Biology:Topiramate

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Short description: Medication used to treat epilepsy and migraine
Topiramate
Topiramate structure.svg
Topiramate 3D.png
Clinical data
Trade namesTopamax, Trokendi XR, Qudexy XR, others
Other namesTopiramic acid
AHFS/Drugs.comMonograph
MedlinePlusa697012
License data
Pregnancy
category
  • AU: D
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80%
Protein binding13–17%; 15–41%
MetabolismLiver (20–30%)
Elimination half-life21 hours
ExcretionUrine (70–80%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC12H21NO8S
Molar mass339.36 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines.[7] It has also been used in alcohol dependence and essential tremor.[7] For epilepsy this includes treatment for generalized or focal seizures.[8] It is taken orally (by mouth).[7]

Common side effects include tingling, feeling tired, loss of appetite, abdominal pain, weight loss,[9] and decreased cognitive function such as trouble concentrating.[7][8] Serious side effects may include suicide, increased ammonia levels resulting in encephalopathy, and kidney stones.[7] Topiramate can cause birth defects including cleft lip and palate.[10] Risk/benefit should be carefully discussed with the full treatment team. Topiramate is considered "probably compatible" with lactation and is not contraindicated in breastfeeding, though monitoring of the infant for diarrhea or poor weight gain may be considered.[11] [12] The mechanism of action is unclear.[7]

Topiramate was approved for medical use in the United States in 1996.[7] It is available as a generic medication.[8][13][14] In 2021, it was the 66th most commonly prescribed medication in the United States, with more than 10 million prescriptions.[15][16]

Medical uses

A package of topiramate 25mg from Norway

Topiramate is used to treat epilepsy in children and adults, and it was originally used as an anticonvulsant.[17] In children, it is indicated for the treatment of Lennox-Gastaut syndrome, a disorder that causes seizures and developmental delay. It is most frequently prescribed for the prevention of migraines[17] as it decreases the frequency of attacks.[18][19] Topiramate is used to treat medication overuse headache and is recommended by the European Federation of Neurological Societies as one of the few medications showing effectiveness for this indication.[20]

Pain

A 2018 review found topiramate of no use in chronic low back pain.[21] 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.[22]

Other

One common off-label use for topiramate is in the treatment of bipolar disorder.[23][24][25] 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.[26]

Topiramate has been used as a treatment for alcoholism.[27] 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.[28]

Other uses include treatment of obesity,[29][30] binge eating disorder,[31] and off-setting weight gain induced by taking antipsychotic medications.[32][33] In 2012, the combination of phentermine/topiramate was approved in the United States for weight loss.

Adverse effects

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,[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 cause visual field defects.[35]
  • Topiramate may decrease effectiveness of oestrogen-containing oral contraceptives.
  • Taking topiramate in the first trimester of pregnancy may increase risk of cleft lip/cleft palate in infant.[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 their adverse events are not difficult to tolerate for most individuals.[37]

Frequency

Adverse effects by incidence:[38][39][40][41][42]

Very common (>10% incidence) adverse effects include:


Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.[43]

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.[44] 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.[45] 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.[36]

Cognitive and word-finding difficulties, as they may occur in some patients, may respond to piracetam.[46][47]

Topiramate has been associated with a statistically significant increase in suicidality,[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]

Overdose

Symptoms of acute and acute on chronic exposure to topiramate range from asymptomatic to status epilepticus, including in patients with no seizure history.[50][51] In children, overdose may also result in hallucinations.[51] Topiramate has been deemed the primary substance that led to fatal overdoses in cases that were complicated by polydrug exposure.[52] The most common signs of overdose are dilated pupils, somnolence, dizziness, psychomotor agitation, and abnormal, uncoordinated body movements.[50][51][52]

Interactions

Topiramate has many drug-drug interactions. Some of the most common are listed below:

  • As topiramate inhibits carbonic anhydrase, use with other inhibitors of carbonic anhydrase (e.g. acetazolamide) increases the risk of kidney stones.[citation needed]
  • Enzyme inducers (e.g. carbamazepine) can increase the elimination of topiramate, possibly necessitating dose escalations of topiramate.[citation needed]
  • 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.[53] Neither intrauterine devices (IUDs) nor Depo-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]

Pharmacology

Chair-style representation of skeletal formula

The topiramate molecule is a sulfamate 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 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.[56] 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.[57] 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 seizure activity in electroconvulsive therapy and in 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.[58]

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.[59]

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 to 150 mg/L in overdose victims.[60][61][62]

History

Topiramate was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceuticals.[63][64] Topiramate was first sold in 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]

