Dr Joe Kiff:
{{Biopsy}}
{{drugbox
| IUPAC_name = 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
| image = Topiramate.svg
| image2 = Topiramate 3D.png
| width = 191
| 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 =
| 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]] drug produced by Ortho-McNeil Neurologics and Noramco, Inc., both being divisions of [Johnson & Johnson. It was discovered in 1979 by Drs. Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceutical.<ref>B. E. Maryanoff, S. O. Nortey, J. F. Gardocki, R. P. Shank, and S. P. Dodgson, "Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds", J. Med. Chem., '''30''', 880-887 (1987)</ref><ref>B. E. Maryanoff, M. J. Costanzo, S. O. Nortey, M. N. Greco, R. P. Shank, J. J. Schupsky, M. E. Ortegon, and J. L. Vaught, "Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives", J. Med. Chem., '''41''', 1315-1343 (1998)</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 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. <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>
==Uses==
This drug is used to treat [[epilepsy]] in both children and adults. In many cases it can also be used as an antidepressant. In children it is also indicated for treatment of [[Lennox-Gastaut syndrome]] (a disorder that causes seizures and developmental delay). It is also [[Food and Drug Administration]] (FDA) approved for, and now most frequently prescribed for, the prevention of [[migraine]]s. It has been used by psychiatrists to treat [[bipolar disorder]],<ref>Kusumakar, V.;Lakshmi, N.;Yatham, MB.;O'Donovan, CA.; Kutcher, SP. 152nd Annual Meeting of the American Psychiatric Association. Washington, DC; 1999. Topiramate in rapid cycling bipolar women.</ref><ref>Marcotte D. Longer term treatment with topiramate for bipolar disorders. Bipolar Disord. 2001;3:46.</ref><ref>Sachs, G.;Koslow, GC.;Orsini, C.;Cosgrove, V.;Sambur, M.;Demopulos, C.; Ghaemi, S. Topiramate shows efficacy in the treatment of refractory bipolar mood disorder. 22nd Congress of the Collegium of Internationale Psychopharmacologieum. Brussels, Belgium. 2000.</ref> although it is not FDA approved for this purpose. This drug has been investigated for use in treatment of obesity,<ref>Van Ameringen M, Mancini C, Pipe B, Campbell M, Oakman J. Topiramate treatment for SSRI-induced weight gain in anxiety disorders. J Clin Psychiatry. 2002;63:981-984.</ref><ref>Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M; OBES-002 Study Group. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004 Nov;28(11):1399-410.</ref> especially to aid in the reduction of [[binge eating]],<ref>Shapira NA, Goldsmith TD, McElroy S. Treatment of binge disorder with topiramate: a clinical case series. J Clin Psychiatry. 2000;61:368-372.</ref><ref>McElroy SL, Arnold LM, Shapira NA, Keck PE, Rosenthal NR, Rezaul Karim M, Kamin M, Hudson JI. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160:255-261.</ref> and also as a possible treatment for alcoholism.<ref>Johnson BA, Ait-Daoud , Bowden CL, DiClemente C, Roache JD, Lawson K, Javors MA, MA JZ. Oral Topiramate in the treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361:1677-85.</ref><ref name="pmid17925516">{{cite journal |author=Johnson BA, Rosenthal N, Capece JA, ''et al.'' |title=Topiramate for treating alcohol dependence: a randomized controlled trial |journal=JAMA |volume=298 |issue=14 |pages=1641–51 |year=2007 |month=October |pmid=17925516 |doi=10.1001/jama.298.14.1641 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17925516}}</ref> However, these uses are not actively promoted by the manufacturer, and like its use for bipolar disorder, are [[Off-label use|off-label]] uses.
