Topamax (Topiramate) – Birth Defects Update

March 4, 2011

The US FDA Research issued an FDA Warning on March 4, 2011 citing the possibility of serious side effects and birth defects linked Topamax use by pregnant women, including the increased risk of congenital birth defects such as cleft palate and cleft lip:

FDA: Risk of Oral Birth Defects in Children Born to Mothers Taking Topiramate (Topamax)

New data suggest that the drug Topamax (topiramate) and its generic versions increase the risk for the birth defects cleft lip and cleft palate in babies born to women who use the medication during pregnancy, the U.S. Food and Drug Administration said today.

Although at the present time no official FDA RECALL has been issued by the FDA, this potential link between Topamax and the risk of congenital cleft palate and cleft lip birth defects has medical professionals concerned that women who are pregnent should not be prescribed Topamax, and that Topamax should not be taken by women while pregnant.

Topamax Information:

What is Topamax?

Topamax (topiramate) treats epilepsy in children and adults and was originally marketed 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.

Topamax (topiramate) has been investigated for use in treating alcoholism and obesity, especially to reduce binge eating.

Topamax (topiramate) 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.

Off the Label Usage of Topamax (topiramate)

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, and cocaine dependence. Topiramate is also being studied with a mixture of phentermine to form a drug called Qnexa for the treatment of obesity.

Pharmacology of Topamax (topiramate)

Chemically, topiramate is a sulfamate-substituted monosaccharide, related to fructose, a rather unusual chemical structure for an anticonvulsant.

Topamax (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 Topamax (topiramate) 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. Topamax (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.

Side effects of Topamax (topiramate)

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:

  • 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%)

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.

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.

Interactions of Topamax (topiramate)

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

Dosage of Topamax (topiramate)

The exact dosage of Topamax (topiramate) depends on the diagnosis being treated. 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, but higher doses have been used in patients using Topiramate as a primary seizure medication; doses up to 1600 mg/day have been well tolerated.

Overdose of Topamax (topiramate)

Overdose of Topamax (topiramate) 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 of Topamax (topiramate) 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.

Patient Warnings of Topamax (topiramate)

People taking Topamax (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)

Speak to a Topamax Lawyer about a Topamax Lawsuit

If you took Topamax (topiramate) or any other anti-seizure drug during pregnancy and your child was born with a cleft palate, cleft lip or any other congenital cranio-facial birth defect, we encourage you to contact a Topamax Birth Defects Lawsuit Attorney at our law firm immediately. It may be too late to recover from all of the devastating effects of Topamax but an experienced products liability pharmaceutical lawsuit lawyer at the Willis Law Firm can assist you in legal action against Johnson & Johnson (JNJ) and Ortho-McNeil Pharmaceutical LLC, the makers of Topamax. You are not alone. Join other birth defect victims and their families in speaking up and fighting for your legal rights.

Please fill out our free online legal evaluation form and we will contact you within 24 hours. Please keep in mind that certain states have statutes of limitation that limit the amount of time you have to file a lawsuit or seek legal action. Contact our law firm immediately so that we may explain the rights and options available to you and your family.

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