Primidone Dosing Recommendations
For adults and children 8 years and older, start primidone at 100-125 mg at bedtime for days 1-3, then gradually increase to a maintenance dose of 250 mg three times daily (750 mg/day), with a maximum of 500 mg four times daily (2000 mg/day) if needed. 1
Initial Titration Schedule (Adults and Children ≥8 Years)
The FDA-approved titration schedule follows a structured 10-day approach 1:
- Days 1-3: 100-125 mg at bedtime
- Days 4-6: 100-125 mg twice daily
- Days 7-9: 100-125 mg three times daily
- Day 10 onward: 250 mg three times daily (maintenance)
Maintenance Dosing
- Standard maintenance: 750-1000 mg/day (250 mg three or four times daily) 1
- Maximum dose: 2000 mg/day (500 mg four times daily) if required 1
- Therapeutic serum level: 5-12 mcg/mL (23-46 µmol/L) 1, 2
Pediatric Dosing (Children <8 Years)
For younger children, use a more conservative approach 1:
- Days 1-3: 50 mg at bedtime
- Days 4-6: 50 mg twice daily
- Days 7-9: 100 mg twice daily
- Day 10 onward: 125-250 mg three times daily (maintenance)
- Weight-based dosing: 10-25 mg/kg/day in divided doses 1
Special Considerations When Transitioning from Other Anticonvulsants
When patients are already receiving other anticonvulsants, start primidone at 100-125 mg at bedtime and gradually increase while simultaneously tapering the other medication 1. This transition should take at least 2 weeks to complete 1.
Critical Tolerability Strategy
A major pitfall is acute primidone toxicity during initiation, which causes up to one-third of patients to discontinue treatment. 3 However, pretreatment with phenobarbital can dramatically improve tolerability through cross-tolerance 4. In one study, 87% of patients pretreated with phenobarbital tolerated primidone initiation with minimal adverse events, compared to historical rates of significant early dropout 4.
Therapeutic Drug Monitoring
- Monitor both primidone AND phenobarbital levels since primidone is metabolized to phenobarbital, and conversion rates vary significantly between individuals 2
- Primidone therapeutic range: 5-10 mg/L 2
- Phenobarbital therapeutic range: 10-40 mg/L 2
- Seizure control correlates best with primidone and its metabolite phenylethylmalondiamide (PEMA), not phenobarbital levels, particularly in neonates 5
Clinical Efficacy Timeline
Therapeutic effects typically manifest within 3-5 days when primidone levels exceed 10 mcg/mL 5. For essential tremor, significant improvement may be observed within 6-12 weeks, with primidone doses up to 750 mg/day showing efficacy and good tolerability 6.
Dosing Pitfalls to Avoid
- Do not use very low initial doses (2.5 mg) in suspension form thinking it will improve tolerability—studies show no benefit and potentially worse compliance compared to standard tablet initiation 3
- Do not increase doses too rapidly without allowing adequate time for metabolic adaptation 1
- Do not monitor primidone levels alone—always check phenobarbital levels concurrently 2