Common side effects includetingling, feeling tired,loss of appetite, abdominal pain, weight loss,[10] and decreased cognitive function such as trouble concentrating.[8][9] Serious side effects may includesuicidal ideation, increasedammonia levels resulting inencephalopathy, andkidney stones.[8] Topiramate can cause birth defects, including cleft lip and palate.[11] Risks/benefits should be carefully discussed with the full treatment team. Topiramate is considered "probably compatible" with lactation and is not contraindicated for breastfeeding, though monitoring of the infant for diarrhea or poor weight gain may be considered.[12][13] Itsmechanism of action is unclear.[8]
Topiramate was first synthesized with the intent of being an oral hypoglycemic agent; however, it received its initial approval as an anticonvulsant in 1996.[8] It is available as ageneric medication.[9][14][15] In 2023, it was the 71st most commonly prescribed medication in the United States, with more than 9million prescriptions.[16][17]
A 2018 review found topiramate of no use in chroniclow back pain.[22] Topiramate has not been shown to work as a pain medicine indiabetic neuropathy, the only neuropathic condition for which it has been adequately tested.[23]
One commonoff-label use for topiramate is in the treatment ofbipolar disorder.[24][25][26] A review published in 2010 suggested a benefit of topiramate in the treatment of symptoms ofborderline personality disorder; however, the authors noted that this was based only on one randomized controlled trial and requires replication.[27]
Topiramate has been used as a treatment foralcoholism.[28] The U.S. Veterans Affairs and Department of Defense 2015 guidelines on substance use disorders list topiramate as a "strong for" in its recommendations for alcohol use disorder.[29]
Topiramate is also utilized in combination with other medications for its effect as a weight loss aid, particularly in the context of obesity management[30][31],binge eating disorder,[32] and off-setting weight gain induced by takingantipsychotic medications.[33] In 2012, the combination ofphentermine/topiramate was approved in the United States for weight loss.[30]
The most significant adverse effects associated with topiramate treatment are predominantly central nervous system (CNS) related. A notable proportion of patients, ranging from 11% to 28%, discontinue topiramate therapy due to adverse effects.[10]
People taking topiramate should be aware of the following risks:
Avoid activities requiring mental alertness and coordination until drug effects are realized. Psychomotor slowing is a frequently reported adverse effect, though it often diminishes with prolonged use or through careful adjustment of dosage.
Topiramate may impair heat regulation,[34] especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration.
Topiramate may decrease the effectiveness of oestrogen-containing oral contraceptives.
Taking topiramate in the first trimester of pregnancy may increase the risk of cleft lip/cleft palate in infants.[36]
As is the case for all antiepileptic drugs, it is advisable not to suddenly discontinue topiramate, as there is a theoretical risk of rebound seizures.
Some studies have attributed loss of appetite and upper respiratory tract infection to topiramate, but studies have concluded these adverse events are not difficult to tolerate for most individuals.[37]
The U.S.Food and Drug Administration (FDA) has notified prescribers that topiramate can cause acutemyopia and secondary angle closureglaucoma in a small subset of people who take topiramate regularly.[43] 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.[44] 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 ofcleft lip and/orcleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy and placed it inPregnancy Category D.[36]
Carbonation dysgeusia (distortion of the sense of taste-sensation of carbonation) may respond to and/or be prevented withzinc.[47]
Topiramate has been associated with astatistically significant increase insuicidality,[48] 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."[34][49]
Topiramate may increase the plasma levels of phenytoin.
Topiramate itself is a weak inhibitor ofCYP2C19 and inducesCYP3A4; a decrease in plasma levels of estrogens anddigoxin has been noted during topiramate therapy. This can reduce the effectiveness oforal contraceptives (birth control pills); use of alternative birth control methods is recommended.[53] Neitherintrauterine devices (IUDs) norDepo-Provera are affected by topiramate.[53]
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.[54]
Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate;antimuscarinic drugs (like trospium) can aggravate these disorders.[citation needed]
The topiramate molecule is asulfamate modified sugar – more specifically,fructose diacetonide, an unusual chemical structure for a pharmaceutical.
