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Topiramate
Systematic (IUPAC) name
2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
Identifiers
CAS number 97240-79-4
ATC code N03AX11
PubChem 5284627
DrugBank APRD00237
ChemSpider 4447672
Chemical data
Formula C12H21NO8S 
Mol. mass 339.363 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 80%
Metabolism 30% hepatic, 70% is excreted unchanged
Half life 19 to 23 hours
Excretion 70% renal (in urine) in unchanged form
Therapeutic considerations
Pregnancy cat. B3(AU) C(US)
Legal status POM (UK) -only (US)
Routes Oral
 Yes check.svgY(what is this?)  (verify)

Topiramate (brand name Topamax) is an anticonvulsant drug produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of Johnson & Johnson. It was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceutical.[1][2][3] Generic versions are available in Canada and were FDA approved in September 2006. Mylan Pharmaceuticals was recently granted final approval for generic topiramate 25, 100, and 200 mg tablets and sprinkle capsules by the FDA for sale in the US. 50 mg tablets were granted tentative approval.[4] The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009.[5]

Contents

Uses

Topiramate treats epilepsy in children and adults and was originally marked as an anticonvulsant. In children it is indicated for the treatment of Lennox-Gastaut syndrome, a disorder that causes seizures and developmental delay. It is also Food and Drug Administration (FDA) approved for, and most frequently prescribed for, the prevention of migraines. Psychiatrists have used topiramate to treat bipolar disorder,[6] and often use topiramate to augment psychotrophics or counteract weight gain associated with numerous antidepressants. However, a 2006 Cochrane review concluded that there is insufficient evidence on which to base any recommendations regarding the use of topiramate in any phase of bipolar illness.[7]

This drug has been investigated for use in treating alcoholism[8][9] and obesity,[10][11] especially to reduce binge eating.[12][13]

The drug is also used in clinical trials to treat posttraumatic stress disorder.[14] A pilot study suggested that topiramate is effective against infantile spasms.[15] Another study recommends topiramate as an effective treatment in the prevention of periventricular leukomalacia in preterm infants after an hypoxic-ischemic injury.[16] Other off-label and investigational uses of topiramate include the treatment of essential tremor, bulimia nervosa,[17] obsessive-compulsive disorder, alcoholism,[9] smoking cessation,[18] idiopathic intracranial hypertension [19], neuropathic pain,[20] cluster headache,[21] and cocaine dependence.[22] Topiramate is also being studied with a mixture of phentermine to form a drug called Qnexa for the treatment of obesity.

Pharmacology

Chemically, topiramate is a sulfamate-substituted monosaccharide, related to fructose, a rather unusual chemical structure for an anticonvulsant.

Topiramate is quickly absorbed after oral use. Most of the drug (70%) is excreted in the urine as unchanged drug. 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.

Topiramate has a complex mechanism of action [23] The drug enhances GABA-activated chloride channels. In addition, it inhibits excitatory neurotransmission, through actions on kainate and AMPA receptors (but not NMDA receptors). There is evidence that topiramate has a specific effect on GluK1 (GluR5) kainate receptors.[24] It is also an inhibitor of carbonic anhydrase, particularly subtypes II and IV, but this action is weak and unlikely to be related to its anticonvulsant actions, but may account for some of the side effects seen during treatment. Its possible effect as a mood stabilizer seems to occur before anticonvulsant qualities at lower dosages. 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.[25]

Side effects

A GlaxoSmithKline-sponsored Phase IV study suggested that cognitive side effects may be more common with topiramate than with lamotrigine.[26] In studies of healthy volunteers, therapeutic doses of topiramate for bipolar disorder produced greater cognitive deficits than lamotrigine, including short term memory loss and word-finding difficulty.

The side-effects reported by > 10% of subjects in at least 1 clinical study[27] Listed by prevalence: (*indicates placebo rate [%] is the same or higher than side-effect rate)

  • headache (23.8%) *[25.9%]
  • paresthesia (numbness & tingling) (23.1%)
  • upper respiratory tract infection (17.5%)
  • diarrhea (16.8%)
  • nausea (15.4%)
  • somnolence (15.4%) *[16.1%]
  • anorexia (loss of appetite) (13.3%) *[5.6%]
  • insomnia (11.9%) *[11.2%]
  • memory problems (11.2%)
  • dizziness (10.5%) *[10.5]

The side-effects most frequently leading to discontinuation of therapy with topiramate were:

  • Psychomotor slowing (4.1%)
  • Memory problems (3.3%)
  • Fatigue (3.3%)
  • Confusion (3.2%)
  • Somnolence (3.2%)

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

The 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. According to the FDA: "in more than 825,000 patients...As of August 17, 2001 there have been 23 reported cases: 22 in adults and 1 in pediatric patients. It is generally recognized that postmarketing data are subject to substantial under-reporting."

Another serious side-effect is the development of osteoporosis in adults and children (bones affected break more easily) and rickets (abnormal, deformed growth of bones) in children. Topiramate may also slow the growth of children.

