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Topiramate (brand name Topamax) is an anticonvulsant drug 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. 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. The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009.
Topiramate treats epilepsy in children and adults and was originally marked 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, 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.
This drug has been investigated for use in treating alcoholism and obesity, especially to reduce binge eating.
The drug is also used in clinical trials to treat posttraumatic 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. Other off-label and investigational uses of topiramate include the treatment of essential tremor, bulimia nervosa, obsessive-compulsive disorder, alcoholism, smoking cessation, idiopathic intracranial hypertension , neuropathic pain, cluster headache, and cocaine dependence. Topiramate is also being studied with a mixture of phentermine to form a drug called Qnexa for the treatment of obesity.
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 has a complex mechanism of action  The drug enhances GABA-activated chloride channels. In addition, it inhibits excitatory neurotransmission, through actions on kainate and AMPA receptors (but not NMDA receptors). There is evidence that topiramate has a specific effect on GluK1 (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 some of the side effects 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.
A GlaxoSmithKline-sponsored Phase IV study suggested that cognitive side effects may be more common with topiramate than with lamotrigine. 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 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 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%)
Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.
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. 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. 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.
In other postmarketing research, a risk of decreased sweating and hyperthermia was discovered. Pediatric patients (children) are especially prone to this side-effect.
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.
Most antiepileptic drugs have been associated with a statistically significant increase in suicidality, including topiramate.
- 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'.
- Oligohydrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.
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. Common dosages for maintenance treatment are 100 to 200 mg daily. The highest dosage recommended is 400 mg daily in divided doses.
Symptoms of overdose may include but are not limited to:
- Speech problems
- Blurred vision, double vision
- Troubled thinking
- Loss of coordination
- Inability to respond to things around you
- Loss of consciousness
- Confusion and coma
- 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.
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