Glatiramer acetate (formerly known as copolymer-1) is a synthetic random peptide created by polymerizing L-alanine, L-glutamic acid, L-lysine, and L-tyrosine and is similar in structure to myelin basic protein. Glatiramer is given subcutaneously and is used to reduce the frequency of attacks in adult patients with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Glatiramer is often one of the medications used off-label in children and adolescents with MS. In a phase III study with a 2-year follow-up, glatiramer 20 mg daily produced a 29% reduction in relapse rate, prolonged the time to relapse, and increased the number of patients who were relapse-free. In a randomized, double-blind, placebo-controlled trial, use of 40 mg 3 times weekly significantly reduced relapses compared to placebo, with a relative risk reduction of 34% over 1 year. Glatiramer has been associated with significant reductions of cumulative numbers of MS-related lesions on MRI scans. The use of glatiramer delays the time to clinically definite multiple sclerosis (CDMS) among patients who have experienced a first clinical episode and have MRI results consistent with multiple sclerosis. A clinical trial (the PROMiSE trial) of glatiramer in adults with primary progressive multiple sclerosis was terminated after an interim evaluation suggested the drug was unlikely to demonstrate a significant benefit. Development of an oral form of glatiramer was suspended after initial clinical studies did not show efficacy versus placebo at the doses tested. Glatiramer subcutaneous injection may result in an immediate post-injection reactions (flushing, chest pain, dyspnea, and urticaria) have been reported and may be serious, and often present several months after treatment initiation.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Administer by subcutaneous injection only. Do not administer intravenously.
-Visually inspect parenteral products 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 syringe.
Subcutaneous Administration
-Syringes containing glatiramer may be used with a compatible autoinjector that is available by prescription. Refer to the specific autoinjector labeling and "Instructions for Use" to determine if a device is compatible with a specific glatiramer product. The use of an incompatible autoinjector has resulted in missed and partial doses. The availability of a compatible autoinjector for each glatiramer product may change with time. Patients may contact their health care provider, pharmacist, or the manufacturer of the prescribed product for more information about optional compatible autoinjector devices. Compatible autoinjector devices for each product are as follows:
--Autoject 2 (Copaxone)
-Glatopaject (Glatopa), and
-WhisperJECT (glatiramer injection from Viatris or Mylan)
-Patients and/or their caregivers should be trained regarding proper administration. Review the provided detailed "Instructions for Use" for each product.
Subcutaneous injection:
-If refrigerated, remove the prefilled syringe from the refrigerator and allow the solution to warm for 20 minutes at room temperature. Visually inspect the product before use.
-There may be small air bubbles in the syringe. Do not try to push the air bubble from the syringe before administering the injection.
-Sites for injection include upper arms, abdomen, hips, and thighs.
-Pinch about a 2-inch fold of skin at the chosen site. Insert the needle at a 90-degree angle straight into the skin. Slowly inject the entire dose. Pull the needle straight out when finished.
-Rotate injection sites with each dose. Do not use any injection site more than once a week.
-The prefilled syringe is for single use only and does not contain preservatives; use immediately and discard unused portions. Discard of used needles and syringes in an appropriate sharps container.
An immediate post-injection reaction occurred in approximately 2% to 16% of patients during placebo-controlled trials who received glatiramer. This reaction occurs within seconds to minutes, with the majority of symptoms seen within 1 hour after injection. The reaction consisted of a constellation of symptoms that included at least 2 of the following: flushing, chest pain (unspecified), palpitations, tachycardia, anxiety, dyspnea, throat constriction, and urticaria. The symptoms were usually transient and self-limiting and did not require specific treatment. In general, these symptoms have an onset several months after the start of glatiramer treatment; however, they may occur earlier in the course of treatment, and a given patient may experience 1 or several episodes of these symptoms. It is unknown if any of these symptoms represent a specific syndrome. Also, it is unknown if an immunologic or nonimmunologic mechanism mediates these episodes or if several similar episodes seen in a given patient have identical mechanisms. Approximately 2% to 13% of patients treated with glatiramer experienced at least 1 episode of transient chest pain (unspecified). Some of the episodes occurred immediately post-injection, but many did not. The pain was often not associated with other symptoms and appeared to have no important clinical sequelae. Some patients experienced more than one episode, and episodes usually began at least 1 month after initiating therapy. The pathogenesis of this symptom is unknown. Among 563 patients who received 20 mg/day during clinical trials, 3% had urticaria, 14% had dyspnea, 6% had cough, 13% had anxiety, 2% had nervousness, 9% had palpitations, 5% had sinus tachycardia, 3% had hypersensitivity, and 2% had laryngospasm. Patients who received 40 mg three times per week (n = 943) during a controlled clinical trial also experienced dyspnea (3%).