Research

Topiramate is being studied as a potential treatment for post traumatic stress disorder.[68]

There is some evidence for the use of topiramate in the management of cravings related to withdrawal from dextromethorphan.[69]

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]

References

  1. ↑ "Trokendi XR- topiramate capsule, extended release". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2dc7957e-a3e5-46bb-aa66-f3250f872f5e. 
  2. ↑ "Topamax- topiramate tablet, coated Topamax- topiramate capsule, coated pellets". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21628112-0c47-11df-95b3-498d55d89593. 
  3. ↑ "Qsymia- phentermine and topiramate capsule, extended release". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40dd5602-53da-45ac-bb4b-15789aba40f9. 
  4. ↑ "Qudexy XR- topiramate capsule, extended release". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=46f54677-3a22-4c38-9b92-923020164e15. 
  5. ↑ "Eprontia - topiramate solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2a4df59-fead-4a01-9021-9eda02c48010. 
  6. ↑ "Active substance(s): topiramate". List of nationally authorised medicinal products. European Medicines Agency. September 2022. https://www.ema.europa.eu/documents/psusa/topiramate-list-nationally-authorised-medicinal-products-psusa/00002996/202201_en.pdf. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "Topiramate Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/topiramate.html. 
  8. ↑ 8.0 8.1 8.2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 328. ISBN 9780857113382. 
  9. ↑ "Topiramate Side Effects: Common, Severe, Long Term". https://www.drugs.com/sfx/topiramate-side-effects.html. 
  10. ↑ "FDA Drug Safety Communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate)". 18 June 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-risk-oral-clefts-children-born-mothers-taking-topamax-topiramate. 
  11. ↑ Health, MGH Center for Women's Mental (10 August 2022). "Essential Reads: Breastfeeding and Anti-Epileptic Drugs - MGH Center for Women's Mental Health". https://womensmentalhealth.org/posts/essential-reads-breastfeeding-and-anti-epileptic-drugs/,%20https://womensmentalhealth.org/posts/essential-reads-breastfeeding-and-anti-epileptic-drugs/. 
  12. ↑ "Topiramate", Drugs and Lactation Database (LactMed®) (Bethesda (MD): National Institute of Child Health and Human Development), 2006, PMID 30000318, http://www.ncbi.nlm.nih.gov/books/NBK501259/, retrieved 27 December 2023 
  13. ↑ "Competitive Generic Therapy Approvals". 29 June 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  14. ↑ "First Generic Drug Approvals 2023". 30 May 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals. 
  15. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  16. ↑ "Topiramate - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Topiramate. 
  17. ↑ 17.0 17.1 "Topamax Prescribing Information". http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020505s055,020844s046lbl.pdf. 
  18. ↑ "Topiramate for the prophylaxis of episodic migraine in adults". The Cochrane Database of Systematic Reviews 6 (6): CD010610. June 2013. doi:10.1002/14651858.CD010610. PMID 23797676. 
  19. ↑ "Clinical pharmacology of topiramate in migraine prevention". Expert Opinion on Drug Metabolism & Toxicology 7 (9): 1169–1181. September 2011. doi:10.1517/17425255.2011.602067. PMID 21756204. 
  20. ↑ "Treatment of medication overuse headache--guideline of the EFNS headache panel". European Journal of Neurology 18 (9): 1115–1121. September 2011. doi:10.1111/j.1468-1331.2011.03497.x. PMID 21834901. 
  21. ↑ "Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis". CMAJ 190 (26): E786–E793. July 2018. doi:10.1503/cmaj.171333. PMID 29970367. 
  22. ↑ "Topiramate for neuropathic pain and fibromyalgia in adults". The Cochrane Database of Systematic Reviews 2013 (8): CD008314. August 2013. doi:10.1002/14651858.CD008314.pub3. PMID 23996081. PMC 8406931. http://summaries.cochrane.org/CD008314/topiramate-for-treating-neuropathic-pain-or-fibromyalgia#sthash.QswJ7Tr9.dpuf. Retrieved 6 September 2013. 
