily absorbed and that a large part of the dose is rapidly degraded to smaller fragments already in subcutaneous tissue.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, beyond the information included in other sections of the SmPC. Due to the lack of pharmacokinetic data in humans, margins of exposure between humans and animals cannot be established.
Immune complex deposition in the glomeruli of the kidney was reported in a small number of rats and monkeys treated for at least 6 months. In a 2 years rat study, no indication of immune complex deposition in the glomeruli of the kidney was seen.
Anaphylaxis after administration to sensitised animals (guinea pigs or mice) was reported. The relevance of these data for humans is unknown.
Toxicity at the injection site was a common finding after repeated administration in animals.
In rats, a slight but statistically significant reduction in body weight gain of offspring born to dams treated during pregnancy and throughout lactation was observed at subcutaneous doses ≥ 6mg/kg/day (2.83-times the maximum recommended human daily dose for a 60 kg adult based on mg/m2) in comparison to control. No other significant effects on offspring growth and behavioral development were observed.
Indications/Uses
COPAXONE PEN is indicated for the treatment of relapsing forms of multiple sclerosis (MS) (see Pharmacology: Pharmacodynamics under Actions for important information on the population for which efficacy has been established).
COPAXONE PEN is not indicated in primary or secondary progressive MS.
Dosage/Direction for Use
The initiation of COPAXONE PEN treatment should be supervised by a neurologist or a physician experienced in the treatment of MS.
Posology: The recommended dose in adults is 40 mg of glatiramer acetate (one pre-filled pen), administered as a subcutaneous injection three times a week with at least 48 hours apart.
At the present time, it is not known for how long the patient should be treated.
A decision concerning long term treatment should be made on an individual basis by the treating physician.
Renal impairment: Glatiramer acetate has not been specifically studied in patients with renal impairment (see Precautions).
Elderly: Glatiramer acetate has not been specifically studied in the elderly.
Paediatric population: The safety and efficacy of glatiramer acetate in children and adolescents has not been established. There is not enough information available on the use of glatiramer acetate 40 mg/ml in children and adolescents below 18 years of age to make any recommendation for its use. Therefore, COPAXONE PEN should not be used in this population.
Method of administration: COPAXONE PEN is for subcutaneous use.
Patients should be instructed in self-injection techniques and should be supervised by a health-care professional the first time they self-inject and for 30 minutes after.
A different site should be chosen for every injection, so this will reduce the chances of any irritation or pain at the site of the injection. Sites for self-injection include the abdomen, arms, hips and thighs.
COPAXONE PEN is for single use only.
Overdosage
Symptoms: A few cases of overdose with glatiramer acetate (up to 300 mg glatiramer acetate) have been reported. These cases were not associated with any adverse reactions other than those mentioned in Adverse Reactions.
Management: In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.
Contraindications
Hypersensitivity to the active substance (glatiramer acetate) or to any of the excipients listed in Excipients/Inactive Ingredients under Description.
Special Precautions
COPAXONE PEN should only be administered subcutaneously.
COPAXONE PEN should not be administered by intravenous or intramuscular routes.
The treating physician should explain to the patient that a reaction associated with at least one of the following symptoms may occur within minutes of a COPAXONE PEN injection: vasodilatation (flushing), chest pain, dyspnoea, palpitations or tachycardia (see Adverse Reactions). The majority of these symptoms is short-lived and resolves spontaneously without any sequelae. Should a severe adverse event occur, the patient must immediately stop COPAXONE PEN treatment and contact his/her physician or any emergency doctor. Symptomatic treatment may be instituted at the discretion of the physician.
There is no evidence to suggest that any particular patient groups are at special risk of these reactions. Nevertheless, caution should be exercised when administering COPAXONE PEN to patients with pre-existing cardiac disorders. These patients should be followed up regularly during treatment.
Convulsions and/or anaphylactoid or allergic reactions have been reportedly rarely. Serious hypersensitivity reactions (e.g. bronchospasm, anaphylaxis or urticaria) may rarely occur. If reactions are severe, appropriate treatment should be instituted and COPAXONE PEN should be discontinued.
Glatiramer acetate-reactive antibodies were detected in patients' sera during daily chronic treatment with glatiramer acetate. Maximal levels were attained after an average treatment duration of 3-4 months and, thereafter, declined and stabilised at a level slightly higher than baseline.
There is no evidence to suggest that these glatiramer acetate-reactive antibodies are neutralising or that their formation is likely to affect the clinical efficacy of glatiramer acetate.
In patients with renal impairment, renal function should be monitored while they are treated with COPAXONE PEN. Whilst there is no evidence of glomerular deposition of immune complexes in patients, the possibility cannot be excluded.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use In Pregnancy & Lactation
Pregnancy: Studies in animals have not shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Current data on the use of glatiramer acetate 20 mg/ml in pregnant women indicate no malformative or feto/neonatal toxicity. Data on the use of glatiramer acetate 40 mg/ml are consistent with these findings. To date, no relevant epidemiological data are available. As a precautionary measure, it is preferable to avoid the use of COPAXONE PEN during pregnancy unless the benefit to the mother outweighs the risk to the foetus.
Breastfeeding: It is unknown whether glatiramer acetate or its metabolites are excreted in human milk. In rats, no significant effects on offspring were observed except for a slight reduction in body weight gains in the offspring of mothers dosed during pregnancy and throughout lactation (see Pharmacology: Toxicology: Preclinical safety data under Actions).
A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or discontinue/abstain from COPAXONE PEN therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Adverse Reactions
This section presents accumulated safety data from four placebo-controlled trials with glatiramer acetate 20 mg/ml administered once daily, and from one placebo-controlled trial with glatiramer acetate 40 mg/ml administered three times a week.
