Topiramate

1
Topiramate
Topiramate
Systematic (IUPAC) name
2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
Clinical data
Trade names Topamax
AHFS/Drugs.com
monograph
[1]
MedlinePlus
a697012
[2]
Licence data
USFDA:link
[3]
Pregnancy cat. D (AU) D (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 80%
Protein binding 13-17%; 15-41%
Metabolism Hepatic (20-30%)
Half-life 19-25 hours
Excretion Urine (70-80%)
Identifiers
CAS number
97240-79-4
[4]

ATC code
N03AX11
[5]
PubChem
CID 5284627
[6]
DrugBank
DB00273
[7]
ChemSpider
4447672
[8]

Topiramate
2
UNII
0H73WJJ391
[9]

KEGG
D00537
[10]

ChEMBL
CHEMBL220492
[11]

Chemical data
Formula C
12
H
21
NO
8
S
Mol. mass 339.363 g/mol
(what is this?) (verify)
[12]
Topiramate (brand name Topamax) is an anticonvulsant (antiepilepsy) drug. In late 2012, topiramate was approved
by the United States Food and Drug Administration (FDA) in combination with phentermine for weight loss. The
drug had previously been used off-label for this purpose. Topiramate was originally produced by Ortho-McNeil
Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was
discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil
Pharmaceutical.
[13]
Topiramate was first approved in the US in 1996. Generic versions are available in Canada and
these were approved by the FDA in September 2006. Mylan Pharmaceuticals was recently granted final approval for
generic topiramate 25, 100, and 200mg tablets and sprinkle capsules by the FDA for sale in the United States. 50mg
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.
[14]
Medical uses
Topiramate is used to treat epilepsy in children and adults, and it was originally used 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, although the available
evidence does not support its use in any phase of bipolar disorder treatment. A more recent review, published in
2010, suggested a benefit of topiramate in the treatment of symptoms of borderline personality disorder, however the
authors note that this was based only on one randomized controlled trial and requires replication. Also the Authors
noted that the long-term effects have not been studied.
This drug has been used successfully as a treatment for alcoholism, methamphetamine addiction, cocaine addiction,
obesity and antipsychotic-induced weight gain. This drug is also widely used to treat migraines due to the effect it
has on the blood vessels in the brain. It is used as a preventative for atypical migraine sufferers. It widens the blood
vessels in the brain which become restricted by increased serotonin levels. It has been found to be increasingly
effective for migraine sufferers with limited side effects.
The drug is also used in clinical trials to treat post traumatic 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.
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, smoking
cessation, idiopathic intracranial hypertension and cluster headache Topiramate has not been shown to work as a
pain medicine in diabetic neuropathy, the only neuropathic condition in which it has been adequately tested.
Topiramate
3
Adverse effects
A GlaxoSmithKline-sponsored Phase IV study suggested that cognitive side effects may be more common with
topiramate than with lamotrigine.
Adverse effects by incidence:
Very common (>10% incidence) adverse effects include:
Dizziness
Weight loss
Paraesthesia
Somnolence
Nausea
Diarrhea
Fatigue
Nasopharyngitis
Depression
Common (1-10% incidence) adverse effects include:
Weight gain
Anaemia
Disturbance in attention
Memory impairment
Amnesia
Cognitive disorder
Mental impairment
Psychomotor skills impaired
Convulsion
Coordination abnormal
Tremor
Lethargy
Hypoaesthesia
Nystagmus
Dysgeusia
Balance disorder
Dysarthria
Intention tremor
Sedation
Vision blurred
Diplopia
Visual disturbance
Vertigo
Tinnitus
Ear pain
Dyspnoea
Epistaxis
Nasal congestion
Rhinorrhoea
Vomiting
Constipation
Topiramate
4
Abdominal pain upper
Dyspepsia
Abdominal pain
Dry mouth
Stomach discomfort
Paraesthesia oral
Gastritis
Abdominal discomfort
Nephrolithiasis
Pollakisuria
Dysuria
Alopecia (hair loss)
Rash
Pruritus
Arthralgia
Muscle spasms
Myalgia
Muscle twitching
Muscular weakness
Musculoskeletal chest pain
Anorexia
Decreased appetite
Pyrexia
Asthenia
Irritability
