Topiramate

Topiramate (brand name Topamax) is an anticonvulsant (antiepilepsy) drug. It 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. Generic versions are available in Canada and these were approved by the Food and Drug Administration (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. The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009. On May 21, 2010, Ortho-McNeil pled guilty and was fined $6.14 million by the FDA for promoting Topamax to treat psychiatric disorders, without applying for any Federal government approval. Also, there was no data from any well-controlled clinical trial to demonstrate that Topamax was safe and/or effective to treat any psychiatric conditions at all.

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, and they sometimes use topiramate to augment psychotropics, or to counteract the weight gain associated with numerous antidepressants. However in 2006, a 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
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, alcoholism, smoking cessation, idiopathic intracranial hypertension, neuropathic pain, cluster headache, migraine headache, cocaine dependence, and Borderline Personality Disorder. Topiramate is also being studied with a mixture of phentermine to form a drug called Qnexa for the treatment of obesity.

Adverse effects
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 one clinical study Listed by prevalence:


 * paresthesia (numbness & tingling) (23.7%)
 * upper respiratory tract infection (17.5%)
 * diarrhea (16.8%)
 * nausea (15.4%)
 * anorexia (loss of appetite) (13.3%)
 * memory problems (11.2%)

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%)

That same study also reported that in adult patients with Bipolar 1 disorder who were already receiving either lithium or valproate, the addition of topiramate did not produce a statistically-significant improvement versus placebo, while adding the above adverse reactions.

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. 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.

Topiramate has been associated with a statistically significant increase in suicidality.

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. =

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'.
 * 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:


 * 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

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 10 mg/L during therapeutic administration, but can range from 10–150 mg/L in overdose victims.

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 decrease effectiveness of estrogen-containing oral contraceptives
 * Topiramate should not be suddenly discontinued, as this may cause increased seizure activity.
 * Avoid evening primrose (seizure threshold decreased)

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.

The exact mechanism of action is unknown, 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-aminobutyrate 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.

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.