Dosing Tips

• Adverse effects may increase as dose increases

• Topiramate is available in a sprinkle capsule formulation, which can be swallowed whole or sprinkled over approximately a teaspoon of soft food (e.g., applesauce); the mixture should be consumed immediately

• Bipolar patients are generally administered doses at the lower end of the dosing range

• Slow upward titration from doses as low as 25 mg/day can reduce the incidence of unacceptable sedation

• Many bipolar patients do not tolerate more than 200 mg/day

✽ Weight loss is dose-related but most patients treated for weight gain receive doses at the lower end of the dosing range

Overdose

• No fatalities have been reported in monotherapy; convulsions, sedation, speech disturbance, blurred or double vision, metabolic acidosis, impaired coordination, hypotension, abdominal pain, agitation, dizziness

Long-Term Use

• Probably safe

• Periodic monitoring of serum bicarbonate levels may be required

Habit Forming

• No

How to Stop

• Taper

• Epilepsy patients may seize upon withdrawal, especially if withdrawal is abrupt

✽ Rapid discontinuation may increase the risk of relapse in bipolar patients

✽ Discontinuation symptoms uncommon

Pharmacokinetics

• Elimination half-life approximately 21 hours

• Renally excreted

Drug Interactions

• Carbamazepine, phenytoin, and valproate may increase the clearance of topiramate, and thus decrease topiramate levels, possibly requiring a higher dose of topiramate

• Topiramate may increase the clearance of phenytoin and thus decrease phenytoin levels, possibly requiring a higher dose of phenytoin

• Topiramate may increase the clearance of valproate and thus decrease valproate levels, possibly requiring a higher dose of valproate

• Topiramate may increase plasma levels of metformin; also, metformin may reduce clearance of topiramate and increase topiramate levels

• Topiramate may interact with carbonic anhydrase inhibitors to increase the risk of kidney stones

• Topiramate may reduce the effectiveness of oral contraceptives

• Reports of hyperammonemia with or without encephalopthay in patients taking topiramate combined with valproate, though this is not due to a pharmacokinetic interaction; in patients who develop unexplained lethargy, vomiting, or change in mental status, an ammonia level should be measured

Other Warnings/Precautions

✽ If symptoms of metabolic acidosis develop (hyperventilation, fatigue, anorexia, cardiac arrhythmias, stupor), then dose may need to be reduced or treatment may need to be discontinued

• Depressive effects may be increased by other CNS depressants (alcohol, MAOIs, other anticonvulsants, etc.)

• Use with caution when combining with other drugs that predispose patients to heat-related disorders, including carbonic anhydrase inhibitors and anticholinergics

• Warn patients and their caregivers about the possibility of activation of suicidal ideation and advise them to report such side effects immediately

Do Not Use

• Within 6 hours prior to and 6 hours after alcohol use (extended release)

• In patients with metabolic acidosis who are taking metformin (extended release)

• If there is a proven allergy to topiramate

TOPIRAMATE: SPECIAL POPULATIONS

Renal Impairment

• Topiramate is renally excreted, so the dose should be lowered by half

• Can be removed by hemodialysis; patients receiving hemodialysis may require supplemental doses of topiramate

Hepatic Impairment

• Drug should be used with caution

Cardiac Impairment

• Drug should be used with caution

Elderly

• Elderly patients may be more susceptible to adverse effects

Children and Adolescents

• Approved for use in children age 2 and older (immediate release) for treatment of seizures

• Clearance is increased in pediatric patients

• Seizures (immediate release, ages 2–16): initial 1–3 mg/kg per day at night; after 1 week increase by 1–3 mg/kg per day every 1–2 weeks with total daily dose administered in 2 divided doses; recommended dose generally 5–9 mg/kg per day in 2 divided doses

• Effectiveness was not demonstrated in infants/toddlers 1 to 24 months of age with refractory partial onset seizures; some adverse effects/toxicities not observed in older patients did occur

• Seizures (extended release, adjunct): initial 25 mg once nightly (1–3 mg/kg/night) for first week; increase at 1- or 2-week intervals by increments of 1–3 mg/kg/night; recommended dose 5–9 mg/kg/night