Primidone - Drug Monograph

Introduction

Primidone is an anticonvulsant medication structurally related to barbiturates that has been used in clinical practice since the 1950s. It is primarily indicated for the management of seizure disorders, particularly essential tremor and certain types of epilepsy. Primidone is metabolized to active compounds including phenobarbital and phenylethylmalonamide (PEMA), which contribute significantly to its therapeutic effects.

Mechanism of Action

Primidone exerts its anticonvulsant effects through multiple mechanisms. The drug itself and its metabolites (phenobarbital and PEMA) enhance GABAergic inhibition in the central nervous system by potentiating GABA-A receptor-mediated chloride currents. Additionally, primidone and its metabolites reduce glutamate-mediated excitation and inhibit voltage-gated sodium channels, thereby stabilizing neuronal membranes and raising the seizure threshold. The exact contribution of each metabolite to the overall clinical effect varies among patients.

Indications

• FDA-approved indications:

- Monotherapy or adjunctive therapy for generalized tonic-clonic seizures - Complex partial (psychomotor) seizures - Essential tremor

• Off-label uses:

- Juvenile myoclonic epilepsy - Febrile seizures (in specific cases) - Second-line treatment for status epilepticus

Dosage and Administration

• Initial: 100-125 mg at bedtime
• Gradually increase by 100-125 mg every 3-7 days
• Maintenance: 750-1500 mg/day in divided doses (2-4 times daily)

• Initial: 12.5-25 mg at bedtime
• Titrate slowly to 50-750 mg/day in divided doses

• Initial: 50 mg at bedtime
• Increase by 50 mg weekly
• Maintenance: 10-25 mg/kg/day in divided doses

• Renal impairment: Reduce dose by 25-50% if CrCl <50 mL/min
• Hepatic impairment: Use with caution; consider dose reduction
• Elderly: Initiate with lower doses due to increased sensitivity

Pharmacokinetics

• Absorption: Well absorbed from GI tract (90% bioavailability)
• Distribution: Widely distributed throughout body tissues; crosses placenta and blood-brain barrier
• Protein binding: Approximately 20%
• Metabolism: Hepatic via cytochrome P450 system to active metabolites (phenobarbital and PEMA)
• Elimination: Renal excretion (40% as unchanged drug, 15% as phenobarbital)
• Half-life: Primidone: 10-12 hours; Phenobarbital: 75-120 hours; PEMA: 10-15 hours

Contraindications

• Hypersensitivity to primidone or barbiturates
• Porphyria
• Severe hepatic impairment
• Severe respiratory depression
• Concurrent use with MAO inhibitors

Warnings and Precautions

• Boxed Warning: Risk of suicidal thoughts and behavior
• Habit formation: Potential for psychological and physical dependence
• Withdrawal symptoms: May occur with abrupt discontinuation
• Hematologic effects: May cause megaloblastic anemia
• Osteomalacia: Long-term use associated with vitamin D deficiency
• Sedation: May impair mental and physical abilities
• Paradoxical reactions: May cause excitement in children and elderly

Drug Interactions

• Enzyme inducers: Carbamazepine, phenytoin, rifampin (decrease primidone levels)
• Enzyme inhibitors: Valproic acid, fluoxetine (increase primidone levels)
• CNS depressants: Alcohol, opioids, benzodiazepines (additive sedation)
• Oral contraceptives: Reduced efficacy
• Vitamin K antagonists: Altered anticoagulant effect
• Other anticonvulsants: Complex interactions requiring monitoring

Adverse Effects

• Drowsiness
• Ataxia
• Vertigo
• Nausea
• Fatigue

• Diplopia
• Nystagmus
• Emotional disturbances
• Anorexia
• Rash

• Stevens-Johnson syndrome
• Agranulocytosis
• Thrombocytopenia
• Hepatitis
• Suicidal ideation
• Megaloblastic anemia

Monitoring Parameters

• Efficacy: Seizure frequency, tremor severity
• Toxicity: CNS depression, ataxia, nystagmus
• Laboratory:

- CBC with platelets (baseline and periodically) - Liver function tests (baseline and every 6-12 months) - Vitamin D levels (annually with long-term use) - Serum primidone and phenobarbital levels (therapeutic range: primidone 5-12 μg/mL; phenobarbital 15-40 μg/mL)

• Clinical: Mental status, mood changes, signs of abuse

Patient Education

• Take medication exactly as prescribed
• Do not abruptly discontinue medication
• Avoid alcohol and other CNS depressants
• Use caution when driving or operating machinery
• Report any mood changes or suicidal thoughts immediately
• Use effective contraception (if applicable)
• Maintain regular follow-up appointments
• Be aware of potential vitamin D deficiency with long-term use
• Carry medication identification

References

1. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563.

2. Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2005;64(12):2008-2020.

3. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276.

4. Micromedex Solutions. Primidone monograph. Truven Health Analytics. 2023.

5. Lexicomp Online. Primidone drug information. Wolters Kluwer Health. 2023.

6. FDA prescribing information: Mysoline® (primidone) tablets. 2022.