Gait disturbance
Feeling abnormal
Malaise
Hypersensitivity
Bradyphrenia
Insomnia
Expressive language disorder
Anxiety
Confusional state
Disorientation
Aggression
Mood altered
Agitation
Mood swings
Anger
Abnormal behaviour
Uncommon (0.1-1% incidence) adverse effects include:
Crystal urine present
Tandem gait test abnormal
White blood cell count decreased
Bradycardia
Sinus bradycardia
Topiramate
5
Palpitations
Leucopenia
Thrombocytopenia
Lymphadenopathy
Eosinophilia
Depressed level of consciousness
Grand mal convulsion
Visual field defect
Complex partial seizures
Speech disorder
Psychomotor hyperactivity
Syncope, sensory disturbance
Drooling
Hypersomnia
Aphasia
Repetitive speech
Hypokinesia
Dyskinesia
Dizziness postural
Poor quality sleep
Burning sensation
Sensory loss
Parosmia
Cerebellar syndrome
Dysaesthesia
Hypogeusia
Stupor
Clumsiness
Aura
Ageusia
Dysgraphia
Dysphasia
Neuropathy peripheral
Presyncope
Dystonia
Formication (the sensation of insects crawling under the skin)
Visual acuity reduced
Scotoma
Myopia
Abnormal sensation in eye
Dry eye
Photophobia
Blepharospasm
Lacrimation increased
Photopsia
Mydriasis
Presbyopia
Topiramate
6
Deafness
Deafness unilateral
Deafness neurosensory
Ear discomfort
Hearing impaired
Dyspnoea exertional
Paranasal sinus hypersecretion
Dysphonia
Pancreatitis
Flatulence
Gastrooesophageal reflux disease
Abdominal pain lower
Hypoaesthesia oral
Gingival bleeding
Abdominal distension
Epigastric discomfort
Abdominal tenderness
Salivary hypersecretion
Oral pain
Breath odour
Glossodynia
Calculus urinary
Urinary incontinence
Haematuria (blood in urine)
Incontinence
Micturition urgency
Renal colic
Renal pain
Anhidrosis
Hypoaesthesia facial
Urticaria
Erythema
Pruritus generalized
Rash macular
Skin discolouration
Allergic dermatitis
Swelling face
Joint swelling
Musculoskeletal stiffness
Flank pain
Muscle fatigue
Metabolic acidosis
Hypokalaemia
Increased appetite
Polydipsia
Hypotension
Orthostatic hypotension flushing
Topiramate
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Hot flush
Hyperthermia
Thirst
Influenza like illness
Sluggishness
Peripheral coldness
Feeling drunk
Feeling jittery
Learning disability
Erectile dysfunction
Sexual dysfunction
Suicidal ideation
Suicide attempt
Hallucination
Psychotic disorder
Apathy
Lack of spontaneous speech
Sleep disorder
Affect lability
Libido decreased
Restlessness
Crying
Dysphemia
Euphoric mood
Paranoia
Perseveration
Panic attack
Tearfulness
Reading disorder
Initial insomnia
Flat affect
Thinking abnormal
Loss of libido
Listless
Middle insomnia
Distractibility
Early morning awakening
Panic reaction
Elevated mood
Rare (0.01-0.1% incidence) adverse effects include:
Blood bicarbonate decreased
Neutropaenia
Apraxia
Circadian rhythm sleep disorder
Hyperaesthesia
Hyposmia
Anosmia
Topiramate
8
Essential tremor
Akinesia
Unresponsive to stimuli
Blindness unilateral
Blindness transient
Glaucoma
Accommodation disorder
Altered visual depth perception
Scintillating scotoma
Eyelid oedema
Night blindness
Amblyopia
Calculus ureteric
Renal tubular acidosis
Stevens-Johnson syndrome
Erythema multiforme
Skin odour abnormal
Periorbital oedema
Urticaria localised
Limb discomfort
Acidosis hyperchloraemic
Raynaud's phenomenon
Face oedema
Calcinosis
Mania
Anorgasmia
Panic disorder
Disturbance in sexual arousal
Feeling of despair
Orgasm abnormal
Hypomania
Orgasmic sensation decreased
Unknown incidence adverse effects include:
Angle closure glaucoma
Maculopathy
Eye movement disorder
Toxic epidermal necrolysis
Allergic oedema
Conjunctival oedema
Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical
importance.
The U.S. 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.
[15]
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.
Topiramate
9
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. In March 2011 the FDA notified healthcare professionals and patients of an increased risk of development of
cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during
pregnancy and placed it in Pregnancy Category D.
Topiramate has been associated with a statistically significant increase in suicidality, and "suicidal thoughts or
actions" is now listed as one of the possible side effects of the drug "in a very small number of people, about 1 in
500."