  23. ↑ "Review of the use of Topiramate for treatment of psychiatric disorders". Annals of General Psychiatry 4 (1): 5. February 2005. doi:10.1186/1744-859X-4-5. PMID 15845141. 
  24. ↑ "Topiramate for acute affective episodes in bipolar disorder". The Cochrane Database of Systematic Reviews (1): CD003384. January 2006. doi:10.1002/14651858.CD003384.pub2. PMID 16437453. 
  25. ↑ "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet 378 (9799): 1306–1315. October 2011. doi:10.1016/s0140-6736(11)60873-8. PMID 21851976. 
  26. ↑ "Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials". The British Journal of Psychiatry 196 (1): 4–12. January 2010. doi:10.1192/bjp.bp.108.062984. PMID 20044651. 
  27. ↑ "Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients". Current Pharmaceutical Design 16 (19): 2103–2112. 2010. doi:10.2174/138161210791516404. PMID 20482511. 
  28. ↑ "VA/DoD Clinical Practice Guideline for the management of substance use disorders". 31 December 2015. https://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf. 
  29. ↑ "Topiramate-induced weight loss: a review". Epilepsy Research 95 (3): 189–199. August 2011. doi:10.1016/j.eplepsyres.2011.05.014. PMID 21684121. 
  30. ↑ "Efficacy and safety of topiramate on weight loss: a meta-analysis of randomized controlled trials". Obesity Reviews 12 (5): e338–e347. May 2011. doi:10.1111/j.1467-789X.2010.00846.x. PMID 21438989. 
  31. ↑ "Topiramate for Binge Eating Disorder". https://wa.kaiserpermanente.org/kbase/topic.jhtml?docId=ty7109. 
  32. ↑ "Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters". Clinical Schizophrenia & Related Psychoses 6 (4): 186–196. January 2013. doi:10.3371/CSRP.HACO.01062013. PMID 23302448. 
  33. ↑ "Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents". Journal of Clinical Psychopharmacology 33 (1): 90–94. February 2013. doi:10.1097/JCP.0b013e31827cb2b7. PMID 23277264. 
  34. ↑ 34.0 34.1 "Possible Side Effects - Topamax (topiramate)". Topamax.xom. http://www.topamax.com/how-topamax-may-help--what-to-expect.html. 
  35. ↑ "Topamax (topiramate) tablets and sprinkle capsules". Fda.gov. https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm195797.htm. 
  36. ↑ 36.0 36.1 "Risk of oral clefts in children born to mothers taking Topamax (topiramate)". FDA Drug Safety Communication. Fda.gov. 6 January 2011. https://www.fda.gov/Drugs/DrugSafety/ucm245085.htm. 
  37. ↑ "Seizures and Epilepsy in Children". 8 August 2021. https://www.hopkinsmedicine.org/health/conditions-and-diseases/epilepsy/seizures-and-epilepsy-in-children. 
  38. ↑ "Topamax Tablets and Sprinkle Capsules PRODUCT INFORMATION" (PDF). TGA eBusiness Services. JANSSEN-CILAG Pty Ltd. 30 May 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-02205-3. 
  39. ↑ "topiramate (Rx) - Topamax, Trokendi XR". Medscape Reference. WebMD. http://reference.medscape.com/drug/topamax-trokendi-xr-topiramate-343023. 
  40. ↑ "Topiramate 100 mg film-coated Tablets". electronic Medicines Compendium. Sandoz Limited. 6 March 2013. http://www.medicines.org.uk/emc/medicine/22416/SPC/Topiramate+100+mg+film-coated+Tablets/. 
  41. ↑ "TOPIRAMATE ( topiramate ) tablet TOPIRAMATE ( topiramate ) tablet [Torrent Pharmaceuticals Limited"]. DailyMed. Torrent Pharmaceuticals Limited. August 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a4ff77b8-04bc-4edb-a085-8d6d8687f8d1. 
  42. ↑ "Topiramate-Associated Movement Disorder: Case Series and Literature Review". Clinical Neuropharmacology 43 (4): 116–120. July–August 2020. doi:10.1097/WNF.0000000000000395. PMID 32541330. 
  43. ↑ "Effect of topiramate on acid-base balance: extent, mechanism and effects". British Journal of Clinical Pharmacology 68 (5): 655–661. November 2009. doi:10.1111/j.1365-2125.2009.03521.x. PMID 19916989. 
  44. ↑ "IMPORTANT DRUG WARNING". Ortho-McNeil Pharmaceutical. 2001. https://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM173936.pdf. 
  45. ↑ "Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register". Neurology 71 (4): 272–276. July 2008. doi:10.1212/01.wnl.0000318293.28278.33. PMID 18645165. 
  46. ↑ Berthier, M.L. and Dávila, G., 2023. Pharmacotherapy for post-stroke aphasia: what are the options?. Expert Opinion on Pharmacotherapy, (just-accepted).