Glatiramer may interfere with the recognition of foreign antigens in a way that would undermine the body's defenses against infection. A systematic evaluation of this risk is unavailable. Among 563 patients who received glatiramer 20 mg daily during controlled clinical trials, 30% had infection, 14% had influenza, 7% had rhinitis, 6% had bronchitis, 6% had gastroenteritis, 7% had lymphadenopathy, 6% had fever, 3% had chills, and 4% had vaginal candidiasis. Herpes simplex occurred in only 4 or 5 more glatiramer recipients than placebo recipients, but a relationship to glatiramer could not be excluded. Oral moniliasis, abscess, and herpes zoster occurred in at least 1% of patients whereas leukopenia, pancytopenia, cellulitis, osteomyelitis, fungal dermatitis, pyelonephritis, pneumonia, otitis externa, and urethritis occurred in 0.1% to 1% of patients. Patients who received 40 mg 3 times weekly during a controlled clinical trial (n = 943) experienced fever (3%), influenza-like illness (3%), naso-pharyngitis (11%), viral respiratory tract infections (3%), and chills (2%). Sepsis and meningitis were noted during postmarketing experience.
Among 563 patients who received glatiramer, 3% had an eye disorder, and 3% had diplopia. Visual field defect or visual impairment was noted in at least 1% of patients, and xerophthalmia, ptosis, cataracts, corneal ulcer, mydriasis, optic neuritis, and photophobia were noted in 0.1% to 1% of patients, but the causality of the events to glatiramer cannot be established. Glaucoma, blindness, and visual field defect have all been reported postmarketing.
Glatiramer may cause a new primary malignancy, as it may interfere with the recognition of foreign antigens in a way that would undermine the body's tumor surveillance. A systematic evaluation of this risk is unavailable. Among 563 patients who received glatiramer, 0.1% to 1% had carcinoma in situ cervix and skin carcinoma; the causality to glatiramer has not been established. CNS neoplasm, urogenital neoplasm, ovarian carcinoma, breast carcinoma, bladder carcinoma, acute leukemia, lymphoma-like reaction, and lung carcinoma have been noted postmarketing.
Among 563 patients who received glatiramer 20 mg daily during controlled clinical trials, 15% had nausea, 7% had vomiting, 3% had weight gain, and 2% had dysphagia. Adverse events where causality could not be determined and that occurred in at least 1% of patients included bowel or fecal urgency, salivary gland enlargement, tooth caries, and ulcerative stomatitis; events in 0.1% to 1% of patients included xerostomia, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulceration, esophagitis, hepatomegaly, hernia, alcohol intolerance, increased appetite (appetite stimulation), melena, mouth or oral ulceration, pancreas disorder, pancreatitis, taste loss, tenesmus, tongue discoloration, weight loss, and duodenal ulcer. Among patients who received 40 mg 3 times weekly during a controlled trial (n = 943), 2% experienced nausea. During postmarketing surveillance, tongue edema, stomach ulcer, hemorrhage, and eructation have been observed. Cases of hepatotoxicity and hepatic injury, including hepatic failure and hepatitis with jaundice, have been reported with glatiramer during postmarketing surveillance. Hepatic injury has occurred from days to years after initiating treatment. If signs or symptoms of liver dysfunction occur, consider discontinuation of glatiramer. Cholelithiasis, liver function abnormality, and cirrhosis have been reported.
Among 563 patients who received glatiramer, 12% had back pain, 20% had unspecified pain, and 22% had asthenia. Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, tendon pain, gout, serum sickness, and tenosynovitis were noted in 0.1% to 1% of patients, although causality has not been established. Rheumatoid arthritis and generalized spasm were noted postmarketing. Arthralgia occurred in 4 to 5 more patients who received glatiramer as compared with placebo recipients, and a relationship of arthralgia to glatiramer could not be excluded.
Among 563 glatiramer recipients, 4% had tremor, 4% had migraine, 3% had syncope, and 2% had speech disorder. Abnormal dreams, emotional lability, and stupor were reported at an incidence of at least 1% whereas aphasia, ataxia, seizures, circumoral paresthesias, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, libido decrease, manic reaction, memory impairment, myoclonia, neuralgia, paranoid reaction or paranoia, paraplegia, psychotic depression, suicide attempt, and transient stupor were reported in 0.1% to 1%; the causality of glatiramer to any of the events has not been established. Myelitis, cerebrovascular accident or stroke, brain or cerebral edema, abnormal dreams, aphasia, seizures, and neuralgia were reported postmarketing.