[16]
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; a decrease in plasma levels of estrogens
and digoxin has been noted during topiramate therapy. This can reduce the effectiveness of oral contraceptives
(the pill); use of alternative birth control methods is recommended. Neither intrauterine devices (IUDs) nor
Depo-Provera are affected by topiramate.
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'.
[17]
Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs
(like trospium) can aggravate these disorders.
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:Wikipedia:Citation needed
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
Topiramate
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Seizures
A specific antidote is not available. Treatment is entirely supportive.
Detection in body fluids
Blood, serum or plasma topiramate concentrations may be measured using immunoassay or chromatographic
methods to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal
death investigation. Plasma levels are usually less than 10mg/L during therapeutic administration, but can range
from 10150mg/L in overdose victims.
[18][19]
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 cause visual field defects.
[20]
Topiramate may decrease effectiveness of estrogen-containing oral contraceptives.
Taking topiramate in the 1st trimester of pregnancy may increase risk of cleft lip/cleft palate in infant.
As is the case for all antiepileptic drugs, it is advisable not to suddenly discontinue topiramate as there is a
theoretical risk of rebound seizures.
Avoid evening primrose (seizure threshold decreased)
[21]
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.
Several cellular targets have been proposed to be relevant to the therapeutic activity of topiramate. These include (1)
voltage-gated sodium channels; (2) high-voltage-activated calcium channels; (3) GABA-A receptors; (4)
AMPA/kainate receptors; and (5) carbonic anhydrase isoenzymes. There is evidence that topiramate may alter the
activity of its targets by modifying their phosphorylation state instead of by a direct action. The effect on sodium
channels could be of particular relevance for seizure protection. Although topiramate does inhibit
high-voltage-activated calcium channels, the relevance to clinical activity is uncertain. Effects on specific GABA-A
receptor isoforms could also contribute to the antiseizure activity of the drug. Topiramate selectively inhibits
cytosolic (type II) and membrane associated (type IV) forms of carbonic anhydrase. The action on carbonic
anhydrase isoenzymes may contribute to the drugs side-effects, including its propensity to cause metabolic acidosis
and calcium phosphate kidney stones.
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.
Topiramate
11
References
[1] http:/ / www. drugs. com/ monograph/ topiramate. html
[2] http:/ / www. nlm. nih.gov/ medlineplus/ druginfo/ meds/ a697012. html
[3] http:/ / www. accessdata.fda. gov/ scripts/ cder/ drugsatfda/ index. cfm?fuseaction=Search. SearchAction& SearchTerm=Topiramate&
SearchType=BasicSearch
[4] http:/ / www. nlm. nih.gov/ cgi/ mesh/ 2009/ MB_cgi?term=97240-79-4& rn=1
[5] http:/ / www. whocc.no/ atc_ddd_index/ ?code=N03AX11
[6] http:/ / pubchem. ncbi. nlm.nih. gov/ summary/ summary. cgi?cid=5284627
[7] http:/ / www. drugbank. ca/ drugs/ DB00273
[8] http:/ / www. chemspider.com/ Chemical-Structure.4447672. html
[9] http:/ / fdasis.nlm. nih. gov/ srs/ srsdirect. jsp?regno=0H73WJJ391
[10] http:/ / www.kegg. jp/ entry/ D00537
[11] https:/ / www.ebi.ac. uk/ chembldb/ index.php/ compound/ inspect/ CHEMBL220492
[12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=408971931& page2=Topiramate
[13] [13] B. E. Maryanoff and J. F. Gardocki, "Anticonvulsant sulfamate derivatives", U.S. Patent number 4,513,006 (1985)
[14] http:/ / www.accessdata.fda. gov/ scripts/ cder/ ob/ docs/ patexclnew. cfm?Appl_No=020844& Product_No=002& table1=OB_Rx
[15] http:/ / www.fda. gov/ downloads/ Safety/ MedWatch/ SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ UCM173936. pdf
[16] "Topomax side effects": http:/ / www.topamax.com/ how-topamax-may-help--what-to-expect. html (retrieved Jan 6 2011)' "Migraine
prevention medicine: Topomax": http:/ / www.topamax. com/ (retrieved Jan 6 2011); NIH Pubmed Health, "Topiramate": http:/ / www. ncbi.
nlm.nih.gov/ pubmedhealth/ PMH0000998/ (retrieved Jan 6 2011)
[17] FDA.gov (http:/ / www.fda. gov/ cder/ foi/ label/ 2005/ 020505s018lbl. pdf)
[18] [18] Goswami D, Kumar A, Khuroo AH, et al. Bioanalytical LC-MS/MS method validation for plasma determination of topiramate in healthy
Indian volunteers. Biomed. Chromatogr. 23: 1227-1241, 2009.