  47. ↑ 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.
  48. ↑ "Suicidality and Antiepileptic Drugs". https://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4344s1_09_01_Trileptal%20slides.pdf. 
  49. ↑ "Topiramate". PubMed Health. National Center for Biotechnology Information, U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000998/. 
  50. ↑ 50.0 50.1 "Acute topiramate overdose--clinical manifestations". Clinical Toxicology 47 (4): 317–320. April 2009. doi:10.1080/15563650601117954. PMID 19514879. 
  51. ↑ 51.0 51.1 51.2 "Clinical outcomes in newer anticonvulsant overdose: a poison center observational study". Journal of Medical Toxicology 10 (3): 254–260. September 2014. doi:10.1007/s13181-014-0384-5. PMID 24515527. 
  52. ↑ 52.0 52.1 "Evaluation of toxicity of topiramate exposures reported to poison centers". Human & Experimental Toxicology 24 (11): 591–595. November 2005. doi:10.1191/0960327105ht561oa. PMID 16323576. Bibcode: 2005HETox..24..591L. 
  53. ↑ 53.0 53.1 "Sex hormones and their modulators". Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. 2009. p. 2068. ISBN 978-0-85369-840-1. 
  54. ↑ "TOPAMAX (topiramate) Tablets Approved Labeling Text". Ortho-McNeil Pharmaceutical. U.S. Food and Drug Administration. 29 June 2005. p. 14. https://www.fda.gov/cder/foi/label/2005/020505s018lbl.pdf. 
  55. ↑ "FDA Data on Topamax". https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020505s038s039,020844s032s034lbl.pdf. 
  56. ↑ "Mechanisms of action of antiseizure drugs". Handb Clin Neurol. Handbook of Clinical Neurology. 108. 2012. pp. 663–681. doi:10.1016/B978-0-444-52899-5.00021-6. ISBN 9780444528995. http://works.bepress.com/michael_rogawski/41/. Retrieved 22 May 2014. 
  57. ↑ "Molecular targets for antiepileptic drug development". Neurotherapeutics 4 (1): 18–61. January 2007. doi:10.1016/j.nurt.2006.11.010. PMID 17199015. 
  58. ↑ "The mechanism of neuroprotection by topiramate in an animal model of epilepsy". Epilepsia 45 (12): 1478–1487. December 2004. doi:10.1111/j.0013-9580.2004.13504.x. PMID 15571505. 
  59. ↑ "[Neuroprotective activity of antiepileptic drugs]". Przeglad Lekarski 61 (11): 1268–1271. 2004. PMID 15727029. 
  60. ↑ "Bioanalytical LC-MS/MS method validation for plasma determination of topiramate in healthy Indian volunteers". Biomedical Chromatography 23 (11): 1227–41. November 2009. doi:10.1002/bmc.1273. PMID 19593736. 
  61. ↑ "Topiramate overdose: a case report of a patient with extremely high topiramate serum concentrations and nonconvulsive status epilepticus". Epilepsia 51 (6): 1090–1093. June 2010. doi:10.1111/j.1528-1167.2009.02395.x. PMID 19889015. 
  62. ↑ Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. 2008. pp. 1567–1569. 
  63. ↑ "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. May 1987. doi:10.1021/jm00388a023. PMID 3572976. 
  64. ↑ "Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives". Journal of Medicinal Chemistry 41 (8): 1315–1343. April 1998. doi:10.1021/jm970790w. PMID 9548821. 
  65. ↑ Models of Seizures and Epilepsy. Burlington: Elsevier. 2005. p. 539. ISBN 9780080457024. https://books.google.com/books?id=Qw6KqLjwtZQC&pg=PA539. Retrieved 17 September 2017. 
  66. ↑ "First-Time Generic Approvals: Seasonale, Imodium Advanced, and Topamax". Medscape.com. 22 September 2006. http://www.medscape.com/viewarticle/544994. 
  67. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". Accessdata.fda.gov. http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=020844&Product_No=002&table1=OB_Rx. 
  68. ↑ "Treatment of civilian and combat-related posttraumatic stress disorder with topiramate". The Annals of Pharmacotherapy 44 (11): 1810–1816. November 2010. doi:10.1345/aph.1P163. PMID 20923947. 
  69. ↑ Roy AK 3rd, Hsieh C, Crapanzano K. Dextromethorphan Addiction Mediated Through the NMDA System: Common Pathways With Alcohol? J Addict Med. 2015 Nov-Dec;9(6):499-501. doi: 10.1097/ADM.0000000000000152. PMID 26441400.
  70. ↑ Management of Infantile Epilepsies (Report). Agency for Healthcare Research and Quality. 25 October 2022. doi:10.23970/ahrqepccer252. 

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