In other postmarketing research, a risk of decreased sweating and hyperthermia was discovered. Pediatric patients (children) are especially prone to this side-effect.

Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations.[28] This might be particularly important for women who take topiramate to prevent migraine attacks.

Most antiepileptic drugs have been associated with a statistically significant increase in suicidality, including topiramate.[29]

Interactions

  • As topiramate inhibits carbonic anhydrase, use with other inhibitors of carbonic anhydrase (e.g. acetazolamide) increases the risk of kidney stones.
  • Enzyme inductors (e.g. carbamazepine) can increase the elimination of topiramate, possibly necessitating dose escalations of topiramate.
  • Topiramate may increase the plasma-levels of phenytoin.
  • Topiramate itself is a weak inhibitor of CYP2C19 and induces CYP3A4. Under topiramate a decrease of plasma-levels of estrogens (e.g. 'the pill') and digoxin have been noted.
  • Alcohol may cause increased sedation or drowsiness, and increase the risk of having a seizure.
  • As listed in the 06/29/2005 label posted at the Drugs@FDA website page 14,'conditions or therapies that predispose to acidosis may be additive to the bicarbonate lowering effects of Topiramate'.[30]
  • Oligohydrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.

Dosage

In order to avoid early side-effects (e.g. cognitive dysfunction) the initial dosage normally is low and increased in slow steps. The usual initial dosage is 25 to 50 mg daily in 2 single doses. Common dosages for maintenance treatment are 100 to 200 mg daily. The highest dosage recommended is 400 mg daily in divided doses.

Overdose

Symptoms of overdose may include but are not limited to:

  • Agitation
  • Depression
  • Speech problems
  • Blurred vision, double vision
  • Troubled thinking
  • Loss of coordination
  • Inability to respond to things around you
  • Loss of consciousness
  • Confusion and coma[citation needed]
  • Fainting
  • Upset stomach and stomach pain
  • Loss of appetite and vomiting
  • Excessive hunger
  • Shortness of breath; fast, shallow breathing
  • Pounding or irregular heartbeat
  • Muscle weakness
  • Bone pain

A specific antidote is not available. Treatment is entirely symptomatic.

