What is topiramate?

Topiramate: A Comprehensive Overview

Topiramate is an anticonvulsant medication with multiple mechanisms of action that has demonstrated safety and efficacy in reducing heavy drinking in alcohol use disorder and promoting weight loss when used alone or in combination with phentermine. It is primarily FDA-approved for epilepsy and migraine prophylaxis, though it has several important off-label uses including treatment of alcohol use disorder and binge eating disorder. 1, 2

Mechanisms of Action

• Topiramate works through multiple mechanisms including:
  • Blockade of voltage-dependent sodium channels 3
  • Potentiation of GABAergic transmission 3
  • Inhibition of excitatory pathways through action at AMPA receptor sites 3
  • Modulation of gamma-aminobutyric acid receptors 1
  • Inhibition of carbonic anhydrase 3
  • Reduction of food intake by decreasing appetite and increasing satiation 1

FDA-Approved Indications

• Epilepsy treatment:
  • Adjunctive and monotherapy for partial-onset seizures 2
  • Treatment of generalized tonic-clonic seizures of nonfocal origin 2
  • Management of seizures associated with Lennox-Gastaut syndrome 4
• Migraine prophylaxis 2
• Weight management (in combination with phentermine as Qsymia) 1

Off-Label Uses

• Alcohol use disorder treatment:
  • Has demonstrated efficacy in reducing heavy drinking 1
  • Associated with decreased liver enzyme levels in patients treated for alcohol use disorder 1
  • Not specifically tested in patients with alcohol-related liver disease 1
• Binge eating disorder:
  • Starting dose of 25-50 mg per day 5
  • Gradual increase to effective dose of 100-400 mg per day based on tolerance 5
  • Consider discontinuation if no improvement after 12 weeks at maximum tolerated dose 5

Dosing Information

For Epilepsy:

• Initial monotherapy for new-onset seizures: target dose of 100 mg/day for adults 2
• Adjunctive use with enzyme-inducing drugs may require higher dosages 2
• Optimum dose for most patients does not exceed 400 mg/day 2

For Weight Management (as Qsymia with phentermine):

• Available in 4 doses: 3.75/23 mg, 7.5/46 mg, 11.25/69 mg, and 15/92 mg of phentermine/topiramate 1, 6
• Recommended titration schedule:
  • Initial dose: 3.75/23 mg daily for 14 days 1, 6
  • Maintenance dose: 7.5/46 mg daily 1, 6
  • May increase to 11.25/69 mg daily and then 15/92 mg daily if needed 1
• Discontinue or escalate dose if 3% weight loss not achieved after 12 weeks at 7.5/46 mg 1, 6
• Discontinue if 5% weight loss not achieved after 12 weeks at 15/92 mg 1, 6

Pharmacokinetics

• Well absorbed from the gastrointestinal tract 3
• Peak plasma levels typically reached in 2-3 hours 3
• Minimally bound (9-17%) to plasma proteins 3
• Half-life of approximately 20-30 hours in healthy volunteers 3
• Elimination occurs through:
  • Renal excretion in unchanged form 3
  • Oxidation and hydrolysis 3
• Elimination rate accelerated when taken with enzyme-inducing drugs like phenytoin, carbamazepine, and barbiturates 3

Adverse Effects

Common Side Effects:

• CNS-related effects: dizziness, fatigue, visual disturbances, ataxia, mental slowing, impaired concentration 3
• Paresthesias, xerostomia (dry mouth), constipation, headache 6, 3
• Weight loss (which may be beneficial in some contexts) 3
• Dysgeusia (taste disturbances) and insomnia 6

Serious Adverse Effects:

• Increased risk of nephrolithiasis (kidney stones) 3
• Teratogenic effects - associated with cleft lip/palate when used during pregnancy 6
• May reduce efficacy of hormonal contraceptives 6

Special Considerations

• Discontinuation should be gradual (over one week or more) to minimize risk of seizures 5, 6
• May be particularly beneficial in patients with both binge eating disorder and migraines 5
• Elderly patients or those with renal insufficiency should start with lower doses and increase more slowly 5
• Patients undergoing hemodialysis may need supplemental doses to maintain anticonvulsant effects 6

Clinical Efficacy

• As an anticonvulsant:

  • Reduces seizure frequency by ≥50% in 35-52% of adult patients with resistant partial epilepsy 7
  • Effective for generalized tonic-clonic seizures and Lennox-Gastaut syndrome 7
  • Efficacy maintained for up to 7 years in some patients 7

• For alcohol use disorder:

  • Demonstrated safety and efficacy in reducing heavy drinking 1
  • Associated with decreased liver enzyme levels 1

• For weight management (as Qsymia with phentermine):

  • Average weight loss of 6.7 kg (7.5/46 mg dose) to 8.9 kg (15/92 mg dose) 1
  • 45-70% of patients achieve ≥5% weight loss 1