Topiramate

Topiramate, marketed as Topamax among other names, is an oral medication primarily prescribed for the treatment of epilepsy and the prophylaxis of migraines.

Common side effects include tingling, feeling tired, loss of appetite, abdominal pain, weight loss, and cognitive dysfunction, such as trouble concentrating. Serious side effects may include suicidal ideation, increased ammonia levels resulting in encephalopathy, and kidney stones. Risks and benefits should be carefully discussed with the full treatment team. Topiramate is considered "probably compatible" with lactation and is not contraindicated for breastfeeding, though monitoring of the infant for diarrhea or poor weight gain may be considered. Its mechanism of action is unclear. In 2023, it was the 71st most commonly prescribed medication in the United States, with more than 9million prescriptions.

Medical uses

thumb|A package of topiramate 25mg from Norway

Topiramate is used to treat epilepsy in children and adults, and it was originally used as an anticonvulsant. as it decreases the frequency of attacks. Topiramate is used to treat medication overuse headache and is recommended by the European Federation of Neurological Societies as one of the few medications showing effectiveness for this indication.

Pain

A 2018 review found topiramate to be of no use in chronic low back pain. Topiramate has not been shown to work as a pain medicine in diabetic neuropathy, the only neuropathic condition for which it has been adequately tested.

Other

One common off-label use for topiramate is in the treatment of bipolar disorder. A review published in 2010 suggested a benefit of topiramate in the treatment of symptoms of borderline personality disorder; however, the authors noted that this was based on only one randomized controlled trial and requires replication.

Topiramate has been used as a treatment for alcoholism. The U.S. Veterans Affairs and Department of Defense 2015 guideline on substance use disorders lists topiramate as a "strong for" in its recommendations for alcohol use disorder.

Topiramate/phentermine combination therapy (trade name Qsymia) was approved by the USFDA in July 2012 for use by adults with obesity or overweight and a weight-related condition. Qsymia was approved by the USFDA in July 2022 for children and adolescents with age- and sex-standardized BMIs in or above the 95th percentile. Prior work had established single-agent topiramate therapy as weight loss-inducing in select populations (e.g., those with binge eating disorder or atypical antipsychotic-induced weight gain).

Adverse effects

The most significant adverse effects associated with topiramate treatment are predominantly central nervous system (CNS) related. A notable proportion of patients, ranging from 11% to 28%, discontinue topiramate therapy due to adverse effects.

Topiramate may decrease the effectiveness of oestrogen-containing oral contraceptives.
Taking topiramate in the first trimester of pregnancy may increase the risk of cleft lip/cleft palate in infants.

Frequency

Adverse effects by incidence:

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

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 a lot of topiramate. 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. 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.

Cognitive and word-finding difficulties, which may occur in some patients, may respond to piracetam.

Carbonation dysgeusia (distortion of the sense of taste-sensation of carbonation) may respond to and/or be prevented with zinc.

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."

Overdose

Symptoms of acute and acute on chronic exposure to topiramate range from asymptomatic to status epilepticus, including in patients with no seizure history. In children, overdose may also result in hallucinations. The most common signs of overdose are dilated pupils, somnolence, dizziness, psychomotor agitation, and abnormal, uncoordinated body movements. Neither intrauterine devices (IUDs) nor Depo-Provera are affected by topiramate.

Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.

Pharmacology

class=skin-invert-image|thumb|right|Chair-style representation of skeletal formula

The topiramate molecule is a sulfamate modified sugar—more specifically, fructose diacetonide, an unusual chemical structure for a pharmaceutical.

Topiramate is quickly absorbed after oral use. It has a half-life of 21 hours, and steady-state drug levels are reached in 4 days in patients with normal renal function. 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 as relevant to topiramate's therapeutic activity. These include voltage-gated sodium channels, high-voltage-activated calcium channels, GABA<sub>A</sub> receptors, AMPA/kainate receptors, and carbonic anhydrase isoenzymes. There is evidence that topiramate may alter the activity of its targets by altering their phosphorylation state rather than by direct action. The effect on sodium channels could be of particular relevance for seizure protection. Although topiramate does inhibit high-voltage-activated calcium channels, its relevance to clinical activity is uncertain. Effects on specific GABA<sub>A</sub> receptor isoforms could also contribute to the anticonvulsant activity of the drug. Topiramate selectively inhibits cytosolic (type II) and membrane-associated (type IV) forms of carbonic anhydrase. Its action on carbonic anhydrase isoenzymes may contribute to the drug's side effects, including its propensity to cause metabolic acidosis and calcium phosphate kidney stones.

Topiramate inhibits maximal seizure activity in electroconvulsive therapy and in 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 one of the very few anticonvulsants that do not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect.

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 assist in a medicolegal death investigation. Plasma levels are usually less than 10 mg/L during therapeutic administration, but can range from 10 to 150 mg/L in overdose victims.

History

Topiramate was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceuticals. Topiramate was first sold

in 1996. Mylan Pharmaceuticals was granted final approval by the FDA for the sale of generic topiramate in the United States and the generic version was made available in September 2006. The last patent for topiramate in the U.S. was for use in children and expired on 28 February 2009.

Research

Topiramate is being studied as a potential treatment for post-traumatic stress disorder (PTSD).

There is some evidence for the use of topiramate in the management of cravings related to withdrawal from dextromethorphan.

A 2023 systematic review of seizure treatment for infants aged 1 to 36 months identified three studies that evaluated the use of topiramate. Though its adverse effects, including upper respiratory tract infection and loss of appetite, were rarely severe enough for the medication to be discontinued in this age group, its effectiveness in reducing seizures was inconclusive. The available research suffers from small sample sizes, inconsistent findings, and inadequate comparison groups.