Glatiramer Acetate (Systemic)
VA CLASSIFICATION
Primary: IM409; CN900
Commonly used brand name(s): Copaxone.
Another commonly used name is
copolymer-1 .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Multiple sclerosis (MS) therapy agent{01}—
Indications
General considerations
Because glatiramer acetate can modify immune response, consideration must be given to the possibility that it may interfere with useful immune function {01}. Theoretically, for example, it could interfere with the recognition of foreign antigens in a manner that would undermine the body's defenses against infections and tumor surveillance {01}. There is no evidence of this, although no systematic evaluation of this risk has been conducted {01}.
Because glatiramer acetate is an antigenic material, its use possibly could induce unwanted host responses {01}. There is no evidence that this occurs in humans, although no systematic evaluation of this risk has been conducted {01}. Studies in rats and monkeys, however, have suggested that immune complexes are deposited in the renal glomeruli {01}. Furthermore, in a controlled trial of 125 patients with relapsing-remitting multiple sclerosis who received 20 mg of glatiramer acetate subcutaneously every day for 2 years, serum IgG levels reached approximately three times the baseline values in 80% of patients within 3 to 6 months of initiation of treatment {01}. These values decreased to about 50% greater than baseline during the remainder of treatment {01}.
Although treatment with glatiramer acetate is intended to minimize the autoimmune response to myelin, the possibility remains that continued alteration of cellular immunity due to long-term treatment may result in untoward effects {01}.
Accepted
Multiple sclerosis (treatment)—Glatiramer acetate is indicated for reduction of the frequency of relapses in patients with relapsing-remitting multiple sclerosis. {01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical group—
Glatiramer acetate is composed 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. {01}
Molecular weight—
The average molecular weight of glatiramer acetate is 4700 to 11,000 daltons {01}
Mechanism of action/Effect:
The mechanism of action is unknown {01}. However, glatiramer acetate is believed to modify immune processes that are thought to be responsible for the pathogenesis of multiple sclerosis (MS) {01}. Glatiramer acetate reduces the incidence and severity of experimentally induced allergic encephalomyelitis; this condition can be induced in several animal species through immunization against myelin-containing material derived from the central nervous system (CNS), and often is used as an experimental animal model of MS {01}.
The ability of glatiramer acetate to modify immune functions raises concerns regarding its potential to alter naturally occurring immune responses {01}. Results of a limited battery of tests designed to evaluate this risk were negative; however, the possibility cannot be absolutely excluded {01}.
Pharmacokinetics
Pharmacokinetic studies have not been performed in humans {01}. Partly on the basis of animal studies, a substantial fraction of subcutaneously injected glatiramer acetate is assumed to be hydrolyzed locally {01}. Some fraction of the injected material is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact {01}.
Precautions to Consider
Carcinogenicity
Studies to assess the carcinogenic potential of glatiramer acetate in mice and rats are in progress {01}.
Mutagenicity
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 {01}. Glatiramer acetate was found to be 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 {01}.
Pregnancy/Reproduction
Fertility—
In a multigeneration reproduction and fertility study in rats, glatiramer acetate at subcutaneous doses of up to 36 mg per kg of body weight (mg/kg) (18 times the recommended human daily dose) had no adverse effects on reproductive parameters {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
In reproduction studies in rats and rabbits receiving subcutaneous doses of glatiramer acetate up to 37.5 mg/kg during the period of organogenesis, no adverse effects on embryo/fetal development occurred {01}. In a prenatal and postnatal study in which rats received subcutaneous glatiramer acetate doses of up to 36 mg/kg from day 15 of pregnancy through lactation, no significant effects on delivery or on offspring growth and development were observed {01}.
FDA Pregnancy Category B {01}.
Breast-feeding
It is not known whether glatiramer acetate is distributed into human milk {01}.
Pediatrics
Safety and efficacy have not been established in patients younger than 18 years of age {01}.
Geriatrics
Glatiramer acetate has not been studied specifically in elderly patients {01}.
Drug interactions and/or related problems
Note: Interactions between glatiramer acetate and other medications have not been fully evaluated {01}. Results from clinical trials do not suggest any significant interactions of glatiramer acetate with other therapies commonly used in multiple sclerosis patients, including concurrent use of corticosteroids for up to 28 days {01}. Glatiramer acetate has not been evaluated formally in combination with interferon beta; however, ten patients who switched from therapy with interferon beta to glatiramer acetate have not reported any serious or unexpected adverse events thought to be related to treatment {01}.
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problem exists
Sensitivity to glatiramer acetate or mannitol
Side/Adverse Effects
Note: Approximately 10% of patients exposed to glatiramer acetate in premarketing studies experienced a constellation of symptoms immediately after injection {01}. Symptoms included flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria {01}. These symptoms were invariably transient and self-limited and did not require specific treatment {01}. In general, these symptoms appear several months after the initiation of therapy, although they may occur earlier in the course of treatment, and a patient may experience one or several episodes of these symptoms {01}. It is not certain if this constellation of symptoms represents a specific syndrome {01}. Whether these episodes are mediated by an immunologic or nonimmunologic mechanism, or whether several similar episodes seen in a particular patient have identical mechanisms is not known {01}.
