View source for Topiramate

{{drugbox
| verifiedrevid = 308503753
| IUPAC_name = 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
| image = Topiramate.svg
| image2 = Topiramate 3D.png
| width = 191
| CASNo_Ref = {{cascite}}
| CAS_number = 97240-79-4
| ChemSpiderID = 4447672
| ATC_prefix = N03
| ATC_suffix = AX11
| ATC_supplemental = 
| PubChem = 5284627
| DrugBank = APRD00237
| C = 12 | H = 21 | N = 1 | O = 8 | S = 1
| molecular_weight = 339.363 g/mol
| smiles = NS(=O)(=O)OC[C@@]13OC(C)(C)O[C@H]3C2OC(C)(C)OC2CO1
| bioavailability = 80%
| protein_bound = 
| metabolism = 30% hepatic, 70% is excreted unchanged
| elimination_half-life = 19 to 23 hours
| pregnancy_AU = B3
| pregnancy_US = C
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral
| excretion = 70% renal (in urine) in unchanged form
}}

'''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.<ref>{{cite pmid|3572976}}</ref><ref>{{cite pmid|9548821}}</ref><ref>B. E. Maryanoff and J. F. Gardocki, "Anticonvulsant sulfamate derivatives", U.S. Patent 4,513,006 (1985)</ref> Generic versions are available in Canada and were FDA approved in September 2006. [[Mylan Inc.|Mylan Pharmaceuticals]] was recently granted final approval for generic topiramate 25, 100, and 200&nbsp;mg tablets and sprinkle capsules by the FDA for sale in the US. 50&nbsp;mg tablets were granted tentative approval.<ref>http://www.medscape.com/viewarticle/544994</ref> The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009.<ref>http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=020844&Product_No=002&table1=OB_Rx</ref>  

==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 [[migraine]]s.  Psychiatrists have used topiramate to treat [[bipolar disorder]],<ref>{{cite pmid|15845141}}</ref> 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.<ref>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.</ref> On May 21, 2010, Ortho-McNeil plead guilty and was fined {{currency|6.14 million|US}} 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.<ref>{{cite web|date=2010-05-21|accessdate=2010-05-25|title=Ortho-McNeil Pharmaceutical, LLC Pleads Guilty to Illegal Promotion of Topamax|work=FDA website|url=http://www.fda.gov/ICECI/CriminalInvestigations/ucm213163}}</ref> 

This drug has been investigated for use in treating alcoholism<ref>{{cite pmid|12767733}}</ref><ref name="Alc">{{cite pmid|17925516}}</ref> and obesity,<ref>{{cite pmid|12444810}}</ref><ref>{{cite pmid|15486569}}</ref> especially to reduce [[binge eating]].<ref>{{cite pmid|10847312}}</ref><ref>{{cite pmid|12562571}}</ref>

The drug is also used in clinical trials to treat [[posttraumatic stress disorder]].<ref>{{cite pmid|11838620}}</ref> A pilot study suggested that topiramate is effective against infantile spasms.<ref>{{cite pmid|9860068}}</ref>  Another study recommends topiramate as an effective treatment in the prevention of [[periventricular leukomalacia]] in preterm infants after an [[Hypoxia (medical)|hypoxic]]-[[ischemic]] injury.<ref>{{cite pmid|15128855}}</ref> Other off-label and investigational uses of topiramate include the treatment of [[essential tremor]], [[bulimia nervosa]],<ref>{{cite pmid|14658948}}</ref> [[obsessive-compulsive disorder]], [[alcoholism]],<ref name="Alc"/> [[smoking cessation]],<ref>{{cite pmid|16732758}}</ref> [[idiopathic intracranial hypertension]] <ref>http://www.ncbi.nlm.nih.gov/pubmed/17922725</ref>, [[neuropathic pain]],<ref>{{cite pmid|12514458}}</ref> cluster headache,<ref>{{cite pmid|12890134}}</ref> and [[cocaine]] dependence.<ref>http://clinicaltrials.gov/ct2/show/NCT00685178?recr=Open&intr=%22Cocaine%22&rank=20</ref>  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 [[sulfamic acid|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 [[metabolite]]s have been identified in humans, none of which constitutes more than 5% of an administered dose. 

