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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Glatiramer Acetate

Last Update: March 14, 2018.

OVERVIEW

Introduction

Glatiramer acetate is a mixture of synthetic polypeptides that has unique antiinflammatory and immunomodulatory activities and that is used to treat relapsing-remitting multiple sclerosis. Glatiramer therapy is associated with a low rate of transient serum enzyme elevations during therapy and has been linked to rare instances of clinically apparent liver injury with jaundice.

Background

Glatiramer (gla tir' a mer) acetate is a mixture of synthetic polypeptides containing 4 amino acids: glutamic acid, alanine, tyrosine and lysine. The amino acid polymers have distinctive immunomodulatory activities in multiple sclerosis which are believed to be due to inhibition of binding of myelin proteins to major histocompatibility complex (MHC) molecules, which interrupts T cell activation directed at basic myelin. In several large, randomized controlled trials, glatiramer was shown to reduce relapse rates and improve neuroradiologic outcomes in adult patients with relapsing-remitting multiple sclerosis. Glatiramer was approved for use for multiple sclerosis in the United States in 1996 and is available in prefilled syringes of 20 mg and 40 mg generically and under the brand names Copaxone and Glatopa. The recommended dose is 20 mg subcutaneously once daily or 40 mg three times weekly. Common side effects are injection site reactions (pain, erythema, pruritus, induration), as well as mild and transient hypersensitivity reactions of flushing, chest tightness, dyspnea and anxiety occurring within minutes of the injection in about 10% of patients.

Hepatotoxicity

In large randomized controlled trials of glatiramer acetate in patients with multiple sclerosis, serum ALT elevations above 3 times ULN were reported in 7% of glatiramer compared to 3% of placebo recipients. The enzyme elevations were usually transient and not associated with symptoms or jaundice, requiring drug discontinuation in less than 1% of patients. No cases of acute hepatitis or clinically apparent liver injury were reported in the preregistration trials of glatiramer. Subsequent to the approval and more wide spread use of glatiramer, however, more than a dozen instances of clinically apparent liver injury with jaundice have been reported. The onset has been within 1 to 3 months of starting therapy, and the typical presentation has been with a hepatocellular pattern of serum enzyme elevations sometimes with autoantibodies (ANA, SMA), but without hyperglobulinemia or histologic features of autoimmune hepatitis. Reported cases have been self-limited with recovery within 1 to 3 months of stopping treatment. Autoantibodies also resolve with resolution of the liver injury. Some patients have later presented with spontaneous autoimmune hepatitis, which has been described in patients with multiple sclerosis not on disease modifying agents.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which glatiramer might cause liver injury is not known, but is likely due to a triggering of an underlying predisposition to autoimmune hepatitis. The synthetic polypeptides are metabolized in multiple cells and the amino acids are probably reused in protein synthesis. Thus, the polypeptides are more likely to trigger an autoimmune reaction rather than cause direct hepatic injury or provide an immunogenic metabolic break-down product.

Outcome and Management

While chronic therapy with glatiramer acetate can be associated with mild-to-moderate serum aminotransferase elevations, these elevations are usually transient and asymptomatic and rarely require dose interruption. Rare instances of acute liver injury with jaundice have resolved with discontinuation. Corticosteroid therapy should be considered in instances with severe or persistent liver injury, but the dose and duration of therapy should be kept to a minimum. There is little evidence for cross sensitivity to liver injury among the various disease modifying drugs for multiple sclerosis such as methyl fumarate, fingolimod, teriflunomide and interferon beta. However, in several instances, the pattern of injury is similar and autoimmunity a likely mechanism.

Drug Class: Multiple Sclerosis Agents

CASE REPORT

Case 1. Acute self-limited hepatitis attributed to glatiramer acetate therapy.

[Modified from: Subramaniam K, Pavli P, Llewellyn H, Chitturi S. Glatiramer acetate induced hepatotoxicity. Curr Drug Saf 2012; 7: 186-8. PubMed Citation].

A 31 year old woman with relapsing multiple sclerosis developed fatigue, anorexia and jaundice five weeks after starting glatiramer acetate (20 mg subcutaneously once daily). Her multiple sclerosis had been recently diagnosed and she had not received previous disease modifying therapy. She had no history of liver disease, drank alcohol sparingly and denied having risk factors for viral hepatitis. She had a melanoma removed surgically 5 years previously, but did not receive systemic chemotherapy and had no evidence of recurrence. Her only other medication was thyroxine for hypothyroidism. She had a history of depression, but was not receiving antidepressants. She had no history of drug allergies and was not taking over-the-counter or herbal medications. Examination revealed jaundice, but no other evidence for acute or chronic liver disease. Laboratory testing showed a serum bilirubin of 6.4 mg/dL, ALT 1056 U/L, AST 276 U/L, alkaline phosphatase 143 U/L and GGT 341 U/L. Values had been normal when tested before glatiramer therapy (Table). Serum albumin was 3.7 g/dL, globulins 2.9 g/dL and prothrombin time 21 seconds. Tests for hepatitis A, B and C and for EBV and CMV infections were negative. While antinuclear and liver-kidney membrane antibodies were negative, smooth muscle antibodies (SMA) were present (1:320). Ultrasonography showed increased echogenicity of the liver without evidence of biliary obstruction or masses. A liver biopsy showed acute hepatitis with bridging hepatic necrosis, which was considered more likely due to a toxic than autoimmune process. Glatiramer was stopped, and she began to improve rapidly. Two months and eight months later her symptoms had resolved, SMA was no longer positive and all liver tests were normal.

