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DRUG RECORD

 

GABAPENTIN

OVERVIEW
Gabapentin

 

Introduction
Gabapentin is a unique anticonvulsant that is used as adjunctive therapy in management of epilepsy and for neuropathic pain syndromes.  Therapy with gabapentin is not associated with serum aminotransferase elevations, and clinically apparent liver injury from gabapentin is very rare.

Background
Gabapentin (gab" a pen' tin) is a structural analogue of gamma-aminobutryic acid (GABA), but demonstrates little or no interaction with GABA receptors and does not appear to alter GABA uptake, synthesis or metabolism.  While initially believed to act on the GABA-ergic neurotransmitter system, the actual mechanism of action of gabapentin as an anticonvulsant and agent for neuropathy is unknown.  Gabapentin was approved for use in the United States in 1993 and is a widely used medication with more than 18 million prescriptions filled yearly.  Current indications include add-on therapy for partial seizures which do not have adequate control with other anticonvulsants, and as a aid to reduce neuropathic pain from diabetic and postherpetic neuropathy.  Gabapentin is available as capsules or tablets of 100, 300, 400, 600 and 800 mg and in oral solution for pediatric use generically and under the brand names Neurontin and Gabarone.  The recommended initial dose for adults is 300 mg three times daily increasing as needed to a maximum dose of 1800 mg daily.  The most common side effects of gabapentin are dose related and include dizziness, somnolence, tremor, ataxia, blurred vision, anxiety, and gastrointestinal upset or nausea.

Hepatotoxicity
Limited data are available on the hepatotoxicity of gabapentin.  In clinical trials in diabetic neuropathy and epilepsy, therapy with gabapentin was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity.  Rare individual case reports of liver injury from gabapentin have been published, although the causal relationship of gabapentin with the liver injury was not always clear.  The latency to onset in these reports was 1 to 8 weeks and associated with cholestatic pattern of enzyme elevations.  Fever and rash have been described but not autoantibody formation.

Mechanism of Injury
The apparent absence or low rate of significant hepatotoxicity from gabapentin may be due to its minimal hepatic metabolism and rapid urinary excretion.

Outcome and Management
The case reports of hepatic injury due to gabapentin were followed by complete recovery without evidence of residual or chronic injury.  No cases of acute liver failure or chronic liver injury due to gabapentin have been described.  There is no information about cross reactivity with other compounds having similar structure (pregabalin).  In general, gabapentin is well tolerated in patients with hypersensitivity reactions to other anticonvulsants.

 

Drug Class:  Anticonvulsants

 

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PRODUCT INFORMATION
Gabapentin

 

REPRESENTATIVE TRADE NAMES
Gabapentin – Neurontin®


DRUG CLASS
Anticonvulsants

 

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Gabapentin 60142-96-3 C9-H17-N-O2  Gabapentin chemical structure

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REFERENCES
Gabapentin

 

References Last Updated: 17 March 2014

  1. Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 498-516.  (Expert review of anticonvulsants and liver injury published in 1999; gabapentin is not discussed).

  2. Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 423-42.  (Review of anticonvulsant induced liver injury; gabapentin is not discussed).

  3. McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 583-607.  (Textbook of pharmacology and therapeutics)

  4. Chadwick D. Gabapentin. Lancet 1994; 343: 89-91. PubMed Citation  (Review of the clinical uses of gabapentin largely as add-on to other anticonvulsants. Most common side effects were somnolence, dizziness, ataxia, fatigue, nystagmus, headache, tremor, diplopia, nausea and rhinitis. “No serious idiosyncratic reactions have been identified with gabapentin and, in particular, there is no evidence of hypersensitivity reactions…”).

  5. US Gabapentin Study Group. The long-term safety and efficacy of gabapentin (Neurotin) as add-on therapy in drug-resistant partial epilepsy. Epilepsy Res 1994; 18: 67-73. PubMed Citation  (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, 1% on carbamazepine, but none reported on tiagabine or gabapentin).

  6. Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Cleve Clin J Med 1999; 66: 239-45. PubMed Citation  (Clinical review of anticonvulsant hypersensitivity syndrome, which occurs in 1 to 5 per 10,000 users of aromatic anticonvulsants with higher risk in African Americans and affected siblings; liver involvement common, but most cases are anicteric; other manifestations include facial edema, lymphadenopathy, bone marrow aplasia, pseudolymphoma, thyroiditis, interstitial nephritis; not linked to gabapentin).

