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Topiramate

Clinical data
Pregnancy category	AU: B3
Routes of administration	Oral
ATC code	N03AX11 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: WARNINGRx-only
Pharmacokinetic data
Bioavailability	80%
Metabolism	30% hepatic, 70% is excreted unchanged
Elimination half-life	19 to 23 hours
Excretion	70% renal (in urine) in unchanged form
Identifiers
IUPAC name 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
CAS Number	97240-79-4
PubChem CID	5284627
DrugBank	APRD00237
ChemSpider	4447672
UNII	0H73WJJ391
KEGG	D00537
ChEMBL	ChEMBL220492
CompTox Dashboard (EPA)	DTXSID8023688
ECHA InfoCard	100.129.713
Chemical and physical data
Formula	C12H21NO8S
Molar mass	339.363 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES O=S(=O)(OC21OC(O13OC(O3CO2)(C)C)(C)C)N
InChI InChI=1S/C12H21NO8S/c1-10(2)18-7-5-16-12(6-17-22(13,14)15)9(8(7)19-10)20-11(3,4)21-12/h7-9H,5-6H2,1-4H3,(H2,13,14,15)/t7-,8-,9+,12+/m1/s1 Key:KJADKKWYZYXHBB-XBWDGYHZSA-N
(verify)

Topiramate (brand name Topamax) is an anticonvulsant (antiepilepsy) drug. It was originally 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. 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. The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009.

Indications

Topiramate treats epilepsy in children and adults and was originally marketed 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, 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. On May 21, 2010, Ortho-McNeil plead guilty and was fined US$6,140,000 by the FDA for promoting Topamax to treat psychiatric disorders, without applying for any approval and there was no data from any well-controlled clinical trial to demonstrate that Topamax was safe and effective to treat any psychiatric conditions.

This drug has been investigated for use in treating alcoholism and obesity, especially to reduce binge eating.

The drug is also used in clinical trials to treat posttraumatic stress disorder. A pilot study suggested that topiramate is effective against infantile spasms. Another study recommends topiramate as an effective treatment in the prevention of periventricular leukomalacia in preterm infants after an hypoxic-ischemic injury.

Off the label usage

Recent clinical reports indicate that it may have mood stabilizing properties. Other off-label and investigational uses of topiramate include the treatment of essential tremor, bulimia nervosa, obsessive-compulsive disorder, alcoholism, smoking cessation, idiopathic intracranial hypertension, neuropathic pain, cluster headache, and cocaine dependence. 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 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.

The exact mechanism of action is unknown, but four properties that may contribute to topiramate's antiepileptic and antimigraine efficacy include a blockage of voltage-dependent sodium channels, an augmentation of gamma-aminobutyrate acid activity at some subtypes of the GABA- A receptors, antagonism of AMPA/kainate subtype of the glutamate receptor, and inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV .

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.

While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is the only anticonvulsant that does not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect.

Side effects

A GlaxoSmithKline-sponsored Phase IV study suggested that cognitive side effects may be more common with topiramate than with lamotrigine. 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 Listed by prevalence:

• paresthesia (numbness & tingling) (23.7%)
• upper respiratory tract infection (17.5%)
• diarrhea (16.8%)
• nausea (15.4%)
• anorexia (loss of appetite) (13.3%)
• memory problems (11.2%)

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.

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.

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.

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

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.
• Enzyme inducers (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'.
• Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.

Dosage

The exact dosage of Topiramate depends on the diagnosis being treated. 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, but higher doses have been used in patients using Topiramate as a primary seizure medication; doses up to 1600mg/day have been well tolerated.

Overdose

Overdose is rare. In most cases, acute exposure produced only minimal to moderate effects. Fatalities have occurred, but were the result of polydrug exposure.