A direct comparison of the safety between glatiramer acetate 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed.
Glatiramer acetate 20 mg/ml (administered once daily): In all clinical trials with glatiramer acetate 20 mg/ml, injection-site reactions were seen to be the most frequent adverse reactions and were reported by the majority of patients receiving glatiramer acetate.
In controlled studies, the proportion of patients reporting these reactions, at least once, was higher following treatment with glatiramer acetate 20 mg/ml (70%) than placebo injections (37%). The most commonly reported injection-site reactions, which were more frequently reported in glatiramer acetate 20 mg/ml vs. placebo-treated patients, were erythema, pain, mass, pruritus, oedema, inflammation and hypersensitivity.
A reaction, associated with at least one or more of the following symptoms, has been described as the immediate post-injection reaction: vasodilatation (flushing), chest pain, dyspnoea, palpitation or tachycardia (see Precautions). This reaction may occur within minutes of a glatiramer acetate injection. At least one component of this immediate post-injection reaction was reported at least once by 31% of patients receiving glatiramer acetate 20 mg/ml compared to 13% of patients receiving placebo.
All adverse reactions, which were more frequently reported in glatiramer acetate 20 mg/ml vs. placebo-treated patients, are presented in the table as follows. This data was derived from four pivotal, double-blind, placebo-controlled clinical trials with a total 512 patients treated with glatiramer acetate 20 mg/day and 509 patients treated with placebo for up to 36 months. Three trials in relapsing-remitting MS (RRMS) included a total of 269 patients treated with glatiramer acetate 20 mg/day and 271 patients treated with placebo for up to 35 months. The fourth trial in patients who have experienced a first clinical episode and were determined to be at high risk of developing clinically definite MS included 243 patients treated with glatiramer acetate 20mg/day and 238 patients treated with placebo for up to 36 months. (See Table 2.)

Click on icon to see table/diagram/image

In the fourth trial noted as previously mentioned, an open-label treatment phase followed the placebo-controlled period. No change in the known risk profile of glatiramer acetate 20 mg/ml was observed during the open-label follow-up period of up to 5 years.
Rare (≥1/10,000 to <1/1,000) reports of anaphylactoid reactions were collected from MS patients treated with glatiramer acetate in uncontrolled clinical trials and from post-marketing experience with glatiramer acetate.
Glatiramer acetate 40 mg/ml (administered three times per week): The safety of glatiramer acetate 40 mg/ml was assessed based on a double-blind, placebo-controlled clinical trial in RRMS patients with a total of 943 patients treated with glatiramer acetate 40 mg/ml three times per week, and 461 patients treated with placebo for 12 months.
In general, the kind of adverse drug reactions seen in patients treated with glatiramer acetate 40 mg/ml administered three times per week were those already known and labelled for glatiramer acetate 20 mg/ml administered daily. In particular, adverse injection site reactions (ISR) and immediate post-injection reactions (IPIR) were reported at lower frequency for glatiramer acetate 40 mg/ml administered three times per week than for glatiramer acetate 20 mg/ml administered daily (35.5% vs. 70% for ISRs and 7.8% vs. 31% for IPIRs, respectively).
Injection site reactions were reported by 36% of the patients on glatiramer acetate 40 mg/ml compared to 5% on placebo. Immediate post-injection reaction was reported by 8% of the patients on glatiramer acetate 40 mg/ml compared to 2% on placebo.
A few specific adverse reactions are noted: Anaphylactic response was seen rarely (≥1/10,000, <1/1,000) in MS patients treated with glatiramer acetate 20 mg/ml in uncontrolled clinical trials and from post-marketing experience. It was reported by 0.3% of the patients on glatiramer acetate 40 mg/ml (Uncommon: ≥ 1/1,000 to < 1/100).
No injection site necrosis was reported.
Skin erythema and pain in extremity, not labelled for glatiramer acetate 20 mg/ml, were reported each by 2.1% of the patients on glatiramer acetate 40 mg/ml (Common: ≥ 1/100 to < 1/10).
Drug-induced liver injury and toxic hepatitis, also seen rarely in MS patients treated with glatiramer acetate 20 mg/ml in post marketing surveillance, were each reported by one patient (0.1%) on glatiramer acetate 40 mg/ml (Uncommon: ≥ 1/1,000 to < 1/100).
Drug Interactions
Interaction between glatiramer acetate and other medicinal products have not been formally evaluated. There are no data on interaction with interferon beta.
An increased incidence of injection site reactions has been seen in glatiramer acetate patients receiving concurrent administration of corticosteroids.
In vitro work suggests that glatiramer acetate in blood is highly bound to plasma proteins but that it is not displaced by, and does not itself displace, phenytoin or carbamazepine. Nevertheless, as glatiramer acetate has, theoretically, the potential to affect the distribution of protein-bound substances, concomitant use of such medicinal products should be monitored carefully.
Caution For Usage
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Keep the pre-filled pens in the outer carton, in order to protect from light.
Store in a refrigerator (2°C - 8°C).
Do not freeze.
If the pre-filled pens cannot be stored in a refrigerator, they can be stored between 15°C and 25°C, once for up to one month.
After this one month period, if the COPAXONE PEN pre-filled pens have not been used and are still in their original packaging, they must be returned to storage in a refrigerator (2°C to 8°C).
Shelf life: 24 months.
ATC Classification
L03AX13 - glatiramer acetate ; Belongs to the class of other immunostimulants.
Presentation/Packing
Soln for inj (pre-filled pen) 40 mg/ml (clear solution free of visible particles) x 12's.
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