Among 563 glatiramer recipients, 8% had edema, 3% had face edema, and 3% had peripheral edema. Generalized edema was noted in 0.1% to 1% of patients, although causality has not been established.
Localized lipoatrophy and rare skin necrosis have been reported at the injection site with glatiramer use. Approximately 2% of patients who received 20 mg/day during multiple controlled trials (n = 563) experienced lipoatrophy, a type of lipodystrophy, while 0.5% of those exposed to 40 mg three times per week during a single trial (n = 943) had lipoatrophy. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. No known therapy for lipoatrophy exists. Advise the patient to follow proper injection technique and to rotate injection sites daily to assist in possibly minimizing these events. Among patients in clinical trials who received either 20 mg/day or 40 mg three times per week, the following injection site reactions were reported: erythema 43% (20 mg daily) vs. 22% (40 mg 3 times weekly), pain (40% vs. 10%), pruritus (27% vs. 6%), mass formation (26% vs. 6%), edema (19% vs. 6%), and inflammation (9% vs. 2%). Rash (unspecified) was reported in 19% and 2% of patients who received the once daily regimen or 3 times/week regimen, respectively. Peripheral vasodilation was observed in 20% of those who received the daily regimen and 3% of those who received the 3 times/week regimen. Erythema not specific to the injection site was observed in 2% of patients who were given the 3 times/week regimen. Among 563 patients who received 20 mg daily during clinical trials, 8% had an injection site reaction, 5% had pruritus, 4% had injection site hypersensitivity, 3% had a local reaction, and 2% had injection site fibrosis. Hyperhidrosis was noted in 7%, benign skin neoplasm in 2%, and skin disorder in 3%. Although causality has not been established, injection site abscess, injection site hypertrophy, injection site melanosis, lipoma, skin atrophy, and photosensitivity reaction were noted in 0.1% to 1% of patients.
Micturition or urinary urgency was noted in 5% of 563 glatiramer recipients. Although causality has not been established, amenorrhea, hematuria, impotence (erectile dysfunction), menorrhagia, suspicious Papanicolaou smear, and increased urinary frequency occurred in at least 1% of patients, and vaginitis, flank pain, breast engorgement, breast enlargement, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, and abnormal sexual function were noted in 0.1 to 1% of treated patients. Urine abnormality, nephrosis, renal failure (unspecified), and increased urinary frequency have been reported postmarketing.
Gum hemorrhage, epistaxis, hematemesis, injection site hematoma, anemia, cyanosis, splenomegaly, and rectal hemorrhage were noted in 0.1% to 1% of patients, and vaginal bleeding occurred in at least 1% of patients, although the causality has not been established. Thrombocytopenia was noted postmarketing, and one patient discontinued glatiramer due to a platelet count of 16 billion/L, which resolved after discontinuation of treatment.
Although causality has not been established, goiter, hyperthyroidism, and hypothyroidism were noted in 0.1% to 1% of patients who received glatiramer.
Although causality has not been established, hyperventilation and hay fever occurred in at least 1% of patients who received glatiramer. Hypoventilation, asthma, and voice alteration were noted in 0.1% to 1% of patients. Pulmonary embolism, pleural effusion, and hay fever were noted postmarketing.
Although causality has not been established, hypertension was noted in at least 1% of patients who received glatiramer 20 mg daily during open and uncontrolled pre-marketing studies, and hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins were noted in 0.1% to 1% of patients. During postmarketing experience, thrombosis, peripheral vascular disease, pericardial effusion, myocardial infarction, deep thrombo-phlebitis, coronary occlusion, congestive heart failure, cardiomyopathy, cardiomegaly, arrhythmia exacerbation, hypercholesterolemia, and angina pectoris were reported.
Although causality has not been established, at least 1% of patients who received glatiramer had eczema, pustular rash, skin atrophy, and warts. Xerosis, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, maculopapular rash, pigmentation, skin striae, xanthoma, abnormal or impaired wound healing, eosinophilia, and vesiculobullous rash (vesicular rash or bullous rash) were noted in 0.1% to 1% of patients. Allergic reaction and anaphylactoid reactions were noted postmarketing.
Although causality is not established, 0.1% to 1% of patients who received glatiramer had Cushing's syndrome or moon face.
Glatiramer acetate is contraindicated in patients with known glatiramer hypersensitivity or mannitol hypersensitivity. The only recommended route of administration is subcutaneously; glatiramer should not be given by intravenous administration.
