Topiramate

Topiramate (brand name Topamax) is an anticonvulsant drug produced by Ortho-McNeil Neurologics and Noramco, Inc., both being divisions of Johnson & Johnson. 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. ^[1] It was discovered in 1979 by Drs. Bruce E. Maryanoff and Joseph F. Gardocki during their research work in McNeil Pharmaceutical.^[2]^[3]^[4]

Uses

This drug is used to treat epilepsy in both children and adults. 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 migraines. It has been used by psychiatrists to treat bipolar disorder,^[5]^[6]^[7] although it is not FDA approved for this purpose. This drug has been investigated for use in treatment of obesity,^[8]^[9] especially to aid in the reduction of binge eating,^[10]^[11] and also as a possible treatment for alcoholism.^[12]^[13] However, these uses are not actively promoted by the manufacturer, and like its use for bipolar disorder, are off-label uses.

Pharmacodynamics

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 enhances GABA-activated chloride channels. In addition, topiramate inhibits excitatory neurotransmission, through actions on kainate and AMPA receptors. 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 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.

Side effects

A GlaxoSmithKline-sponsored Phase IV (post-marketing) study suggested that cognitive side effects may be more common with topiramate than with lamotrigine.^[24] 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).^{citation needed}

The Following side effects have been seen during clinical trials of topamax in preventing frequently recurring migrainnes: 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, diarrhoea, indigestion, dry mouth, weight lost, 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.

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

The side-effects reported by > 10% of subjects in at least 1 clinical study^[25] Listed by prevalence: (*indicates placebo rate [%] is the same or higher than side-effect rate)

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.^[26] This might be particularly important for women who take topiramate to prevent migraine attacks.

Interactions

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 50mg every 1 or 2 weeks. Common dosages for maintenance treatment are 100 to 200 mg daily. The highest dosage possible is 1,000 mg daily in divided doses.

Overdose

References

^ http://www.medscape.com/viewarticle/544994
^ 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)
^ 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)
^ B. E. Maryanoff and J. F. Gardocki, "Anticonvulsant sulfamate derivatives", U.S. Patent 4,513,006 (1985)
^ 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.
^ Marcotte D. Longer term treatment with topiramate for bipolar disorders. Bipolar Disord. 2001;3:46.
^ 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.
^ 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.
^ 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.
^ Shapira NA, Goldsmith TD, McElroy S. Treatment of binge disorder with topiramate: a clinical case series. J Clin Psychiatry. 2000;61:368-372.
^ 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.
^ 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.
^ Johnson BA, Rosenthal N, Capece JA, et al (October 2007). "Topiramate for treating alcohol dependence: a randomized controlled trial". JAMA 298 (14): 1641–51. doi:10.1001/jama.298.14.1641. PMID 17925516.
^ 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.
^ Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia. 1998 Dec;39(12):1324-8.
^ 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
^ 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.
^ 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.
^ Study: Migraine pill helps some alcoholics taper off - CNN.com
^ Khazaal Y, Cornuz J, Bilancioni R, Zullino DF. Topiramate for smoking cessation. Psychiatry Clin Neurosci. 2006 Jun;60(3):384-8.
^ Chong MS, Libretto SE. The rationale and use of topiramate for treating neuropathic pain. Clin J Pain. 2003 Jan-Feb;19(1):59-68.
^ Kudin AP, Debska-Vielhaber G, Vielhaber S, Elger CE, Kunz WS (December 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.
^ "Topiramate in the Treatment of Sciatica - Full Text View - ClinicalTrials.gov".
^ Blum D, Meador K, Biton V, et al (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.
^ Chengappa, K. N. Roy; LK Schwarzman, JF Hulihan, J Xiang, NR Rosenthal (November 2006). "Adjunctive Topiramate Therapy in Patients Receiving a Mood Stabilizer fo Bipolar I Disorder: A Randomized Placebo-Controlled Trial". J Clin Psychiatry 67 (11): 1703. Physicians Postgraduate Press. ISSN 0160-6689.
^ Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J, Craig J (2008). "Preliminary experience from the UK Epilepsy and Pregnancy Register". Neurology 71 (4): 272-276. PMID 18645165.
^ [Shttp://www.fda.gov/cder/foi/label/2005/020505s018lbl.pdf FDA.gov]

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