The exact mechanism of action is unknown,<ref>http://www.rxlist.com/topamax-drug.htm</ref> 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.<ref name="pmid15571505">{{cite pmid|15571505}}</ref>

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.<ref name="Czuczwar-2004">{{Cite journal | last1 = Czuczwar | first1 = K. | last2 = Czuczwar | first2 = M. | last3 = Cieszczyk | first3 = J. | last4 = Gawlik | first4 = P. | last5 = Luszczki | first5 = JJ. | last6 = Borowicz | first6 = KK. | last7 = Czuczwar | first7 = SJ. | title = [Neuroprotective activity of antiepileptic drugs] | journal = Przegl Lek | volume = 61 | issue = 11 | pages = 1268–71 | month =  | year = 2004 | doi =  | pmid = 15727029 }}</ref>

==Side effects==
A [[GlaxoSmithKline]]-sponsored [[Clinical trial#Phase IV|Phase IV]] study suggested that cognitive side effects may be more common with topiramate than with [[lamotrigine]].<ref>{{cite pmid|16894098}}</ref> 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<ref>{{cite pmid|17196048}}</ref>
Listed by prevalence:

* [[paresthesia]] (numbness & tingling) (23.1%)
* [[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 disorders|psychomotor slowing]] (4.1%) 
* memory problems (3.3%) 
* [[Fatigue (medical)|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.<ref>{{cite journal | author = Mirza N, Marson AG, Pirmohamed M. | journal = Br J Clin Pharmacol | year = 2009 | volume = 68 | issue = 5 | pages = 655–61 | doi = 10.1111/j.1365-2125.2009.03521.x | pmid = 19916989 | title = Effect of topiramate on acid-base balance: extent, mechanism and effects. | pmc = 2791971}}</ref>

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.{{Citation needed|date=June 2010}} 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.<ref name="pmid18645165">{{cite pmid|18645165}}</ref> This might be particularly important for women who take topiramate to prevent migraine attacks.

Most antiepileptic drugs, including topiramate, have been associated with a [[statistical significance|statistically significant]] increase in [[suicide|suicidality]].<ref>http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4344s1_09_01_Trileptal%20slides.pdf</ref>

==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 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'.<ref>[http://www.fda.gov/cder/foi/label/2005/020505s018lbl.pdf FDA.gov]</ref>
* Oligohydrosis 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&nbsp;mg daily in 2 single doses. Common dosages for maintenance treatment are 100 to 200&nbsp;mg daily. The highest dosage recommended is 400&nbsp;mg daily in divided doses, but higher doses have been used in patients using Topiramate as a primary seizure medication, doses upto 1600mg/day have been well tolerated.<ref>http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7412</ref>

==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:<ref>http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7412</ref>

* 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.<ref>http://www.rxlist.com/topamax-drug.htm</ref>

==References==
{{Reflist|2}}

==External links==
{{Commons category}}
* [http://www.topamax.com Topamax (topiramate): Treatment for Migraine Prevention]
* [http://www.topamax-epilepsy.com Topamax: Treatment for Epilepsy]
* [http://www.clinicaltrials.gov/ct/gui/search?term=topiramate&submit=Search Currently listed clinical trials related to topiramate]
* [http://www.fda.gov/medwatch/safety/2001/topamax.htm FDA topiramate safety]
* [http://content.health.msn.com/content/article/70/81128.htm MSN article]
* [http://www.mdsupport.org/library/effects.html Effects of topiramate]
* [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a697012.html MedlinePlus: Topiramate]
* [http://www.psycom.net/depression.central.topiramate.html FAQ: Topiramate (Topamax), Mood Disorders and PTSD]
* [http://www.rxlist.com/cgi/generic2/topiram_cp.htm RxList.com: Topiramate]
* [http://www.priory.com/focus7.htm Focus on Topiramate - a new anti-epileptic], Ben Green, Priory Lodge Education Ltd., 1997-99. Version 1.1

{{Anticonvulsants}}
{{Mood stabilizers}}
{{Bipolar disorder}}
{{Antimigraine preparations}}

[[Category:Anticonvulsants]]
[[Category:Carbonic anhydrase inhibitors]]
[[Category:Monosaccharides]]
[[Category:Mood stabilizers]]
[[Category:Treatment of bipolar disorder]]

[[de:Topiramat]]
[[es:Topiramato]]
[[fr:Topiramate]]
[[it:Topiramato]]
[[hu:Topiramát]]
[[nl:Topiramaat]]
[[no:Topiramat]]
[[ru:Топирамат]]
[[sv:Topiramat]]
[[Category:2Fix]]