Topiramate

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Topiramate
Topiramate2DACS.svg
Topiramate3Dan.gif
Systematic (IUPAC) name
2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate
Clinical data
Trade names Topamax
AHFS/Drugs.com monograph
MedlinePlus a697012
Licence data US FDA:link
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 YesY
ATC code N03AX11
PubChem CID 5284627
DrugBank DB00273
ChemSpider 4447672 YesY
UNII 0H73WJJ391 YesY
KEGG D00537 YesY
ChEMBL CHEMBL220492 YesY
Chemical data
Formula C12H21NO8S 
Mol. mass 339.363 g/mol
 N (what is this?)  (verify)

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.[1][2][3] Topiramate was first approved in the US in 1996.[4] 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 200 mg tablets and sprinkle capsules by the FDA for sale in the United States. 50 mg tablets were granted tentative approval.[5] The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009.[6]

Medical uses[edit]

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.[7][8][9] 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.[10]

This drug has been used successfully as a treatment for alcoholism,[11] methamphetamine addiction, cocaine addiction,[12][13] obesity[14][15] and antipsychotic-induced weight gain.[16][17] 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.[18][19]

The drug is also used in clinical trials to treat post traumatic stress disorder.[20] A pilot study suggested that topiramate is effective against infantile spasms.[21] Another study recommends topiramate as an effective treatment in the prevention of periventricular leukomalacia in preterm infants after an hypoxic-ischemic injury.[22]

Recent clinical reports indicate that it may have mood stabilizing properties.[23] Other off-label and investigational uses of topiramate include the treatment of essential tremor, bulimia nervosa,[24] obsessive-compulsive disorder, smoking cessation,[25] idiopathic intracranial hypertension[26] and cluster headache[27] 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.[28]

Adverse effects[edit]

A GlaxoSmithKline-sponsored Phase IV study suggested that cognitive side effects may be more common with topiramate than with lamotrigine.[29]

Adverse effects by incidence:[30][31][32][33]

Very common (>10% incidence) adverse effects include:

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
  • 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
  • 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
  • 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
  • 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
  • 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:

Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.[34]

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.[35] 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.[36] 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.[37]

Topiramate has been associated with a statistically significant increase in suicidality,[38] 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." [39]

Interactions[edit]

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.[40] Neither intrauterine devices (IUDs) nor Depo-Provera are affected by topiramate.[40]
  • 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'.[41]
  • Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.

Overdose[edit]

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:[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
  • Seizures

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

Detection in body fluids[edit]

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 10 mg/L during therapeutic administration, but can range from 10–150 mg/L in overdose victims.[42][43][44]

Warnings[edit]

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,[39] 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.[45]
  • 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.[37]
  • Topiramate should not be suddenly discontinued, as this may cause increased seizure activity.[46]
  • Avoid evening primrose (seizure threshold decreased) [47]

Pharmacology[edit]

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,[46] 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-aminobutyric 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.[48]

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.[49]

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