Use glatiramer acetate cautiously in patients with preexisting immunosuppression or those who are receiving vaccination. Glatiramer acetate can modify the human immune response. It should be kept in mind that glatiramer could interfere with useful immune function. The manufacturer theorizes that glatiramer might interfere with the body's recognition of foreign antigens in a way that would undermine the body's defenses against infection and tumor surveillance. Although glatiramer 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 might lead to the induction of host responses that can cause adverse events. Results of limited tests reveal no risk of glatiramer-induced suppression of human immune function; however, there is no way to absolutely exclude this possibility.
There are no adequate and well-controlled studies of glatiramer use during pregnancy. No adverse effects were noted in animal reproduction studies. Because animal reproduction studies are not always predictive of human response, glatiramer acetate should be used during pregnancy only if necessary. If a patient does become pregnant while receiving glatiramer therapy, she should be educated regarding the benefits or risks of continuing treatment for multiple sclerosis (MS). Data are limited but provide no evidence that glatiramer acetate poses a substantial teratogenic risk; data are insufficient to demonstrate safety or the absence of later-onset problems in an exposed infant. In many cases, disease-modifying drugs for MS are discontinued during pregnancy. Data from a large, multicenter trial of pregnant patients with MS suggest that patients have a decrease in the number and severity of MS relapses during pregnancy, despite discontinuation or lack of receipt of disease-modifying medications. Experts generally recommend the discontinuation of glatiramer when trying to conceive and throughout gestation. However, in pregnant women with severe or highly active MS, the benefit of treating the mother with glatiramer acetate may outweigh the possible risk to the fetus.
Breast-feeding is not expected to result in clinically relevant exposure of the infant to glatiramer as data support that a substantial fraction of a dose is hydrolyzed locally following subcutaneous administration. There are no data on the effects of glatiramer on milk production. Glatiramer is rated as "probably compatible" with breast-feeding by expert groups. Interferon beta-1a and beta-1b are considered alternative therapies.
Cases of hepatic injury (hepatotoxicity), some severe, including liver failure and hepatitis with jaundice, have been reported with glatiramer. Hepatic injury has occurred from days to years after initiating treatment with glatiramer. If signs or symptoms of liver dysfunction occur, consider discontinuation of the drug.
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
NOTE: Glatiramer has been designated an orphan drug by the FDA for this indication.
NOTE: Glatiramer 20 mg/mL and 40 mg/mL solutions for injection are not interchangeable.
Subcutaneous dosage (20 mg/mL injection solution):
Adults: 20 mg subcutaneously once daily.
Subcutaneous dosage (40 mg/mL injection solution):
Adults: 40 mg subcutaneously 3 times weekly and at least 48 hours apart.
Maximum Dosage Limits:
-Adults
Once daily dose schedule: 20 mg/day subcutaneously using the 20 mg/mL solution.
Three times weekly dose schedule: 40 mg/dose subcutaneously using the 40 mg/mL solution.
-Geriatric
Once daily dose schedule: 20 mg/day subcutaneously using the 20 mg/mL solution.
Three times weekly dose schedule: 40 mg/dose subcutaneously using the 40 mg/mL solution.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Alemtuzumab: (Major) Concomitant use of glatiramer with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as glatiramer. Concomitant use of ocrelizumab with glatiramer may increase the risk of immunosuppression. Avoid the use of these drugs together.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with glatiramer may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as glatiramer. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Ozanimod: (Moderate) Concomitant use of ozanimod with glatiramer may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis. Ozanimod can generally be started immediately after discontinuation of glatiramer.
Glatiramer acetate modifies immune processes that are responsible for the pathogenesis of multiple sclerosis (MS). The exact mechanism of action in treating MS is unclear at this time. It is proposed that the drug serves as a decoy to locally-generated autoantibodies. These antibodies, along with certain T-cells, are thereby neutralized before they can cause tissue damage. Studies in animals and in vitro systems suggest that glatiramer-specific suppressor T-cells are induced and activated in the periphery. Because glatiramer modifies immune functions, concerns exist about its potential to alter naturally occurring immune responses. Results of limited tests reveal no risk of this concern; however, there is no way to absolutely exclude this possibility.
Pharmacokinetics:
Glatiramer acetate is administered subcutaneously.
-Route-Specific Pharmacokinetics
Subcutaneous Route
It is assumed that a substantial fraction of glatiramer acetate is hydrolyzed locally after subcutaneous injection. Nevertheless, larger fragments of glatiramer acetate can be recognized by glatiramer-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation thereby enabling it to reach regional lymph nodes, and some of the injected material may enter the systemic circulation intact.