Topiramate was approved for medical use in the United States in 1996. It is available as a generic medication. A month supply in the United Kingdom costs the NHS about £1.40 per month as of 2019. In the United States, the wholesale cost of this amount is about US$4.00. In 2017, it was the 77th most commonly prescribed medication in the United States, with more than ten million prescriptions.
A 2018 review found topiramate of no use in chronic low back pain. Topiramate has not been shown to work as a pain medicine in diabetic neuropathy, the only neuropathic condition in which it has been adequately tested.
People taking topiramate should be aware of the following risks:
Avoid activities requiring mental alertness and coordination until drug effects are realized.
Topiramate may impair heat regulation, especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration.
The U.S. Food and Drug Administration (FDA) has notified prescribers that topiramate can cause acute myopia and secondary angle closure glaucoma in a small subset of people who take topiramate regularly. The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. Discontinuation of topiramate may halt the progression of the ocular damage and may reverse the visual impairment.
Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations. This might be particularly important for women who take topiramate to prevent migraine attacks. In March 2011, the FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy and placed it in Pregnancy Category D.
Topiramate has been associated with a statistically significant increase in suicidality, and "suicidal thoughts or actions" is now listed as one of the possible side effects of the drug "in a very small number of people, about 1 in 500."
Topiramate is quickly absorbed after oral use. Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized by hydroxylation, hydrolysis, and glucuronidation. Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose.
Several cellular targets have been proposed to be relevant to the therapeutic activity of topiramate. These include (1) voltage-gated sodium channels; (2) high-voltage-activated calcium channels; (3) GABA-A receptors; (4) AMPA/kainate receptors; and (5) carbonic anhydrase isoenzymes. There is evidence that topiramate may alter the activity of its targets by modifying their phosphorylation state instead of by a direct action. The effect on sodium channels could be of particular relevance for seizure protection. Although topiramate does inhibit high-voltage-activated calcium channels, the relevance to clinical activity is uncertain. Effects on specific GABA-A receptor isoforms could also contribute to the antiseizure activity of the drug. Topiramate selectively inhibits cytosolic (type II) and membrane associated (type IV) forms of carbonic anhydrase. The action on carbonic anhydrase isoenzymes may contribute to the drug's side-effects, including its propensity to cause metabolic acidosis and calcium phosphate kidney stones.
Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of activities clinically. Its action on mitochondrial permeability transition pores has been proposed as a mechanism.
While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is one of the very few anticonvulsants [see: levetiracetam, carbamazepine, lamotrigine] that do not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect.
Detection in body fluids
Blood, serum, or plasma topiramate concentrations may be measured using immunoassay or chromatographic methods to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, or to assist in a medicolegal death investigation. Plasma levels are usually less than 10 mg/L during therapeutic administration, but can range from 10-150 mg/L in overdose victims.
Topiramate was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceuticals. The commercial usage of Topiramate began in 1996.Mylan Pharmaceuticals was granted final approval by the FDA for the sale of generic topiramate in the United States and the generic version was made available in September 2006. The last patent for topiramate in the U.S. was for use in children and expired on February 28, 2009.
^Linde, M; Mulleners, WM; Chronicle, EP; McCrory, DC (24 June 2013). "Topiramate for the prophylaxis of episodic migraine in adults". The Cochrane Database of Systematic Reviews. 6 (6): CD010610. doi:10.1002/14651858.CD010610. PMID23797676.
^Ferrari, A; Tiraferri, I; Neri, L; Sternieri, E (September 2011). "Clinical pharmacology of topiramate in migraine prevention". Expert Opinion on Drug Metabolism & Toxicology. 7 (9): 1169-81. doi:10.1517/17425255.2011.602067. PMID21756204.
^Evers, S.; Jensen, R. (September 2011). "Treatment of medication overuse headache - guideline of the EFNS headache panel". European Journal of Neurology. 18 (9): 1115-1121. doi:10.1111/j.1468-1331.2011.03497.x.
^Kramer, CK; Leitão, CB; Pinto, LC; Canani, LH; Azevedo, MJ; Gross, JL (May 2011). "Efficacy and safety of topiramate on weight loss: a meta-analysis of randomized controlled trials". Obesity Reviews. 12 (5): e338-47. doi:10.1111/j.1467-789X.2010.00846.x. PMID21438989.
^Hahn, MK; Cohn, T; Teo, C; Remington, G (January 2013). "Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters". Clinical Schizophrenia & Related Psychoses. 6 (4): 186-96. doi:10.3371/CSRP.HACO.01062013. PMID23302448.
^Mahmood, S; Booker, I; Huang, J; Coleman, CI (February 2013). "Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents". Journal of Clinical Psychopharmacology. 33 (1): 90-4. doi:10.1097/JCP.0b013e31827cb2b7. PMID23277264.
^Andrus, MR; Gilbert, E (November 2010). "Treatment of civilian and combat-related posttraumatic stress disorder with topiramate". The Annals of Pharmacotherapy. 44 (11): 1810-6. doi:10.1345/aph.1P163. PMID20923947.
^ abLofton, AL; Klein-Schwartz, W (2005), "Evaluation of toxicity of topiramate exposures reported to poison centers", Human & Experimental Toxicology, 24 (11): 591-595, doi:10.1191/0960327105ht561oa, PMID16323576
^Goswami D, Kumar A, Khuroo AH, et al. Bioanalytical LC-MS/MS method validation for plasma determination of topiramate in healthy Indian volunteers. Biomed. Chromatogr. 23: 1227-1241, 2009.
^Brandt C; Elsner H; Füratsch N; et al. (2010). "Topiramate overdose: a case report of a patient with extremely high topiramate serum concentrations and nonconvulsive status epilepticus". Epilepsia. 51 (6): 1090-1093. doi:10.1111/j.1528-1167.2009.02395.x. PMID19889015.
^R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1567-1569.
^Maryanoff, BE; Nortey, SO; Gardocki, JF; Shank, RP; Dodgson, SP (1987). "Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds". Journal of Medicinal Chemistry. 30 (5): 880-7. doi:10.1021/jm00388a023. PMID3572976.
^Maryanoff, BE; Costanzo, MJ; Nortey, SO; Greco, MN; Shank, RP; Schupsky, JJ; Ortegon, MP; Vaught, JL (1998). "Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives". Journal of Medicinal Chemistry. 41 (8): 1315-43. doi:10.1021/jm970790w. PMID9548821.