The drug is also used in clinical trials to treat [[Post Traumatic Stress Disorder]].<ref>Berlant JL, Van Kammen DP. Open label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry. 2002;63:15-20.</ref> A pilot study suggests that Topiramate is possibly effective against infantile spasms.<ref>Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia. 1998 Dec;39(12):1324-8.</ref> A study by Harvard recommends topiramate as an effective treatment in the prevention of [[Periventricular leukomalacia]] in preterm infants after an [[Hypoxia (medical)|hypoxic]]-[[ischemic]] injury.<ref>Follett PL, Deng W, Dai W, Talos DM, Massillon LJ, Rosenberg PA, Volpe JJ, Jensen FE. Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J Neurosci. 2004 May 5;24(18):4412-20. PMID 15128855</ref> In May 2006 the U.S. National Institutes of Health web site clinicaltrials.gov listed several studies sponsored by Ortho-McNeil which propose to examine the use of topiramate on [[migraine]], [[cluster headache|cluster]],<ref>La'inez MJ, Pascual J, Pascual AM, Santonja JM, Ponz A, Salvador A. Topiramate in the prophylactic treatment of cluster headache. Headache. 2003 Jul-Aug;43(7):784-9.</ref> and severe headaches within various demographics. Other off-label and investigational uses of topiramate include: treatment of [[bulimia nervosa]],<ref>Hoopes SP, Reimherr FW, Hedges DW, Rosenthal NR, Kamin M, Karim R, Capece JA, Karvois D. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 1: improvement in binge and purge measures. J Clin Psychiatry. 2003;64:1335-41.</ref> [[obsessive-compulsive disorder]], [[Alcoholism#Medications|treatment of alcoholism]],<ref>[http://www.cnn.com/2007/HEALTH/conditions/10/09/alcoholism.pill.ap/index.html Study: Migraine pill helps some alcoholics taper off - CNN.com<!-- Bot generated title -->]</ref> [[smoking cessation]],<ref>Khazaal Y, Cornuz J, Bilancioni R, Zullino DF. Topiramate for smoking cessation. Psychiatry Clin Neurosci. 2006 Jun;60(3):384-8.</ref> [[Idiopathic intracranial hypertension|Pseudotumor Cerebri]], and treatment of [[neuropathic pain]].<ref>Chong MS, Libretto SE. The rationale and use of topiramate for treating neuropathic pain. Clin J Pain. 2003 Jan-Feb;19(1):59-68.</ref>
==Pharmacodynamics==
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.
Topiramate enhances [[GABA]]-activated chloride channels. In addition, topiramate inhibits excitatory neurotransmission, through actions on [[kainic acid|kainate]] and [[AMPA receptor]]s. There is evidence that topiramate has a specific effect on GluR5 kainate receptors. 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 the bad taste and the development of [[Kidney stone|renal stones]] 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.<ref name="pmid15571505">{{cite journal |author=Kudin AP, Debska-Vielhaber G, Vielhaber S, Elger CE, Kunz WS |title=The mechanism of neuroprotection by topiramate in an animal model of epilepsy |journal=Epilepsia |volume=45 |issue=12 |pages=1478–87 |year=2004 |month=December |pmid=15571505 |doi=10.1111/j.0013-9580.2004.13504.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0013-9580&date=2004&volume=45&issue=12&spage=1478}}</ref>
It also is a [[sodium channel blocker]].<ref name="urlTopiramate in the Treatment of Sciatica - Full Text View - ClinicalTrials.gov">{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT00011804 |title=Topiramate in the Treatment of Sciatica - Full Text View - ClinicalTrials.gov |format= |work= |accessdate=}}</ref>
==Side effects==
A [[GlaxoSmithKline]]-sponsored Phase IV (post-marketing) study suggested that cognitive side effects may be more common with topiramate than with [[lamotrigine]].<ref>{{cite journal
|author=Blum D, Meador K, Biton V, ''et al.''
|title=Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy
|journal=Neurology
|volume=67
|issue=3
|pages=400–6
|year=2006
|pmid=16894098
|doi=10.1212/01.wnl.0000232737.72555.06
}}
</ref> In studies of healthy volunteers, comparing the two medications, therapeutic doses of topiramate for bipolar disorder produced greater cognitive deficits than lamotrigine, including short term memory loss and word-finding difficulty. This effect has led to the occasional use of the name "dopamax" by some dissatisfied customers. A [[flat affect]] was reported in > 75% patients (n=60).{{Fact|date=May 2007}}
'''The Following side effects have been seen during clinical trials of topamax in preventing frequently recurring migraines:'''
The most often reported effects were: tiredness, pins and needles in the fingers and toes, dizziness, lowered sense of feeling in the skin, difficulty with language, nausea, diarrhea, indigestion, dry mouth, weight loss, decrease in appetite, drowsiness, forgetfulness, difficulty with concentration or attention, difficulty in sleeping (insomnia), anxiety, mood swings, depression, changes in taste and vision disorders.