[19] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1567-1569.
[20] http:/ / www.fda. gov/ Safety/ MedWatch/ SafetyInformation/ ucm195797. htm
[21] [21] Lexi-Comp Online, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; 2011; February 18, 2011.
External links
Topamax (topiramate): Treatment for Migraine Prevention (http:/ / www. topamax. com)
Topamax: Treatment for Epilepsy (http:/ / www. topamax-epilepsy. com)
Currently listed clinical trials related to topiramate (http:/ / www. clinicaltrials. gov/ ct/ gui/
search?term=topiramate& submit=Search)
FDA topiramate safety (http:/ / www. fda. gov/ medwatch/ safety/ 2001/ topamax. htm)
MSN article (http:/ / content. health. msn. com/ content/ article/ 70/ 81128. htm)
MedlinePlus: Topiramate (http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ medmaster/ a697012. html)
FAQ: Topiramate (Topamax), Mood Disorders and PTSD (http:/ / www. psycom. net/ depression. central.
topiramate. html)
RxList.com: Topiramate (http:/ / www. rxlist. com/ cgi/ generic2/ topiram_cp. htm)
Focus on Topiramate - a new anti-epileptic (http:/ / www. priory. com/ focus7. htm), Ben Green, Priory Lodge
Education Ltd., 1997-99. Version 1.1
Topiramate bound to proteins (http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ ligand/ ?ligand=TOR) in the
PDB
Article Sources and Contributors
12
Article Sources and Contributors
Topiramate Source: http://en.wikipedia.org/w/index.php?oldid=609769833 Contributors: A. B., A2-33, ABCD, Aediapony, Ageekgal, Agjchs, Alex.tan, Alexrexpvt, Alf.laylah.wa.laylah,
Allens, Anaxial, Andy5421, AnjaManix, Arcadian, Atlant, AuQuebec, AzadMashari, Bachrach44, Beetstra, Biglew97, Bmaryano, Bogwhistle, Brainy J, Brianloftus, Bucsaa18, Buzzbo,
Bwilson226, CXCV, Casforty, ChemNerd, Chemgirl131, Chowbok, Chris Capoccia, Chris the speller, Colin, ColinATL, Crh8075, Daniel Bonniot de Ruisselet, Dasani, DaveBurstein,
Defenestration, Deli nk, Dopaminergic, Dr.starritt, Drmies, Dycedarg, Edgar181, Epolk, Essent, EternamenteAprendiz, Fuse809, Fvasconcellos, Gaius Cornelius, Geoffrey.landis, Gor n bein,
Grillo7, Ground Zero, Headbomb, Heron, Hetoi, Hovea, Idiota777, ImGz, Indy muaddib, Intubate, Ismith5602, Ithacagorges, JamesAM, JasonSpradlin82, Jfdwolff,
JimmyStewartinMrSmithGoesToWashington, Jimp, Jimwkim, Jmh649, Joel2013, Joel7687, Justo, Karada, Karenbenn, Katnap01, Kevin Rector, Koavf, Ladcot, LaurieVill, Lm 997, Lowercase
Sigma, Malkin, Mark Arsten, Mav, Mebcoles, Meewam, Melody Of Confusion, Meredithmarbles, MetrosMan, MiPe, Michael Bailes, Mikael Hggstrm, Mike80, Modify, Moretto, MrADHD,
MrOllie, Mykhal, Nbauman, Ob1-kenogle, Ohnoitsjamie, Onemusicguru, Ott2, Pashihiko, Pentagron, Polkadotcycles, Powers.andy, Psychofarm, RainbowOfLight, Recurring dreams, Rich
Farmbrough, Richardrrt2, Richiez, Rjwilmsi, Rmky87, Runtime, Rytyho usa, Sam Hocevar, Savvo, Shukig, Slooshyingchopin, Smijer, Spicemix, Stevenfruitsmaak, Subversive.sound, Suffusion
of Yellow, TKK, Teiresia, Theofenton, Theshibboleth, Tjako, TomMicheals, Transcendence, Trliner, Uanabana, Unimaginative Username, Vantey, Vees, Yandman, , 196 anonymous
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