Topiramate is quickly absorbed after oral use. It has a half-life of 21 hours and a steady state of the drug is reached in 4 days in patients with normal renal function.[55] Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized byhydroxylation,hydrolysis, andglucuronidation. Sixmetabolites 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.[56] These include voltage-gatedsodium channels, high-voltage-activatedcalcium channels,GABAA receptors,AMPA/kainate receptors, andcarbonic anhydrase isoenzymes. There is evidence that topiramate may alter the activity of its targets by modifying their phosphorylation state instead of by direct action.[57] The effect on sodium channels could be of particular relevance for seizure protection. Although topiramate does inhibit high-voltage-activated calcium channels, its relevance to clinical activity is uncertain. Effects on specific GABAA receptor isoforms could also contribute to theanticonvulsant activity of the drug. Topiramate selectively inhibits cytosolic (type II) and membrane-associated (type IV) forms of carbonic anhydrase. Its 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.[citation needed]
Topiramate inhibits maximal seizure activity in electroconvulsive therapy and inpentylenetetrazol-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 onmitochondrial permeability transition pores has been proposed as a mechanism.[58]
While many anticonvulsants have been associated withapoptosis in young animals, animal experiments have found that topiramate is one of the very few anticonvulsants that do not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect.[59]
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 assist in a medicolegal death investigation. Plasma levels are usually less than 10 mg/L during therapeutic administration, but can range from 10 to 150 mg/L in overdose victims.[60][61][62]
Topiramate was discovered in 1979 byBruce E. Maryanoff and Joseph F. Gardocki during their research work atMcNeil Pharmaceuticals.[63][64] Topiramate was first soldin 1996.[65]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.[66] The last patent for topiramate in the U.S. was for use in children and expired on 28 February 2009.[67]
A 2023 systematic review of seizure treatment for infants aged 1 to 36 months identified three studies that evaluated the use of topiramate. Though its adverse effects, including upper respiratory tract infection and loss of appetite, were rarely severe enough for the medication to be discontinued in this age group, its effectiveness in reducing seizures was inconclusive. The available research suffers from small sample sizes, inconsistent findings, and inadequate comparison groups.[70]
^"Active substance(s): topiramate"(PDF).List of nationally authorised medicinal products. European Medicines Agency. September 2022.Archived(PDF) from the original on 6 September 2022. Retrieved6 September 2022.
^"Topiramate".Drugs and Lactation Database (LactMed®). Bethesda (MD): National Institute of Child Health and Human Development. 2006.PMID30000318. Retrieved27 December 2023.
^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):1169–1181.doi:10.1517/17425255.2011.602067.PMID21756204.S2CID207491096.
^Vasudev K, Macritchie K, Geddes J, Watson S, Young A (January 2006). Young AH (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, et al. (October 2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis".Lancet.378 (9799):1306–1315.doi:10.1016/s0140-6736(11)60873-8.PMID21851976.S2CID25512763.
^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):90–94.doi:10.1097/JCP.0b013e31827cb2b7.PMID23277264.S2CID26085987.
^Hulihan J (2001)."IMPORTANT DRUG WARNING"(PDF).FDA MedWatch. Ortho-McNeil Pharmaceutical. Archived fromthe original(PDF) on 13 January 2017. Retrieved11 June 2018.
^Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, et al. (July 2008). "Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register".Neurology.71 (4):272–276.doi:10.1212/01.wnl.0000318293.28278.33.PMID18645165.S2CID13562052.
^Berthier, M.L. and Dávila, G., 2023. Pharmacotherapy for post-stroke aphasia: what are the options?. Expert Opinion on Pharmacotherapy, (just-accepted).
^Cumbo, E. and Ligori, L.D., 2010. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. Epilepsy & Behavior, 17(4), pp.461-466.
^Charbonneau, M., Doyle-Campbell, C., Laskey, C. and Capoccia, K., 2020. Carbonation dysgeusia associated with topiramate. American Journal of Health-System Pharmacy, 77(14), pp.1113-1116.
^"Topiramate".PubMed Health. National Center for Biotechnology Information, U.S. National Library of Medicine. Archived fromthe original on 5 August 2010.
^Czuczwar K, Czuczwar M, Cieszczyk J, Gawlik P, Luszczki JJ, Borowicz KK, et al. (2004). "[Neuroprotective activity of antiepileptic drugs]".Przeglad Lekarski.61 (11):1268–1271.PMID15727029.
^Goswami D, Kumar A, Khuroo AH, Monif T, Rab S (November 2009). "Bioanalytical LC-MS/MS method validation for plasma determination of topiramate in healthy Indian volunteers".Biomedical Chromatography.23 (11):1227–41.doi:10.1002/bmc.1273.PMID19593736.
^Brandt C, Elsner H, Füratsch N, Hoppe M, Nieder E, Rambeck B, et al. (June 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.
^Baselt R (2008).Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1567–1569.
^Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP (May 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):880–887.doi:10.1021/jm00388a023.PMID3572976.
^Maryanoff BE, Costanzo MJ, Nortey SO, Greco MN, Shank RP, Schupsky JJ, et al. (April 1998). "Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives".Journal of Medicinal Chemistry.41 (8):1315–1343.doi:10.1021/jm970790w.PMID9548821.
^Andrus MR, Gilbert E (November 2010). "Treatment of civilian and combat-related posttraumatic stress disorder with topiramate".The Annals of Pharmacotherapy.44 (11):1810–1816.doi:10.1345/aph.1P163.PMID20923947.S2CID12137726.
^Roy AK, Hsieh C, Crapanzano K (2015). "Dextromethorphan Addiction Mediated Through the NMDA System: Common Pathways With Alcohol?".Journal of Addiction Medicine.9 (6):499–501.doi:10.1097/ADM.0000000000000152.PMID26441400.
^Treadwell JR, Wu M, Tsou AY (25 October 2022). Management of Infantile Epilepsies (Report). Agency for Healthcare Research and Quality.doi:10.23970/ahrqepccer252.
N
Y (what is this?) (verify)
.svg)
Media related toTopiramate at Wikimedia Commons