'''General:'''
Rarely, blood clots have occurred in patients given topamax. However, it has not been proven that these were caused by this medicine. Rarely, blurring of vision and eye pain have been reported.
Rarely and mostly in children, reduced sweating has occurred, mainly during exercise or in warm conditions. If someone taking Topamax becomes flushed or overheated, they should relax in a cool place and drink plenty of water.
Very rarely, drug withdrawal convulsions (fits) have been reported. Psychosis (often with paranoid delusions and prominent visual hallucinations) has also been reported.
Rarely, the inhibition of [[carbonic anhydrase]] may be strong enough to cause [[metabolic acidosis]] of clinical importance.
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%)
The side-effects reported by > 10% of subjects in at least 1 clinical study<ref>{{cite journal
| last = Chengappa
| first = K. N. Roy
| authorlink =
| coauthors = LK Schwarzman, JF Hulihan, J Xiang, NR Rosenthal
| title = Adjunctive Topiramate Therapy in Patients Receiving a Mood Stabilizer fo Bipolar I Disorder: A Randomized Placebo-Controlled Trial
| journal = J Clin Psychiatry
| volume = 67
| issue = 11
| pages = 1703
| publisher = Physicians Postgraduate Press
| month = November | year = 2006
| url =
| doi =
| id = ISSN 0160-6689
| accessdate = }} </ref>
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 Food and Drug Administration (FDA) has issued a notification alerting physicians who prescribe topiramate, and their patients, to the risk of vision loss (blindness). Acute [[myopia]] and secondary angle closure [[glaucoma]], in a small subset of patients who take topiramate regularly, may cause transient (reversible), or permanent, loss of vision. The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. If addressed early in its course, discontinuation of topiramate, along with other measures deemed prudent by the prescribing physician and/or ophthalmologist, may halt the progression of the ocular damage, and may reverse the visual impairment. Patients who take topiramate and who feel pain in or around their eyes, or notice a loss of vision, [[visual acuity]], or blurred vision, are advised to seek consultation with their physician as soon as reasonably possible. 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. All of these conditions should be detected early by performing regular clinical examinations of the patients.
In other postmarketing research, a risk of decreased [[sweating]] and [[hyperthermia]] was discovered. Pediatric patients (children) are especially prone to this side-effect. It is recommended that children treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. All patients, particularly those with other predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of [[kidney stone]] formation.
Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations.<ref name="pmid18645165">{{cite journal |author=Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J, Craig J |title=Preliminary experience from the UK Epilepsy and Pregnancy Register |journal=Neurology |volume=71 |issue=4 |pages=272–276 |year=2008 |pmid=18645165 |doi= 10.1212/01.wnl.0000318293.28278.33|url=http://www.neurology.org/cgi/content/full/71/4/272}}</ref> This might be particularly important for women who take topiramate to prevent migraine attacks.
==Interactions==
* As topiramate inhibits [[carbonic anhydrase]], the concomitant use of other inhibitors of carbonic anhydrase (e.g. [[acetazolamide]]) may lead to an increased risk of renal stones.
* Enzyme inductors (e.g. carbamazepine): The elimination of topiramate may be increased, possibly requiring dose escalations of topiramate.
* [[Phenytoin]]: 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'. Absent from this label is any direct discussion of narcotic (drugs known to promote respiratory acidosis) interactions. This discussion on page 14 is under the topic of Metabolic Acidosis, and is not repeated under the topic of interactions.<ref>[Shttp://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==
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. Recommended increments are 25 to 50 mg every 1 or 2 weeks. Common dosages for maintenance treatment are 100 to 200 mg daily. The highest dosage possible 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{{fact|date=April 2009}}
* 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==
{{reflist|2}}
==External links==
{{Commons cat}}
* [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.loftusmd.com/Articles/AED/topiramate.html Patient oriented article on Topiramate from a neurologist]
* [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}}
{{Bipolar disorder}}
[[Category:Anticonvulsants]]
[[Category:Carbonic anhydrase inhibitors]]
[[Category:Monosaccharides]]
[[Category:Mood stabilizers]]
[[Category:Treatment of bipolar disorder]]
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