Primidone is one of the earliest medications for generalized tonic-clonic, complex, and simple partial seizures. It is as effective as carbamazepine and phenytoin in controlling partial or generalized tonic-clonic seizures, but it has more adverse effects.
Primidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA). Both metabolites contribute to its therapeutic effect. The plasma half-life of primidone ranges from 6 to 8 hours, while phenobarbital is about 70 hours. Phenobarbital levels should be measured anytime a primidone level is requested. Steady state levels are reached 16 to 60 hours after initiating therapy in adults and 20 to 30 hours in children. Hepatocellular disease, renal impairment, valproic acid and isoniazid increase plasma primidone levels.
Primidone is initially dosed in progressively increasing amounts starting with 100 mg at bedtime to 250 mg 3 times a day after 10 days of therapy in adults. Steady state is usually achieved after approximately 2 weeks of therapy.
The therapeutic range of primidone is 5-12 ug/mL. Levels of 15.0 ug/mL or higher are considered critical. Therapeutic phenobarbital concentration is 10-40 ug/mL. Levels of 60 ug/mL or higher are considered critical.
Patients who have had a primidone overdose may present with hypotension, coma, CNS depression, suppressed response to pain, suppressed reflexes, respiratory depression, and decreased urine output.
The primidone to phenobarbital ratio is usually 2.5, but it can be higher (mean of 4.3) in patients receiving other anticonvulsants and lower in patients who are noncompliant. If a patient is noncompliant and starts primidone medication just before his/her visit to the doctor, the ratio will be high because not enough time has elapsed for phenobarbital to accumulate.
Primidone is measured by an homogeneous enzyme immunoassay. Specimen requirement is a red-top gel barrier tube of blood. Trough levels should be drawn immediately before the next dose.
Reference
Lenkapothula N, Cascella M. Primidone. [Updated 2024 Feb 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562297/
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