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
• Fainting
• Upset stomach and stomach pain
• Loss of appetite and vomiting
• Shortness of breath; fast, shallow breathing
• Pounding or irregular heartbeat
• Muscle weakness
• Bone pain

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

Patient warnings

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
• Topiramate may decrease effectiveness of estrogen-containing oral contraceptives
• Topiramate should not be suddenly discontinued, as this may cause increased seizure activity.

References

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
2. 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. PMID 3572976.
3. 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. PMID 9548821.
4. B. E. Maryanoff and J. F. Gardocki, "Anticonvulsant sulfamate derivatives", U.S. Patent 4,513,006 (1985)
5. http://www.medscape.com/viewarticle/544994
6. http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=020844&Product_No=002&table1=OB_Rx
7. Arnone, D (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. PMC 1088011. PMID 15845141.{{cite journal}}: CS1 maint: unflagged free DOI (link)
8. Vasudev, Kamini; MacRitchie, Karine; Geddes, John; Watson, Stuart; Young, Allan H; Young, Allan H (2006). "Topiramate for acute affective episodes in bipolar disorder". doi:10.1002/14651858.CD003384.pub2. {{cite journal}}: Cite journal requires |journal= (help)
9. "Ortho-McNeil Pharmaceutical, LLC Pleads Guilty to Illegal Promotion of Topamax". FDA website. 2010-05-21. Retrieved 2010-05-25.
10. Johnson, BA; Ait-Daoud, N; Bowden, CL; Diclemente, CC; Roache, JD; Lawson, K; Javors, MA; Ma, JZ (2003). "Oral topiramate for treatment of alcohol dependence: a randomised controlled trial". Lancet. 361 (9370): 1677–85. doi:10.1016/S0140-6736(03)13370-3. PMID 12767733.
11. ^ Johnson, BA; Rosenthal, N; Capece, JA; Wiegand, F; Mao, L; Beyers, K; McKay, A; Ait-Daoud, N; Anton, RF (2007). "Topiramate for treating alcohol dependence: a randomized controlled trial". JAMA : the journal of the American Medical Association. 298 (14): 1641–51. doi:10.1001/jama.298.14.1641. PMID 17925516.
12. Van Ameringen, M; Mancini, C; Pipe, B; Campbell, M; Oakman, J (2002). "Topiramate treatment for SSRI-induced weight gain in anxiety disorders". The Journal of clinical psychiatry. 63 (11): 981–4. PMID 12444810.
13. Wilding, J; Van Gaal, L; Rissanen, A; Vercruysse, F; Fitchet, M; Obes-002 Study, Group (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): 1399–410. doi:10.1038/sj.ijo.0802783. PMID 15486569. {{cite journal}}: |first6= has generic name (help)CS1 maint: numeric names: authors list (link)
14. Shapira, NA; Goldsmith, TD; McElroy, SL (2000). "Treatment of binge-eating disorder with topiramate: a clinical case series". The Journal of clinical psychiatry. 61 (5): 368–72. PMID 10847312.
15. McElroy, SL; Arnold, LM; Shapira, NA; Keck Jr, PE; Rosenthal, NR; Karim, MR; Kamin, M; Hudson, JI (2003). "Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial". The American journal of psychiatry. 160 (2): 255–61. PMID 12562571.
16. Berlant, J; Van Kammen, DP (2002). "Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report". The Journal of clinical psychiatry. 63 (1): 15–20. PMID 11838620.
17. Glauser, TA; Clark, PO; Strawsburg, R (1998). "A pilot study of topiramate in the treatment of infantile spasms". Epilepsia. 39 (12): 1324–8. PMID 9860068.
18. Follett, PL; Deng, W; Dai, W; Talos, DM; Massillon, LJ; Rosenberg, PA; Volpe, JJ; Jensen, FE (2004). "Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate". The Journal of neuroscience : the official journal of the Society for Neuroscience. 24 (18): 4412–20. doi:10.1523/JNEUROSCI.0477-04.2004. PMID 15128855.