Approximately 26% of patients receiving glatiramer acetate in the premarketing multicenter controlled trial experienced at least one episode of transient chest pain, as compared with 10% of the patients receiving placebo {01}. Some, but not all, of these episodes occurred in the context of the immediate postinjection reaction {01}. Chest pain usually lasted only a few minutes, was often unassociated with other symptoms, and appeared to have no important sequelae {01}. Electrocardiogram (ECG) monitoring was not performed during these episodes {01}. Chest pain episodes usually began at least 1 month after initiation of treatment, and some patients experienced more than one episode {01}. The pathogenesis of this symptom is unknown {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Anxiety{01}
arthralgia{01} (joint pain)
chest pain{01}
dyspnea{01} (troubled breathing)
facial edema{01} (swelling or puffiness of face)
hypertonia{01} (excessive muscle tone)
injection-site reactions{01}
including hemorrhage{01} (bleeding), induration{01} (hard lump), inflammation{01}
pain{01}
pruritus{01} (itching), redness{01}
urticaria{01} (hives or welts)
lymphadenopathy{01} (swollen lymph glands)
neck pain{01}
palpitations{01} (irregular or pounding heartbeat)
vaginal moniliasis{01} (vaginal yeast infection)
vasodilatation{01} (flushing)
Incidence less frequent
Agitation{01}
bronchitis{01} (tightness in chest or wheezing)
chills{01}
confusion{01}
ecchymosis{01} (purple spots under the skin)
edema{01} (bloating or swelling)
flu-like syndrome{01} (chills; fever; muscle aches)
infection{01}
laryngismus{01} (spasm of throat)
migraine{01}
pain{01}
peripheral edema{01} (swelling of fingers, arms, feet, or legs)
skin nodules{01} (small lumps under the skin)
skin rash{01}
syncope{01} (fainting)
urinary urgency{01} (strong urge to urinate)
urticaria{01} (hives)
Incidence rare
Anorexia{01} (loss of appetite)
back pain{01}
diarrhea{01}
dysmenorrhea or other menstrual changes{01}
ear pain{01}
hematuria{01} (blood in urine)
hypertension{01} (high blood pressure)
hyperventilation{01} (fast breathing)
impotence{01} (decreased sexual ability)
nystagmus{01} (continuous, uncontrolled back-and-forth and/or rolling eye movements)
oral moniliasis (irritation of mouth and tongue [thrush] )
speech problems{01}
suspicious Papanicolaou test
tachycardia{01} (fast or racing heartbeat)
vertigo{01} (sensation of motion, usually whirling, either of oneself or of one's surroundings)
vision problems{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Asthenia{01} (unusual tiredness or weakness)
nausea{01}
sweating, increased{01}
tremor{01} (trembling)
vomiting{01}
Incidence less frequent
Rhinitis (runny nose)
weight gain{01}
Overdose
For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance)
Before using this medication
» Conditions affecting use, especially:
Sensitivity to glatiramer acetate or mannitol {01}
Proper use of this medication
» Receiving instructions in self-injection techniques to assure safe administration {01}
» Carefully reading patient instructions contained in package
» Importance of using medication exactly as directed
» Not discontinuing medication without checking with physician
» Proper dosing
Missed dose: Using as soon as remembered; not using if not remembered until next day; not doubling doses
» Proper storage
Side/adverse effects
Signs of potential side effects, especially anxiety, arthralgia, chest pain, dyspnea, facial edema, hypertonia, injection-site reactions, lymphadenopathy, neck pain, palpitations, vaginal moniliasis, vasodilatation, agitation, bronchitis, chills, confusion, ecchymosis, edema, flu-like syndrome, infection, laryngismus, migraine, pain, peripheral edema, skin nodules, skin rash, syncope, urinary urgency, urticaria, anorexia, back pain, diarrhea, dysmenorrhea or other menstrual changes, ear pain, hematuria, hypertension, hyperventilation, impotence, nystagmus, oral moniliasis, speech problems, suspicious Papanicolaou test, tachycardia, vertigo, and vision problems
General Dosing Information
Patients should be instructed in self-injection techniques to assure safe administration {01}.
Patients should be instructed not to change the dose or dosing schedule and not to discontinue the medication without consulting physician {01}.
Parenteral Dosage Forms
GLATIRAMER ACETATE FOR INJECTION
Usual adult dose
Relapsing-remitting multiple sclerosis
Subcutaneously, 20 mg a day {01}.
Usual pediatric dose
Safety and efficacy in patients up to 18 years of age have not been established {01}.
Strength(s) usually available
U.S.—
20 mg (Rx) [Copaxone (diluent—Sterile Water for Injection) (Mannitol USP)]
Packaging and storage:
Vials containing glatiramer acetate should be stored between 2 and 8 ºC (36 and 46 ºF) and protected from light {02}. If refrigeration is not available, vials containing glatiramer acetate may be stored between 15 and 30 ºC (59 and 86 ºF) for up to one week {02}. Vials containing diluent should be stored between 15 and 30 ºC (59 and 86 ºF) {01}.
Preparation of dosage form:
The contents of the diluent vial are transferred into the lyophilized glatiramer acetate vial using aseptic technique {01}. The vial is gently swirled and allowed to stand at room temperature until the solid material is completely dissolved; this occurs in about 5 minutes {01}. If particulate matter remains, glatiramer acetate should not be used, and the vial should be discarded {01}.
After reconstitution, the solution should be withdrawn into a sterile syringe fitted with a new 27-gauge needle and injected subcutaneously {01}.
Stability:
Glatiramer acetate contains no preservatives and should be used immediately after reconstitution or must be discarded {01}.
Auxiliary labeling:
• Store glatiramer acetate vials in refrigerator {02}.
Additional information:
The manufacturer has established a program entitled Shared Solutions™ to provide support to any patient with multiple sclerosis; the program is accessible with a toll-free telephone number.
Revised: 05/21/1998
References
- Copaxone package insert (TEVA Marion Partners—US), Rev 2/97, Rec 3/12/97.
- Copaxone package insert (TEVA Marion Partners—US), Rev 11/97, Rec 11/11/97.
