Rimidon

A. Approved Indications

• Epilepsy (partial and generalized seizures):
• Complex partial seizures
• Focal onset seizures with secondary generalization
• Generalized tonic-clonic seizures
• As monotherapy or adjunctive therapy
• Essential tremor:
• Management of moderate to severe essential tremor
• Particularly effective when beta-blockers are not tolerated

B. Clinically Accepted Off-label Uses

• Myoclonic seizures (in selected cases where other therapies fail)
• Neonatal seizures (used rarely in resistant cases with specialist supervision)
• Trigeminal neuralgia (as an adjunct in refractory cases)
• Benign familial tremor (symptomatic control)

Route: Oral (tablet or suspension)

Adults:

• Epilepsy:
• Initial: 100 to 125 mg at bedtime for 3 days
• Titrate gradually over 2–3 weeks
• Usual maintenance dose: 750–1500 mg/day in 2 or 3 divided doses
• Maximum: 2 g/day in divided doses
• Essential Tremor:
• Initial: 50 mg at bedtime
• Increase by 50 mg every 3 days to maintenance dose
• Usual effective dose: 250–750 mg/day in divided doses

Children:

• Epilepsy:
• <8 years: 125–250 mg/day in divided doses; titrate based on response
• ≥8 years: 250 mg/day initially; maintenance 500–750 mg/day
• Max: up to 1 g/day if tolerated

Elderly:

• Start low (e.g., 50 mg/day) due to altered metabolism and sensitivity
• Titrate slowly with close monitoring of sedation, ataxia, and serum levels

Renal Impairment:

• Use with caution; dosage adjustment required for significant impairment
• Monitor serum phenobarbital levels and clinical response

Hepatic Impairment:

• Use cautiously; avoid in severe hepatic dysfunction
• Monitor liver enzymes periodically

Primidone is metabolized into phenobarbital and phenylethylmalonamide (PEMA), both of which contribute to its antiepileptic activity. It acts by enhancing GABAergic inhibitory neurotransmission in the central nervous system. Phenobarbital, its active metabolite, binds to GABA-A receptors, prolonging chloride channel opening and hyperpolarizing neuronal membranes, thereby reducing neuronal excitability and suppressing seizure activity. PEMA also possesses anticonvulsant properties, although its precise mechanism remains less defined. Collectively, these actions stabilize overactive neuronal circuits and reduce seizure frequency.

• Absorption:
  Well absorbed orally; peak plasma concentration in 3–6 hours
• Bioavailability:

90%; unaffected significantly by food

• Distribution:
  Widely distributed throughout tissues and crosses the blood-brain barrier
  Plasma protein binding: ~20–30%
• Metabolism:
  Primidone is metabolized in the liver to phenobarbital (active) and PEMA (active)
  Enzymatic pathway: primarily hepatic microsomal enzymes
• Half-life:
  Primidone: ~5–15 hours
  Phenobarbital: 75–120 hours
  PEMA: ~24–48 hours
• Elimination:
  Renal excretion (primarily as metabolites)
  Dose adjustment may be required in renal insufficiency

• Pregnancy:
  FDA Pregnancy Category D
  Use only if benefits outweigh fetal risks. Associated with fetal hydantoin syndrome (craniofacial anomalies, developmental delay), especially when used in the first trimester. Supplement with folic acid before and during pregnancy.
• Lactation:
  Excreted into breast milk in small amounts. May cause sedation or feeding difficulties in the infant. Breastfeeding may be acceptable with close infant monitoring.

• Primary Class: Antiepileptic (AED)
• Subclass: Barbiturate-related anticonvulsant (non-benzodiazepine, non-hydantoin)

• Known hypersensitivity to primidone, phenobarbital, or other barbiturates
• Porphyria (acute intermittent or variegate types)
• Severe hepatic dysfunction
• Significant respiratory depression
• History of addiction or barbiturate abuse

• CNS Depression:
  May cause drowsiness, sedation, dizziness; avoid driving and alcohol use
• Dependence and withdrawal risk:
  Taper slowly when discontinuing to avoid seizures or withdrawal syndrome
• Suicidal ideation:
  Increased risk of suicidal thoughts or behavior—monitor closely during initiation
• Hematologic effects:
  Rare reports of megaloblastic anemia, leukopenia—check CBC periodically
• Hepatotoxicity:
  Monitor liver function in long-term use
• Use in elderly:
  Higher risk of sedation, falls, and cognitive impairment

Common:

• Neurologic:
  Sedation, drowsiness, ataxia, dizziness, vertigo, fatigue, headache
• Gastrointestinal:
  Nausea, vomiting, anorexia
• Psychiatric:
  Depression, irritability, agitation

Less Common / Serious:

• Hematologic:
  Megaloblastic anemia (due to folate deficiency), leukopenia, thrombocytopenia
• Hepatic:
  Elevated liver enzymes, rare hepatotoxicity
• Dermatologic:
  Rash, Stevens-Johnson syndrome (rare)
• Suicidal thoughts or behavior
  Especially in adolescents and young adults

Onset of side effects may occur within first few weeks; many diminish with continued use.

• CYP450 enzyme induction:
  Induces CYP3A4, CYP2C9, and CYP1A2, lowering plasma levels of many drugs
• Interacts with:
• Warfarin: Reduced anticoagulant effect
• Oral contraceptives: Decreased efficacy; risk of contraceptive failure
• Other AEDs (e.g., phenytoin, valproate): Complex, bidirectional interactions
• CNS depressants (e.g., alcohol, opioids, benzodiazepines): Additive sedative effects
• Folic acid deficiency:
  May increase risk of anemia—folate supplementation recommended

• FDA and EMA alerts:
  Reinforced warnings regarding risk of suicidality with antiepileptics
• American Academy of Neurology (AAN) Guidelines:
  Recommend primidone for essential tremor when first-line therapies fail or are not tolerated
• Updated prescribing guidelines:
  Emphasize careful titration and GFR monitoring in elderly patients

• Temperature:
  Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C
• Humidity and Light:
  Protect from moisture and direct sunlight
• Handling:
  Keep in original container; tightly closed
• Suspension (if applicable):
  Shake well before use; do not freeze
• Shelf life:
  Use within labeled expiration date; discard opened suspension after 30 days if not specified