  7. Hamer HM, Morris HH. Successful treatment with gabapentin in the presence of hypersensitivity syndrome to phenytoin and carbamazepine: a report of three cases. Seizure 1999; 8: 190-2. PubMed Citation  (3 patients developed rash, fever, lymphadenopathy and eosinophilia 4-6 weeks after starting either phenytoin or carbamazepine [bilirubin 0.5-1.8 mg/dL, ALT 866-1402 U/L, Alk P 69-364 U/L], resolving after stopping and not recurring during gabapentin therapy).

  8. Wong ICK, Lhatto SD. Adverse reactions to new anticonvulsant drugs. Drug Safety 2000; 23: 35-56. PubMed Citation  (Review of side effects of new anticonvulsants: side effects of gabapentin are largely CNS related and include somnolence, dizziness, diplopia, ataxia, tremor and nausea, but no mention of liver toxicity and overdose was associated with lethargy only).

  9. Ragucci MV, Cohen JM. Gabapentin-induced hypersensitivity syndrome. Clin Neuropharmacol 2001; 24: 103-5. PubMed Citation  (72 year old man developed confusion and fever 8 days after starting gabapentin; was then given levofloxacin and developed rash liver abnormalities 2 days later [bilirubin normal, GGT 296 U/L, Alk P 218 U/L], resolving 15 days after stopping gabapentin; case did not fulfill criteria for hypersensitivity syndrome and was complicated by use of levofloxacin).

  10. Lasso-de-la-Vega MC, Zapater P, Such J, Pérez-Mateo M, Horga JF. Gabapentin-associated hepatotoxicity. Am J Gastroenterol 2001; 96: 3460-2. PubMed Citation  (60 year old man developed skin rash and eosinophilia 1 month after starting gabapentin and 1 day after starting ciprofloxacin; 1 week later was found to be jaundiced [bilirubin not given, ALT ~320 U/L, GGT ~1000 U/L], gabapentin was decreased in dose and stopped a week later and laboratory tests improved concurrently: ciprofloxacin might also have been responsible).

  11. Hauben M. Re: Lasso-de-la-Vega et al. Gabapentin as a probable cause of hepatotoxicity and eosinophilia. Am J Gastroenterol 2002; 97: 2156-7. PubMed Citation  (Letter from industry sponsor suggesting that hypersensitivity reaction in patient described by Lasso-de-la-Vega [2001] was more likely due to ciprofloxacin than gabapentin).

  12. Bureau C, Poirson H, Péron JM, Vinel JP. [Gabapentine-induced acute hepatitis] Gastroenterol Clin Biol 2003; 27: 1169-70. French. PubMed Citation  (Patient developed jaundice, fever and pain 2 months after starting gabapentin, had inflamed gallbladder and underwent cholecystectomy, but bilirubin continued to rise [bilirubin either 2.7 or 27 mg/dL, ALT 8 times ULN, Alk P 12 times ULN]; gabapentin was stopped, ultimate complete recovery in ~1 month; unclear whether gabapentin or gallstones were the cause).

  13. Wilby J, Kainth A, Hawkins N, et al. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess 2005; 9: 1-157, iii-iv. PubMed Citation  (Extensive systematic review of anticonvulsant medications including assessment of serious, rare and long term adverse events; severe side effects are rare with gabapentin; no mention of hepatotoxicity).

  14. LaRoche SM. A new look at the second-generation antiepileptic drugs: a decade of experience. Neurologist 2007; 13: 133-9. PubMed Citation  (Review of second generation anticonvulsants approved since 1994 including felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide and pregabalin; serious side effects are rare and no mention of liver toxicity from gabapentin).

  15. Himmerich H, Nickel T, Dalal MA, Müller MB. [Gabapentin treatment in a female patient with panic disorder and adverse effects under carbamazepine during benzodiazepine withdrawal] Psychiatr Prax 2007; 34: 93-4. German. PubMed Citation

  16. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, valproate accounted for 6, lamotrigine 5, phenytoin 5, gabapentin and topiramate 1 each but details not provided).

  17. Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. PubMed Citation  (Review of all anticonvulsant induced liver injury; neither gabapentin or pregabalin are discussed).   

  18. Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. PubMed Citation  (Concise review of drugs of choice for epilepsy; gabapentin is FDA approved as adjunctive therapy of partial seizures and adverse effects include somnolence, dizziness, ataxia, fatigue, and blurred vision; no mention of hepatotoxicity or ALT elevations).

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OTHER REFERENCE LINKS
Gabapentin

 

  1. PubMed logoRecent References on Gabapentin

  2. Clinical Trials logoTrials on Gabapentin

  3. TOXLINE logoTOXLINE Citations on Gabapentin

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