What is primidone?

Primidone: An Anticonvulsant Medication

Primidone is an anticonvulsant medication that functions as a standalone active agent and is metabolized into two active metabolites (phenobarbital and phenylethylmalonamide), used primarily for seizure control and essential tremor treatment. 1

Mechanism of Action

• Primidone raises electroshock or chemoshock seizure thresholds and alters seizure patterns in experimental animals, though its exact anticonvulsant mechanism is not fully understood 1
• The medication works through multiple mechanisms including:
  • Blocking voltage-gated sodium channels
  • Modulating GABA-A and GABA-B intracortical circuits
  • Decreasing corticospinal excitability 2

Clinical Uses

Seizure Control

• FDA-approved for treatment of:
  • Generalized tonic-clonic (grand mal) seizures
  • Complex partial (psychomotor) seizures
  • Partial (focal) epileptic seizures 1
• Has been shown to reduce the recurrence rate of febrile seizures in children at doses of 15-20 mg/kg per day 3

Essential Tremor

• Used as a first-line treatment for essential tremor despite being outside its marketing authorization 4
• Significantly superior to placebo in reducing hand tremor, with efficacy comparable to propranolol 5
• Can be effective for essential vocal tremor, providing an alternative to botulinum neurotoxin therapy in some patients 6

Pharmacokinetics

• Primidone is metabolized into two active metabolites:
  • Phenylethylmalonamide (PEMA)
  • Phenobarbital 1, 4
• The rate of conversion from primidone to phenobarbital varies significantly between individuals 4
• Generally accepted therapeutic range for primidone is between 5-10 mg/L (23-46 mmol/L) 4
• In neonates and young infants, seizure control correlates best with primidone and PEMA levels rather than phenobarbital levels 7

Adverse Effects

• Common side effects include:
  • Behavioral disturbances
  • Irritability
  • Sleep disturbances 3
• Serious potential adverse effects:
  • Suicidal thoughts or actions (in approximately 1 in 500 patients)
  • Depression or worsening depression
  • Anxiety or worsening anxiety
  • Unusual changes in behavior or mood 1
• An acute toxic reaction to initial small doses (62.5 mg) has been observed in some patients 5
• Drowsiness that can be severe, especially when starting treatment 1

Administration Considerations

• Primidone should be taken exactly as prescribed, with dosage changes only under healthcare provider direction 1
• Abrupt discontinuation should be avoided as it can cause serious problems including status epilepticus 1
• Therapeutic drug monitoring of both primidone and its metabolite phenobarbital is recommended during treatment 4

Special Populations

Pregnancy

• May harm unborn babies; healthcare providers should discuss risks and benefits 1
• Pregnant patients taking primidone should consider registering with the North American Antiepileptic Drug Pregnancy Registry 1

Pediatric Use

• In children with febrile seizures, despite evidence of efficacy, the American Academy of Pediatrics does not recommend continuous primidone therapy due to potential toxicities outweighing the relatively minor risks associated with simple febrile seizures 3

Precautions

• Patients should avoid alcohol and other CNS depressants while taking primidone 1
• Driving and operating heavy machinery should be avoided until the patient knows how primidone affects them 1
• Patients should be monitored for signs of suicidal thoughts or actions, especially when starting treatment or changing doses 1