19. Letmaier, M; Schreinzer, D; Wolf, R; Kasper, S (2001). "Topiramate as a mood stabilizer". International clinical psychopharmacology. 16 (5): 295–8. PMID 11552774.
20. Hoopes, SP; Reimherr, FW; Hedges, DW; Rosenthal, NR; Kamin, M; Karim, R; Capece, JA; Karvois, D (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. PMID 14658948.
21. Khazaal, Y; Cornuz, J; Bilancioni, R; Zullino, DF (2006). "Topiramate for smoking cessation". Psychiatry and clinical neurosciences. 60 (3): 384–8. doi:10.1111/j.1440-1819.2006.01518.x. PMID 16732758.
22. Celebisoy, N; Gökçay, F; Sirin, H; Akyürekli, O (2007). "Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study". Acta neurologica Scandinavica. 116 (5): 322–7. doi:10.1111/j.1600-0404.2007.00905.x. PMID 17922725.
23. Chong, MS; Libretto, SE (2003). "The rationale and use of topiramate for treating neuropathic pain". The Clinical journal of pain. 19 (1): 59–68. PMID 12514458.
24. Láinez, MJ; Pascual, J; Pascual, AM; Santonja, JM; Ponz, A; Salvador, A (2003). "Topiramate in the prophylactic treatment of cluster headache". Headache. 43 (7): 784–9. PMID 12890134.
25. Clinical trial number NCT00685178 for "Clinical Trial of Topiramate for Cocaine Addiction" at ClinicalTrials.gov
26. http://www.rxlist.com/topamax-drug.htm
27. 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. PMID 15571505.
28. Czuczwar, K; Czuczwar, M; Cieszczyk, J; Gawlik, P; Luszczki, JJ; Borowicz, KK; Czuczwar, SJ (2004). "Neuroprotective activity of antiepileptic drugs". Przeglad lekarski. 61 (11): 1268–71. PMID 15727029.
29. Blum, D; Meador, K; Biton, V; Fakhoury, T; Shneker, B; Chung, S; Mills, K; Hammer, A; Isoj�rvi, J (2006). "Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy". Neurology. 67 (3): 400–6. doi:10.1212/01.wnl.0000232737.72555.06. PMID 16894098. {{cite journal}}: replacement character in |last9= at position 5 (help)
30. Roy Chengappa, KN; Schwarzman, LK; Hulihan, JF; Xiang, J; Rosenthal, NR; Clinical Affairs Product Support Study-168 Investigators (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. PMID 17196048.{{cite journal}}: CS1 maint: numeric names: authors list (link)
31. Mirza, Nasir; Marson, Anthony G.; Pirmohamed, Munir (2009). "Effect of topiramate on acid-base balance: extent, mechanism and effects". British Journal of Clinical Pharmacology. 68: 655–61. doi:10.1111/j.1365-2125.2009.03521.x.
32. Hunt, S; Russell, A; Smithson, WH; Parsons, L; Robertson, I; Waddell, R; Irwin, B; Morrison, PJ; Morrow, J (2008). "Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register". Neurology. 71 (4): 272–6. doi:10.1212/01.wnl.0000318293.28278.33. PMID 18645165.
33. http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4344s1_09_01_Trileptal%20slides.pdf
34. FDA.gov
35. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7412
36. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7412
37. http://www.rxlist.com/topamax-drug.htm

External links

• Topamax (topiramate): Treatment for Migraine Prevention
• Topamax: Treatment for Epilepsy
• Currently listed clinical trials related to topiramate
• FDA topiramate safety
• MSN article
• Effects of topiramate
• MedlinePlus: Topiramate
• FAQ: Topiramate (Topamax), Mood Disorders and PTSD
• RxList.com: Topiramate
• Focus on Topiramate - a new anti-epileptic, Ben Green, Priory Lodge Education Ltd., 1997-99. Version 1.1

• Anticonvulsants
• Carbonic anhydrase inhibitors
• Monosaccharide derivatives
• Mood stabilizers
• Treatment of bipolar disorder