Primidone is an aromatic anticonvulsant used to treat complex, partial and generalized seizures. Therapy with primidone can be associated with increases in gamma glutamyltranspeptidase levels, but is not associated with serum aminotransferase elevations, and despite its similarity in structure to phenobarbital and phenytoin, clinically apparent liver injury from primidone has not been reported and must be exceedingly rare if it occurs at all.
Primidone (prim' i done) is a pyrimidinedione anticonvulsant and is partially metabolized to phenobarbital. Primidone is effective in suppressing seizure activity, but its mechanism of action is not well defined. It is believed to work centrally via interactions with voltage-gated sodium channels inhibiting repetitive firing of action potentials. Primidone was approved for use in epilepsy in the United States in 1954. For many years, primidone was considered a first line anticonvulsant agent, but it has been largely replaced by more recently developed anticonvulsants that are better tolerated, less sedative and have fewer long term adverse side effects. Primidone has also been used to treat essential tremor. Primidone is available as tablets of 50 and 250 mg in several generic formulations and under the brand names Mysoline, Myidone, Sertan and Apo-Primidone. The recommended initial dose for adults is 100 to 125 mg daily, increasing slowly to a maintenance dose of 250 mg three times daily. The most common side effects are dose related and include drowsiness, ataxia, diplopia, and headache. The initial dose may be associated with an acute toxic reaction with nausea, malaise, sedation, ataxia and confusion. Long term therapy may be associated with megaloblastic anemias and birth defects.
In clinical trials in epilepsy, therapy with primidone was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. Primidone therapy can lead to increases in gamma glutamyltranspeptidase (GGT) levels. Elevations in alkaline phosphatase levels were largely due to bone isoforms of the enzyme. There have been no convincing reports of hepatotoxicity due to primidone in humans and no reports of its association with acute liver failure. Interestingly, primidone appears to cause cirrhosis in dogs. Because of its similarity in structure to phenytoin and phenobarbital (aromatic anticonvulsant), it has been suspected to cross react with those agents in causing anticonvulsant hypersensitivity syndrome, but convincing case reports have not been published.
Mechanism of Injury
Primidone, like phenobarbital, is extensively metabolized by the liver and can induce CYP 450 enzyme activities. Primidone can interfere with prophyrin metabolism and like phenobarbital and phenytoin can cause worsening of porphyria.
REPRESENTATIVE TRADE NAMES
Primidone – Mysoline®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 22 January 2014
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; mentions that there have been no reports of hepatotoxicity from primidone).
Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds.
Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 423-41. (Review of anticonvulsant induced liver injury does not specifically discuss primidone).
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. 583-608. (Textbook
of pharmacology and therapeutics).
Tschudy DP, Valsamis M, Magnussen CR. Acute intermittent porphyria: clinical and selected research aspects. Ann Intern Med 1975; 83: 851-64. PubMed Citation (Review article on porphyria; drugs that can induce an acute exacerbation include the aromatic anticonvulsants).
Reynolds NC Jr, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981; 31: 480-4. PubMed Citation (In vitro studies showing that aromatic anticonvulsants increased intracellular hepatic delta-aminolevulinic acid [ALA] levels).
Bunch SE, Castleman WL, Hornbuckle WE, Tennant BC. Hepatic cirrhosis associated with long-term anticonvulsant drug therapy in dogs. J Am Vet Med Assoc 1982; 181: 357-62. PubMed Citation (Case reports of autopsies showing cirrhosis in dogs who had received long term primidone therapy).
Fichsel H, Spiess S. [Serum alkaline phosphatase izoenzymes in childhood during long-term primidone therapy for convulsions]. Klin Padiatr 1982; 194: 332-4. German. PubMed Citation (Among 69 children on primidone for >1 year and 98 controls, Alk P levels were higher [~30%] in primidone treated children, but elevations were largely in bone isoenzyme levels).
Deutsch J, Fritsch G, Gölles J, Semmelrock HJ. Effects of anticonvulsive drugs on the activity of gammaglutamyltransferase and aminotransferases in serum. J Pediatr Gastroenterol Nutr 1986; 5: 542-48. PubMed Citation (Among 198 children on anticonvulsants in a cross sectional study, GGT and ALT were higher in children on phenytoin; primidone was associated with mild increases in GGT but not ALT).
Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf 1996; 15: 378-93. PubMed Citation (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, 1% on carbamazepine and not reported to be higher on tiagabine or gabapentin; no mention of hepatotoxicity of primidone, although case of systemic lupus related to primidone is discussed).
Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999; 21: 489-501. PubMed Citation (Review of anticonvulsant hypersensitivity syndrome; triad of fever, rash and internal organ injury occurring 1-8 weeks after exposure to anticonvulsant; liver being most common internal organ involved. Occurs in 1:1000-1:10,000 initial exposures to phenytoin, carbamazepine, phenobarbital or lamotrigine, unrelated to dose, perhaps predisposed by valproate; mentions that primidone may be a cause but gives no publications documenting it; nevertheless, cross reactivity among the agents can be assumed).
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 1-5/10,000 users, higher risk in African Americans and affected siblings; liver involvement common, but most cases anicteric; other manifestations include facial edema, lymphadenopathy, bone marrow aplasia, pseudolymphoma, thyroiditis, interstitial nephritis: states that the syndrome occurs with primidone but without documentation).
Newell BD, Moinfar M, Mancini AJ, Nopper AJ. Retrospective analysis of 32
pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS). Pediatr
Dermatol 2009; 26: 536-46. PubMed Citation (Among 32 children with anticonvulsant hypersensivity syndrome the suspected cause was carbamazepine in 13, phenytoin in 12, lamotrigine in 5 and phenobarbital in 5, one patient also received primidone; hepatic involvement occured in 90%, jaundice 18%, eosinophilia 56%, atypical lymphocytes 72%, none died).
Deuschl G, Raethjen J, Hellriegel H, Elble R. Treatment of patients with
essential tremor. Lancet Neurol 2011; 10: 148-61. PubMed Citation (Review of therapy of essential tremor states that primidone is effective in reducing tremor in half of patients, but side effects of drowsiness and sedation are common and can be dose limiting; no mention of hepatotoxicity or ALT elevations).
Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. PubMed Citation (Concise review of drugs of choice for epilepsy; primidone is not discussed, but is mentioned in passing with phenobarbital as effective for partial sizures, but having a higher rate of sedation compared to other drugs).
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