Topamax, also known as topiramate, is broad-spectrum, anti-epileptic drug (AED) with Food and Drug Administration (FDA) indication approval for monotherapy epilepsy and adjunctive therapy epilepsy in children and adults, and prophylactic treatment of migraines in adults.1 The proposed mechanisms of action are that it blocks voltage-sensitive Na+ channels, enhances GABA-A receptors, inhibits the effect of glutamate receptors, and weakly inhibits carbonic anhydrases, isozyme II and isozyme IV. 1 Clinical trials of Topamax® for epilepsy have shown that those patients taking the drug experienced weight loss.2
With a quick oral absorption and an 80% oral bioavailability, topiramate reaches peak concentrations in the plasma after about 2 hours (400 mg).1 Food does not affect its bioavailability. 1 The sprinkle capsules have same bioequivalence to the tablets.1 Topiramate has 15%-41% protein binding when given in concentrations of about 0.5-250 mcg/ml.1 It does not undergo extensive metabolism. 1 There are six metabolites that are formed via hydroxylation, hydrolysis, and glucuronidation--however, these metabolites make up less than 5% of a given dose. 1 70% of the drug is primarily eliminated as unchanged drug in the urine.1 It takes 21 hours for a single or multiple dose to be eliminated.1 It takes 4-8 days for the drug to reach steady-state concentrations in adult patients with healthy kidneys.1 If the adult has moderately impaired kidneys, then the drug is cleared approximately 42% less and it will take 10-15 days longer for the drug to reach steady-state concentrations.1 Children is clear the drug 50% more in adults.1 Being elderly does not affect the drug's absorption or clearance.1
When taking this drug, patients may have increased thoughts of suicide as well as suicidal behavior, clinical depression, acute myopia, or secondary angle closure glaucoma.3 In clinical trials, the most common adverse reactions that patients reported were "paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, and confusion." 1
Literature search:
Literature search was conducted using EMBASE Drugs and Pharmacology (1980 to 4th Quarter 2003), and MEDLINE databases (1966 to November week 1 2003). Key words were: topiramate, weight, weight loss. The limits were: humans, English language, and clinical trials. 80 articles were found and 3 articles were chosen for further evaluation.
DATA:
Bray G et al. performed a six-month, placebo-controlled, dose-ranging study with 385 obese patients randomized to placebo or topiramate.4 The objective was to "evaluate the efficacy and safety of topiramate for weight loss in healthy obese subjects." 4 There were 385 subjects (18 to 75 years of age with a BMI greater or equal to 30 or 27 to 50 kg/m2 for people with hypertension that was controlled and/or dyslipidemia) were randomized to receive either placebo or topiramate at 64-, 96-, 192-, or 384- mg daily.4 Patients were excluded if they have any "weight change…diabetes, uncontrolled hypertension, liver disease, renal dysfunction, and/or cardiovascular, endocrine, neurological, or psychiatric disease."4 Recruitment took place across 17 centers in the United States.4 Dosing began at 16 mg once daily.4 At week 2, the dose was increased to 16 mg twice daily.4 Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until study subjects reached their target dose.4 Twenty-four weeks after the start of treatment, all subjects were tapered off by a 50% reduction in the dose per week.4 All participants did the same lifestyle program (dietary restriction combined with exercise and behavioral modification).4 Mean percent weight loss from baseline to week 24 was 2.6% in placebo-treated patients vs. 5.0%, 4.8%, 6.3%, and 6.3% in the 64 mg/d, 96 mg/d, 192 mg/d, and 384 mg/d topiramate groups, respectively.4 Topiramate-treated patients lost more weight than non-topiramate patients (5% or 10% of body weight).4 Paresthesia, somnolence, difficulty with memory, concentration, and attention were most frequently reported and most events were was related to the dose that the patients were taking.4 These adverse events were experienced early on and usually resolved without any further additional treatment; only 21% receiving topiramate withdrew from the study due to adverse events whereas 11% withdrew if they were taking placebo.4 At all doses topiramate produced more weight loss than in patients who were not taking the drug.4
Astrup A et al performed a "randomized, double-blind, placebo-controlled, parallel-group multicenter trial"5 and stated that the objective of the study was "to examine the safety and efficacy of topiramate for maintaining weight following a low-calorie diet." 5 701 obese subjects from Europe and Australia (ages 18-75 with a BMI of 30 < or = BMI < 50 kg/m2) were enrolled. 5 Subject were excluded if they had a history of diabetes, "significant cardiovascular, hepatic, or renal disease, a history or family history of kidney stones, uncontrolled thyroid disease, or significant central nervous system (CNS)-related or psychiatric disorders." 5 Everyone was on a lifestyle modification plan (dietary restriction in combination with exercise and behavioral modification). 5 Study subjects ate a "low-calorie diet," 5 defined as "a nutritionally balanced diet containing 800 to 1000 kcal daily" 5 for the duration of the trial which was 8 weeks. 5 Those who lost greater to or equal to "8% of their initial weight" 5 received 96 mg daily of topamax or 192 mg daily of topiramate, or placebo. 5 44 weeks of treatment must have been completed by the study subjects to be included in the data analysis for drug efficacy. 5 Subjects were treated with a very low-calorie diet to induce an 8% loss of initial body weight. 5 560 subjects achieved an 8% weight loss and were randomized to take topiramate doses of 96- or 192- mg/day, or placebo. 5 293 subjects completed the 44 week trial. 5 Those in the topiramate groups lost 15.4% and 16.5% of their baseline weight and those in the placebo group lost 8.9% (p < 0.001). 5 Weight loss was maintained by subjects at the beginning of the trial, but not later on and subjects did not report many adverse events. 5
Summary:
Topamax® does not have an FDA indication for weight loss1; but based on study results, it may be used off-label as a weight loss agent.4,5
Criteria for its use include: 18 to 75 years of age with a BMI greater or equal to 30 or 27 to 50 kg/m2 for people with controlled hypertension and/or controlled dyslipidemia
Dosing for Topamax® is16 mg by mouth once daily, then increase dose to 16 mg twice daily, then increase dose by 32 mg daily every week until a target dose of 64 mg daily is reached. 4,5 If tolerated, the target dose can be increased to 96, 192, or 384 mg by mouth daily. 4,5
Monitor for "paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, and confusion." 4
