What is Primidone (anticonvulsant medication)?

What is Primidone?

Primidone is an anticonvulsant medication used to control grand mal, psychomotor, and focal epileptic seizures, either alone or in combination with other antiepileptic drugs. 1

Mechanism of Action and Pharmacology

Primidone is a white, crystalline compound (5-ethyldihydro-5-phenyl-4,6(1H,5H)-pyrimidinedione) that is poorly soluble in water and possesses anticonvulsant activity through multiple mechanisms 1:

• Primidone itself is pharmacologically active and is not merely a prodrug 1, 2
• It raises electro- or chemoshock seizure thresholds and alters seizure patterns in experimental animals 1
• The drug is metabolized into two active metabolites: phenobarbital (PB) and phenylethylmalonamide (PEMA), both of which contribute to its anticonvulsant effects 1, 2
• PEMA additionally potentiates the anticonvulsant activity of phenobarbital 1

Clinical Indications

Approved Uses

Primidone is FDA-approved for controlling 1:

• Grand mal seizures (including those refractory to other anticonvulsants)
• Psychomotor seizures
• Focal epileptic seizures

Off-Label Use

• Essential tremor remains a first-line indication despite being outside the formal marketing authorization 2

Therapeutic Monitoring

The generally accepted therapeutic range for primidone is 5-10 mg/L (23-46 μmol/L) 2:

• Therapeutic drug monitoring (TDM) of primidone should always be accompanied by phenobarbital level determination, as the conversion rate from primidone to phenobarbital is highly variable between individuals 2
• The level of proof for TDM of primidone is considered "probably useless," while TDM for phenobarbital is "recommended" 2
• In neonates and young infants, seizure control correlates best with primidone and PEMA levels rather than phenobarbital levels 3

Dosing Considerations

Pediatric Seizure Control

• In neonates and young infants with refractory seizures, primidone at 25 mg/kg/day in 3 divided doses achieves therapeutic levels by day 3 3
• Mean primidone levels stabilize around 10.6 ± 4.4 μg/mL by day 3 3
• Seizure control typically occurs within 5 days, with most patients achieving control by day 3 when primidone levels exceed 10 μg/mL 3

Febrile Seizures

• The American Academy of Pediatrics does not recommend continuous primidone therapy for children with febrile seizures because potential toxicities outweigh the relatively minor risks of simple febrile seizures 4
• When used at 15-20 mg/kg/day, primidone reduces febrile seizure recurrence rates 4
• In comparative studies, primidone at 17.8 mg/kg/day achieved phenobarbital plasma levels of 14.1 ± 3.7 μg/mL and was effective in 88.2% of patients 5

Adverse Effects

Common side effects include behavioral disturbances, irritability, and sleep disturbances 4:

• In febrile seizure prevention studies, side effects occurred in 53% of patients on primidone, though no treatment changes were required 5
• This represents a significantly lower side effect profile compared to phenobarbital alone (76.7% with side effects) 5
• No toxic effects were observed in neonatal studies at standard dosing 3

Important Clinical Considerations

Metabolic Patterns

• Auto-induction of metabolic systems occurs over time, leading to decreased drug levels during long-term therapy 3
• Under normal conditions, phenobarbital represents the largest portion of total drug concentration (primidone + phenobarbital + PEMA) 6
• A relative phenobarbital concentration below 40% may indicate non-compliance in patients on stable therapy for at least 3 weeks (excluding young children and intoxication cases) 6

Discontinuation Warnings

• Primidone must never be discontinued abruptly, as withdrawal seizures may occur, some of which can be severe 7
• When switching medications is necessary, primidone can be replaced by its main metabolite phenobarbital for simple and quick substitution 7
• In patients seizure-free for many years, discontinuing medication may be considered 7

Special Populations

• In renal insufficiency and acute intoxication, primidone and PEMA levels are elevated while phenobarbital remains relatively low, representing an atypical metabolic pattern 6