topiramate TOPAMAX
Class: AED/Mood StabilizerFDA Indications: Adjunct Therapy For Partial Onset Seizures In Adults And Children Ages 2-16, Adjunct Therapy For Primary Generalized Tonic-clonic Seizures In Adults And Children Ages 2-16, Seizures Associated With Lennox-Gastaut Syndrome (ages 2 And Older), Migraine Prophylaxis
Off-Label Use: Bipolar Disorder, Binge Eating Disorder, PTSD, Drug-induced Weight Gain, Restless Leg Syndrome, Anxiety, Obesity, Stimulant Abuse, Alcohol Dependence
Prescribing
Forms: 25, 100, 200mg tablet; 15, 25mg sprinkle capsuleDose Range: 50-300 mg/day
Starting: 50 mg bid; titrate up to 200-400 mg/day in two doses for epilepsy; 50-300 mg/day for adjunctive treatment of bipolar disorder
Stopping: Withdrawal should be done gradually
Monitoring: Baseline and periodic measurement of serum bicarbonate
Precautions
Contraindications: Use of additional carbonic anhydrase inhibitors, a ketogenic diet, or a family history of nephrolithiasisSerious Side Effects: Metabolic acidosis, kidney stones, oligohidrosis and hyperthermia
Side Effects: sedation/somnolence, weakness/asthenia, dizziness, ataxia, paresthesia, nervousness, nystagmus, tremor, nausea, decreased appetite, weight loss, memory impairment, confusion, speech and language difficulties
Pharmacodynamics
1° MOA: Blocks repetitive firing by acting on sodium channels, can enhance GABAA-mediated chloride flux, and appears to be an antagonist at the AMPA and KA receptors, thus blocking the effect of glutamatePharmacokinetics
t½: 21 (20-30)° TMAX: 1-4°Substrate of: Renally cleared
Inhibits: 2C19; Induces: 3A4
Active Metabolites: ∅
DDIs
- - may interact with carbonic anhydrase inhibitors to increase risk of kidney stones
- - may reduce effectiveness of oral contraceptives
- - as a 2C19 inhibitor, can ↑ levels of co-prescribed 2C19 substrates as a 3A4 inducer, can ↓ levels of co-prescribed 3A4 substrates
Misc
- - weak inhibitor of carbonic anhydrase
- - elimination kinetics are strictly linear & ∴ there is a linear relationship between maintenance dose and steady-state plasma levels
- - excreted predominantly by the kidneys as unmetabolized drug
Special Populations
Category C—Associated with a 2-3X ↑'d risk of malformations, largely d/t an ↑'d risk for cleft lip with or without cleft palate and significant effects on cognitive functions and other matters. Effect on folic acid levels or metabolism is unknown ∴ the safest course is to start folic acid supplementation (4-5 mg/day) before conception, as is done with other antiepileptic agents. Avoid, if possible, during 1st trimester but, if required, monotherapy with the lowest effective dose is preferred. The risk for neonatal hypocalcemic seizures following in utero exposure requires further study.
Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when administered to a nursing woman.
Dosage adjustment may be necessary for elderly with impaired renal function/
↓ dose by 50% in renally impaired patients (CrCl < than 70 mL/min/1.73 m2.
In hepatically impaired patients, topiramate plasma concentrations may be increased.