Key Points

Medication:Glatiramer acetate (20 mg subcutaneously once daily)
Pattern:Hepatocellular (R=~20)
Severity:3+ (jaundice, hospitalization)
Latency:5 weeks
Recovery:Within two months
Other medications:Thyroxine

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
Pre018560.5Routine
5 weeks010561436.4Jaundice, admission
13 weeks8 weeks40791.2Follow-up
1 year8 monthsNormalNormalNormalSMA negative
Normal Values <55 <110 <1.2

Comment

A young woman with new onset multiple sclerosis developed jaundice within 5 weeks of starting subcutaneous injections of glatiramer acetate. She had no other risk factors for liver disease and laboratory testing and hepatic imaging excluded other common causes of jaundice. The disease resolved rapidly once glatiramer was stopped. This case is fairly typical of the clinically apparent acute liver injury reported with glatiramer, with onset between 1 and 3 months of starting, a hepatocellular pattern of liver injury, occasional autoantibody formation (which can also accompany multiple sclerosis), and rapid improvement upon stopping. The cause of the injury is unclear as it is unlikely that small polypeptides could be hepatotoxic. Thus, a more likely possibility is that the liver injury is due to autoimmune response induced by the therapy, perhaps as a part of the autoimmune predisposition that accompanies multiple sclerosis. The liver injury typically resolves even without immunosuppressive therapy. Glatiramer acetate therapy has been associated with activation of other autoimmune conditions during treatment including myasthenia gravis and autoimmune thyroiditis.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Glatiramer Acetate – Generic, Copaxone®, Glatopa®

DRUG CLASS

Multiple Sclerosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Glatiramer Acetate 147245-92-9 ProteinNot Available

ANNOTATED BIBLIOGRAPHY

References updated: 14 March 2018

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    (Expert review of hepatotoxicity published in 1999; glatiramer is not discussed).
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    (Among 250 patients with multiple sclerosis treated with glatiramer or placebo by daily injection for 2 years, relapse rates were 29% lower with glatiramer and side effects were similar except for injection site reactions and immediate post-injection systemic reactions [15% vs 3%]; there were no differences in laboratory test results between the two groups).
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    (46 year old woman developed fatigue 2 months after starting glatiramer acetate [bilirubin 1.8 mg/dL, ALT 579 rising to 1055 U/L, Alk P normal, INR 1.6], biopsy suggesting autoimmune hepatitis despite ANA and SMA negativity, liver tests becoming normal after corticosteroid therapy that was later switched to azathioprine alone).
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    (31 year old woman with relapsing multiple sclerosis developed jaundice 5 weeks after starting glatiramer acetate [bilirubin 6.4 mg/dL, ALT 1056 U/L, Alk P 143 U/L], resolving within 8 weeks of stopping: Case 1).
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    (Concise review of efficacy, safety and costs of new disease modifying drugs for multiple sclerosis lists side effects in a table including "transaminase elevations" for interferon beta, fingolimod and teriflunomide, and "hepatotoxicity" for natalizumab, but not for glatiramer or mitoxantrone).
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    (15 year old girl with relapsing multiple sclerosis developed ALT elevations 6 months after starting interferon beta therapy and again 2 months after starting glatiramer [bilirubin normal, ALT 253 U/L, ANA & SMA negative], resolving within 2 months of stopping ).
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    (28 year old woman with multiple sclerosis developed jaundice 6 months after starting glatiramer [bilirubin 8 mg/dL, ALT 1103 U/L], resolving within 1 month of stopping and not recurring on natalizumab; mentions that FDA has received 95 reports of liver injury attributed to glatiramer).
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    (Two women with relapsing multiple sclerosis, ages 29 and 41 years, developed jaundice one month after starting glatiramer, having had serum enzyme elevations without jaundice on interferon beta [bilirubin 4 and 5 mg/dL, ALT 1260 and 4410 U/L, Alk P 342 and 383 U/L, ANA 1:160 and 1:320], resolving with stopping in one patient, but requiring long term corticosteroid therapy in the second).
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    (25 year old woman with relapsing multiple sclerosis developed ALT elevations 7-8 months after starting glatiramer [ALT 106 rising to 1433 U/L, bilirubin 1.5 mg/dL, Alk P 113 U/L, ANA & SMA negative], resolving within 2 months of stopping).
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  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 7 [0.8%] were attributed to interferon beta, but none were linked to glatiramer or other drugs used for multiple sclerosis).
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    (Commentary on management of progressive multiple sclerosis in which most of the new, disease modifying agents have little effect, and major attention should be paid to management and relief of symptoms such as fatigue, bladder dysfunction, spasticity, pain, depression and cognitive dysfunction; no discussion of liver related adverse effects).
  • Fernández Fernández N, Joao Matias D, Pisabarros Blanco C, Rodríguez Martín L, Aparicio Cabezudo M, Linares Torres P, Hernando Martín M, et al. [Hepatitis induced by glatiramer acetate]. Gastroenterol Hepatol 2015; 38: 280-1. [PubMed: 25042243]
    (42 year old woman with multiple sclerosis on glatiramer for 6 months was found to have ALT elevations [bilirubin 2.2 mg/dL, ALT 602 U/L, Alk P normal] which fell into the near normal range within one month of stopping, although ANA became positive [1:640]).
  • Almeida J, Solà-Valls N, Pose E, Blanco Y, Sepúlveda M, Llufriu S, Gines P, et al. Liver injury and glatiramer acetate, an uncommon association: case report and literature review. Ther Adv Neurol Disord 2017; 10: 367-372. [PMC free article: PMC5642009] [PubMed: 29090021]
    (65 year old woman with multiple sclerosis developed abnormal liver tests one week after starting glatiramer acetate [bilirubin normal, ALT 481 rising to 667 U/L, Alk P normal], resolving 5 months after stopping).

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