References

  1. ^ 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): 880–7. doi:10.1021/jm00388a023. ISSN 0022-2623. PMID 3572976.  edit
  2. ^ Maryanoff, E.; Costanzo, J.; Nortey, O.; Greco, N.; Shank, P.; Schupsky, J.; Ortegon, P.; Vaught, L. (Apr 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. ISSN 0022-2623. PMID 9548821.  edit
  3. ^ B. E. Maryanoff and J. F. Gardocki, "Anticonvulsant sulfamate derivatives", U.S. Patent 4,513,006 (1985)
  4. ^ http://www.medscape.com/viewarticle/544994
  5. ^ http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=020844&Product_No=002&table1=OB_Rx
  6. ^ Arnone, D (Feb 2005). "Review of the use of Topiramate for treatment of psychiatric disorders". Annals of general psychiatry 4 (1): 5. doi:10.1186/1744-859X-4-5. PMID 15845141.  edit
  7. ^ Vasudev K, Macritchie K, Geddes J, Watson S, Young AH. Topiramate for acute affective episodes in bipolar disorder. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD003384. DOI: 10.1002/14651858.CD003384.pub2.
  8. ^ Johnson, B.; Aitdaoud, N.; Bowden, C.; Diclemente, C.; Roache, J.; Lawson, K.; Javors, M.; Ma, J. (2003). "Oral topiramate for treatment of alcohol dependence: a randomised controlled trial". The Lancet 361: 1677–1685. doi:10.1016/S0140-6736(03)13370-3.  edit
  9. ^ a b Johnson, B. A.; Rosenthal, N.; Capece, J. A.; Wiegand, F.; Mao, L.; Beyers, K.; McKay, A.; Ait-daoud, N. et al. (Oct 2007). "Topiramate for treating alcohol dependence: a randomized controlled trial" (Free full text). JAMA : the journal of the American Medical Association 298 (14): 1641–1651. doi:10.1001/jama.298.14.1641. ISSN 0098-7484. PMID 17925516. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17925516.  edit
  10. ^ Van, Ameringen; Mancini, C; Pipe, B; Campbell, M; Oakman, J (Nov 2002). "Topiramate treatment for SSRI-induced weight gain in anxiety disorders". The Journal of clinical psychiatry 63 (11): 981–4. ISSN 0160-6689. PMID 12444810.  edit
  11. ^ Wilding, J.; Van Gaal, L.; Rissanen, A.; Vercruysse, F.; Fitchet, M.; Obes-002 Study, P. (Nov 2004). "A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects". International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 28 (11): 1399–1410. doi:10.1038/sj.ijo.0802783. ISSN 0307-0565. PMID 15486569.  edit
  12. ^ Shapira NA, Goldsmith TD, McElroy SL (May 2000). "Treatment of binge-eating disorder with topiramate: a clinical case series". The Journal of Clinical Psychiatry 61 (5): 368–72. PMID 10847312.  edit
  13. ^ McElroy, Sl; Arnold, Lm; Shapira, Na; Keck, Pe; Rosenthal, Nr; Karim, Mr; Kamin, M; Hudson, Ji (Feb 2003). "Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial" (Free full text). The American journal of psychiatry 160 (2): 255–61. doi:10.1176/appi.ajp.160.2.255. ISSN 0002-953X. PMID 12562571. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=.  edit
  14. ^ Berlant, J; Van, Kammen (Jan 2002). "Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report" (Free full text). The Journal of clinical psychiatry 63 (1): 15–20. ISSN 0160-6689. PMID 11838620. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+7660-25-5.  edit
  15. ^ Glauser, Ta; Clark, Po; Strawsburg, R (Dec 1998). "A pilot study of topiramate in the treatment of infantile spasms". Epilepsia 39 (12): 1324–8. doi:10.1111/j.1528-1157.1998.tb01331.x. ISSN 0013-9580. PMID 9860068.  edit
  16. ^ Follett, L.; Deng, W.; Dai, W.; Talos, M.; Massillon, J.; Rosenberg, A.; Volpe, J.; Jensen, E. (May 2004). "Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate" (Free full text). The Journal of neuroscience : the official journal of the Society for Neuroscience 24 (18): 4412–4420. doi:10.1523/JNEUROSCI.0477-04.2004. ISSN 0270-6474. PMID 15128855. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15128855.  edit
  17. ^ Hoopes, Sp; Reimherr, Fw; Hedges, Dw; Rosenthal, Nr; Kamin, M; Karim, R; Capece, Ja; Karvois, D (Nov 2003). "Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 1: improvement in binge and purge measures". The Journal of clinical psychiatry 64 (11): 1335–41. ISSN 0160-6689. PMID 14658948.  edit
  18. ^ Khazaal, Y.; Cornuz, J.; Bilancioni, R.; Zullino, F. (Jun 2006). "Topiramate for smoking cessation". Psychiatry and clinical neurosciences 60 (3): 384–388. doi:10.1111/j.1440-1819.2006.01518.x. ISSN 1323-1316. PMID 16732758.  edit
  19. ^ http://www.ncbi.nlm.nih.gov/pubmed/17922725
  20. ^ Chong, Ms; Libretto, Se (Jan 2003). "The rationale and use of topiramate for treating neuropathic pain". The Clinical journal of pain 19 (1): 59–68. doi:10.1097/00002508-200301000-00008. ISSN 0749-8047. PMID 12514458.  edit
  21. ^ Láinez, Mj; Pascual, J; Pascual, Am; Santonja, Jm; Ponz, A; Salvador, A (Jul 2003). "Topiramate in the prophylactic treatment of cluster headache". Headache 43 (7): 784–9. doi:10.1046/j.1526-4610.2003.03137.x. ISSN 0017-8748. PMID 12890134.  edit
  22. ^ http://clinicaltrials.gov/ct2/show/NCT00685178?recr=Open&intr=%22Cocaine%22&rank=20
  23. ^ Rogawski, A.; Löscher, W. (Jul 2004). "The neurobiology of antiepileptic drugs". Nature reviews. Neuroscience 5 (7): 553–564. doi:10.1038/nrn1430. ISSN 1471-003X. PMID 15208697.  edit
  24. ^ Braga, F.; Aroniadou-Anderjaska, V.; Li, H.; Rogawski, A. (Aug 2009). "Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons". The Journal of pharmacology and experimental therapeutics 330 (2): 558–566. doi:10.1124/jpet.109.153908. ISSN 0022-3565. PMID 19417176.  edit
  25. ^ Kudin, P.; Debska-Vielhaber, G.; Vielhaber, S.; Elger, E.; Kunz, S. (Dec 2004). "The mechanism of neuroprotection by topiramate in an animal model of epilepsy". Epilepsia 45 (12): 1478–1487. doi:10.1111/j.0013-9580.2004.13504.x. ISSN 0013-9580. PMID 15571505.  edit
  26. ^ Blum, D.; Meador, K.; Biton, V.; Fakhoury, T.; Shneker, B.; Chung, S.; Mills, K.; Hammer, A. et al. (Aug 2006). "Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy". Neurology 67 (3): 400–406. doi:10.1212/01.wnl.0000232737.72555.06. ISSN 0028-3878. PMID 16894098.  edit
  27. ^ Roy, Chengappa; Schwarzman, Lk; Hulihan, Jf; Xiang, J; Rosenthal, Nr; Clinical, Affairs (Nov 2006). "Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial". The Journal of clinical psychiatry 67 (11): 1698–706. ISSN 0160-6689. PMID 17196048.  edit
  28. ^ Hunt, S.; Russell, A.; Smithson, H.; Parsons, L.; Robertson, I.; Waddell, R.; Irwin, B.; Morrison, J. et al. (Jul 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. ISSN 0028-3878. PMID 18645165.  edit
  29. ^ http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4344s1_09_01_Trileptal%20slides.pdf
  30. ^ FDA.gov

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