Topiramate

Topiramate (brand name Topamax) is an anticonvulsant drug produced by Ortho-McNeil Neurologics, a division of Johnson & Johnson. It is used to treat epilepsy in both children and adults. In children it is also indicated for treatment of Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays). It is also Food and Drug Administration (FDA) approved for, and now most frequently prescribed for, the prevention of migraines. It has been used by psychiatrists to treat bipolar disorder,  although it is not FDA approved for this purpose. This drug has been investigated for use in treatment of obesity, especially to aid in the reduction of binge eating,  and also as a possible treatment for alcoholism. However, these uses are not actively promoted by the manufacturer, and like its use for bipolar disorder, are off-label uses. The drug is also used in clinical trials to treat Post Traumatic Stress Disorder. A pilot study suggests that Topiramate is possibly effective against infantile spasm. In May 2006 the U.S. National Institutes of Health web site clinicaltrials.gov listed several studies sponsored by Ortho-McNeil which propose to examine the use of topiramate on migraine, cluster, and severe headaches within various demographics. Other off-label and investigational uses of topiramate include: treatment of bulimia nervosa, obsessive-compulsive disorder, treatment of alcoholism, smoking cessation, and treatment of neuropathic pain.

Pharmacodynamics
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 enhances GABA-activated chloride channels. In addition, topiramate inhibits excitatory neurotransmission, through actions on kainate and AMPA receptors. There is evidence that topiramate has a specific effect on 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 the bad taste and the development of renal stones 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.

Side effects
A GlaxoSmithKline-sponsored Phase IV (post-marketing) study suggested that cognitive side effects may be more common with topiramate than with lamotrigine. In studies of healthy volunteers, comparing the two medications, therapeutic doses of topiramate for bipolar disorder produced greater cognitive deficits than lamotrigine, including short term memory loss and word-finding difficulty. This effect has led to the occasional use of the name "dopamax" by some dissatisfied customers. A flat affect was reported in > 75% patients (n=60).

The most common side effects include a change in taste (carbonated beverages, especially diet sodas and beer, taste particularly bad) and feelings of pins and needles in the head and extremities. Less common side effects include cognitive deficiency (particularly word-finding difficulty); grogginess; lethargy; renal (kidney) stones, impairment of fine motor skills; vision abnormality and transient or permanent vision loss (see below for FDA warning); weight loss; breast pain; abdominal pain; intense sweating; menstrual disorder; taste changes; pharyngitis; sinusitis; diplopia; rash; leukopenia; fatigue; dizziness; insomnia; anxiety; depression; paresthesia; diarrhea; nausea; dyspepsia; constipation; dry-mouth; dysmenorrhea.

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

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%)

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 Food and Drug Administration (FDA) has issued a notification alerting physicians who prescribe topiramate, and their patients, to the risk of vision loss (blindness). Acute myopia and secondary angle closure glaucoma, in a small subset of patients who take topiramate regularly, may cause transient (reversible), or permanent, loss of vision. The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. If addressed early in its course, discontinuation of topiramate, along with other measures deemed prudent by the prescribing physician and/or ophthalmologist, may halt the progression of the ocular damage, and may reverse the visual impairment. Patients who take topiramate and who feel pain in or around their eyes, or notice a loss of vision, visual acuity, or blurred vision, are advised to seek consultation with their physician as soon as reasonably possible. 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. All of these conditions should be detected early by performing regular clinical examinations of the patients.

In other postmarketing research, a risk of decreased sweating and hyperthermia was discovered. Pediatric patients (children) are especially prone to this side-effect. It is recommended that children treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. All patients, particularly those with other predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation.

Interactions

 * As topiramate inhibits carbonic anhydrase, the concomitant use of other inhibitors of carbonic anhydrase (e.g. acetazolamide) may lead to an increased risk of renal stones.
 * Enzyme inductors (e.g. carbamazepine) : The elimination of topiramate may be increased, possibly requiring dose escalations of topiramate.
 * Phenytoin : Topiramate may increase the plasma-levels of phenytoin.
 * Topiramate itself is a weak inhibitor of CYP 2C19 and induces CYP 3A4. 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'. Absent from this label is any direct discussion of narcotic (drugs known to promote respiratory acidosis) interactions. This discussion on page 14 is under the topic of Metabolic Acidosis, and is not repeated under the topic of interactions.

Doses
In order to avoid early side-effects (e.g. cognitive dysfunction) the initial dose normally is low and increased in slow steps. The usual initial dose is 25 to 50 mg daily in 2 single doses. Recommended increments are 25 to 50mg every 1 or 2 weeks. Common doses for maintenance treatment are 100 to 200 mg daily. The highest dose possible is 1,000 mg daily in divided doses.

Overdose
Symptoms of overdose may include but are not limited to:


 * Seizures
 * Dizziness, drowsiness, tiredness
 * 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
 * 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.