TOPIRAMATE

TOPIRAMATE

Topiramate

What’s of Interest:

• In 2014, Topamax (topiramate) became the first medication approved to prevent migraine headaches in adolescents (ages 12 to 17)

Brands

• Topamax, others

Class

• Anticonvulsant, voltage-sensitive sodium channel modulator

Approved For:

• Migraine prophylaxis (ages 12 and older)
•  Other indications include partial onset seizures, primary generalized tonic-clonic seizures, seizures associated with Lennox-Gastaut Syndrome, and chronic weight management in obese or overweight adults (in combination with phentermine)

Dosing

Formulation:

• Tablet 25 mg, 50 mg, 100 mg, 200 mg
• Sprinkle capsule 15 mg, 25 mg
• An extended release capsule (25 mg, 50 mg, 100 mg, 200 mg) is also available; this formulation is not approved for migraine prophylaxis

Dosing Tips:

• Migraine: initial 25 mg/night for the first week; increase weekly in 25-mg increments; approved dose 100 mg/day in two divided doses
• For migraine, the individual dose may vary widely. Some patients benefit from doses as low as 25 mg/day but others may require much higher doses than the 100 mg/day approved for migraine prophylaxis
• Adverse effects may increase as dose increases
• Weight loss is often dose-related, but patients on lower doses (50 mg) still lose weight
• Slow titration minimizes sedation and other adverse effects
• Can be taken with or without food
• Sprinkle capsule formulation can be swallowed whole or sprinkled over approximately a teaspoon of soft food (e.g., applesauce); the mixture should be consumed immediately
• Headaches may return within days to months of stopping, but patients often continue to do well for 6 or more months after stopping
• Baseline and periodic serum bicarbonate levels to monitor for hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis)

Pearls:

• Migraines may decrease in as little as 2 weeks but can take up to 3 months on a stable dose to see the full effect
• The goal when using topiramate for migraine prophylaxis is a 50% or greater reduction in migraine frequency or severity; consider tapering or stopping if headaches remit for more than 6 months or if considering pregnancy
• Augmenting options for a migraine include beta blockers, antidepressants, natural products, other anticonvulsants, and nonmedication treatments such as biofeedback to improve headache control

 Children and Adolescents:

• Approved for use in adolescents ages 12 and older for migraine prophylaxis
• Approved for use in children age 2 and older for treatment of partial-onset seizures (adjunct and monotherapy), primary generalized tonic-clonic seizures (adjunct and monotherapy), and seizures associated with Lennox-Gastaut syndrome (adjunct only)
• Clearance is increased in pediatric patients

 Pregnancy:

• Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001
• Controlled studies have not been conducted in pregnant women
• Increased risk of cleft lip/palate
• Hypospadia has occurred in some male infants whose mothers took topiramate during pregnancy
• Patients with migraine should generally stop topiramate before considering pregnancy
• Migraine usually improves in the last 2 trimesters
• Antiepileptic Drug Pregnancy Registry: (888) 233–2334

Side Effects

Weight Gain:

Sedation:

 Notable or Dangerous Side Effects:

• Sedation; cognitive problems, especially word-finding difficulties; mood problems
• Nausea, appetite loss, weight loss
• Taste perversion, pallinopsia (a rare visual disturbance that causes persistence of images; benign but frightening for the patient)
• Carbonic anhydrase inhibition can cause paresthesias and metabolic acidosis and may lead to kidney stones
• Secondary angle-closure glaucoma
• Oligohidrosis and hyperthermia (more common in children)
• Sudden unexplained deaths have occurred in epilepsy (unknown if related to topiramate use)

 Drug Interactions:

• Carbamazepine, phenytoin, and valproate may increase the clearance of topiramate, and thus decrease topiramate levels, possibly requiring a higher dose of topiramate
• Lamotrigine, hydrochlorothiazide, and metformin may increase topiramate levels
• Topiramate can decrease levels of lithium, digoxin, valproic acid, and phenytoin
• Topiramate may increase levels of amitriptyline and metformin
• Topiramate may interact with carbonic anhydrase inhibitors to increase the risk of kidney stones
• Higher-dose topiramate (>200 mg) can decrease plasma concentrations of estrogens and progestins in patients taking oral contraceptives; a higher dose of estrogen or alternative methods of contraception should be considered
• Topiramate can interact with CNS depressants and alcohol with neuropsychiatric and cognitive consequences

 Cardiac Impairment:

• No known effects

 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:

• Use with caution