Topiramate was approved for medical use in the United States in 1996.[2] It is available as a generic medication.[3] A month supply in the United Kingdom costs the NHS about £1.40 per month as of 2019.[3] In the United States, the wholesale cost of this amount is about US$4.00.[5] In 2017, it was the 77th most commonly prescribed medication in the United States, with more than ten million prescriptions.[6][7]
A 2018 review found topiramate of no use in chronic low back pain.[12] 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.[13]
Other
One common off-label use for topiramate is in the treatment of bipolar disorder.[14][15][16] A review published in 2010 suggested a benefit of topiramate in the treatment of symptoms of borderline personality disorder, however the authors noted that this was based only on one randomized controlled trial and requires replication.[17]
Topiramate has been used as a treatment for alcoholism.[18] The VA/DoD 2015 guideline on substance use disorders lists topiramate as a "strong for" in its recommendations for alcohol use disorder.[19]
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,[26] 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.[34] 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.[35] 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.[28]
Topiramate has been associated with a statistically significant increase in suicidality,[36] 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."[26][37]
Topiramate may increase the plasma-levels of phenytoin.
Topiramate itself is a weak inhibitor of CYP2C19 and induces CYP3A4; a decrease in plasma levels of estrogens and digoxin has been noted during topiramate therapy. This can reduce the effectiveness of oral contraceptives (birth control pills); use of alternative birth control methods is recommended.[41] Neither intrauterine devices (IUDs) nor Depo-Provera are affected by topiramate.[41]
Alcohol may cause increased sedation or drowsiness, and increase the risk of having a seizure.
As topiramate may result in acidosis other treatments that also do so may worsen this effect.[42]
Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.[citation needed]
Pharmacology
Chemically, topiramate is a sulfamate modified fructose diacetonide - a rather unusual chemical structure for a pharmaceutical.
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.[43] 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.[44] 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.[45]
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.[46]
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.[47][48][49]
History
Topiramate was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceuticals.[50][51] The commercial usage of Topiramate began in 1996.[52]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.[53] The last patent for topiramate in the U.S. was for use in children and expired on February 28, 2009.[54]
^Vasudev, K; Macritchie, K; Geddes, J; Watson, S; Young, A (25 January 2006). Young, Allan H (ed.). "Topiramate for acute affective episodes in bipolar disorder". The Cochrane Database of Systematic Reviews (1): CD003384. doi:10.1002/14651858.CD003384.pub2. PMID16437453.
^Cipriani, A; Barbui, C; Salanti, G; Rendell, J; Brown, R; Stockton, S; Purgato, M; Spineli, LM; Goodwin, GM; Geddes, JR (8 October 2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet. 378 (9799): 1306–15. doi:10.1016/s0140-6736(11)60873-8. PMID21851976. S2CID25512763.
^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. S2CID24358798.
^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. S2CID26085987.
^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. S2CID12137726.
^Hulihan, Joseph (2001). "IMPORTANT DRUG WARNING"(PDF). FDA MedWatch. Ortho-McNeil Pharmaceutical. Archived from the original(PDF) on 13 January 2017. Retrieved 11 June 2018.
^Kudin, AP; Debska-Vielhaber, G; Vielhaber, S; Elger, CE; Kunz, WS (2004). "The mechanism of neuroprotection by topiramate in an animal model of epilepsy". Epilepsia. 45 (12): 1478–87. doi:10.1111/j.0013-9580.2004.13504.x. PMID15571505. S2CID7067509.
^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. S2CID35752877.
^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.