Topamax

Topamax (topiramate, Ortho-McNeil-Janssen)
Topiragen (topiramate, Upshur-Smith)
Generic Topamax

Topamax is an anti-convulsant medication taken by people with epilepsy to treat certain kinds of seizures. Its most popular use, however, is to prevent migraine headaches. About 9 million Topamax prescriptions are filled each year – some of them for unsuspecting pregnant women whose babies are born with a cleft lip, cleft palate, or other serious birth defect.

About half of adults and adolescents newly-diagnosed with epilepsy can achieve control of their seizures with a moderate dose of an antiepileptic drug (AED). Topamax and Topiragen are brand names for a class of AEDs that work by decreasing abnormal excitement in the brain. These drugs are used alone, or in combination with other medications.

• Topamax was first approved by the Food and Drug Administration (FDA) in December 1996 for adjunctive use (with one or more other medications) by adults with partial onset seizures. In July 1999, FDA approval was gained for use by children ages 2–16 with partial onset seizures. In October of that year, the drugs were approved for what are called generalized tonic-clonic seizures (GTCS).
  
  In people with epilepsy, partial onset seizures come from a specific region of the brain and are localized in one part of the body. Generalized tonic-clonic seizures - often labeled “grand mal” seizures - stem from the thalamus and other subcortical structures in the brain, and produce symptoms throughout the body, usually resulting in loss of consciousness. (“Tonic” is defined by sudden muscle rigidity; “clonic” means violent contractions or rhythmic shaking.)
• By August 2001, FDA approval for Topamax was extended to patients two years or older with Lennox Gastaut syndrome, a condition that includes seizures but also can cause developmental delays and mental retardation.
• Three years later, in 2004, Topamax was approved for prevention of migraine headaches in adults. Sales soared, even though this drug does not relieve the pain after migraine headaches occur. By 2009, there were as many as 19 generic versions of topiramate on the market in addition to the Topamax and Topiragen brand names.

In the 15 years that Topamax has been on the market, studies have confirmed suspicions that this drug causes oral clefts (cleft lip or cleft palate) in infants whose mothers took Topamax while pregnant.

Recent research shows that Topamax can cause a fetus to develop a cleft lip or cleft palate when it's mother takes the drug during the first trimester of pregnancy – a time when many women are unaware that they are pregnant. While there are no definitive data on how many women are exposed to Topamax during pregnancy, an estimated 25,000 to 30,000 babies are born each year to mothers with epilepsy – and many thousands more to mothers who may have been taking Topamax for prevention of migraine headaches or for other off-label uses.

In the early 1990s, several AED pregnancy registries were established to gather accurate data about the potential risks of antiepilectic drugs – especially newer ones such as Topamax. Active registries monitoring outcomes of AED-exposed pregnancies worldwide are:

• The North American Pregnancy Registry (United States and Canada)
• The United Kingdom Epilepsy and Pregnancy Registry
• The Australian Registry of Antiepileptic Drugs in Pregnancy
• The European Pregnancy Registry (40 countries)

Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry suggest the risk of oral clefts in babies whose mothers take anti-seizure medications during the first three months of their pregnancy is increased more than 20-fold – an incidence of 1.4% compared to .07% in babies of mothers who did not take anticonvulsant drugs.

Cleft lip and cleft palate are craniofacial birth defects, the result of faulty formation of the upper lip or palate during fetal development. An infant with a cleft lip will have a vertical fissure in his or her upper lip. A cleft palate – incomplete closure of the palate – is a split along part of or the entire roof of the mouth. There is no question that these oral clefts are tragic for parents and their babies, who often face life-long difficulties that can include:

• Need for feeding tubes or special bottles
• Inadequate nutrition due to feeding difficulties
• Need for artificial palates
• Dental problems
• Ear infections
• Hearing loss
• Speech and language delays
• Emotional issues

While some oral cleft defects can be alleviated at least somewhat with surgery, surgical intervention means months – even years – of painful procedures that can cost hundreds of thousands of dollars.

By March 2011, the FDA had accumulated sufficient evidence to shift Topamax from Pregnancy Category C (animal studies suggest fetal risks, but human clinical trials are inadequate) to Category D. Category D means that the FDA finds positive evidence of human fetal risk, and that Topamax is acceptable for use by pregnant women only in certain situations.

• On March 4, 2011, the FDA ordered a change in the patient medication guide and warning labeling for Topamax,because increased risk of oral clefts in infants exposed to topiramate monotherapy (that is, the drug is taken by itself, not in combination with other anti-seizure drugs) during a mother’s first three months of pregnancy:

The prevalence of oral clefts was 1.4% compared to a prevalence of 0.38 – 0.55% in infants exposed to other antiepileptic drugs, also known as AEDs, and a prevalence of 0.07% in infants of mothers without epilepsy or treatment with other AEDs. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 21.3% as compared to the risk in a background population of untreated women.

• In corollary drug safety information for healthcare professionals, the FDA also noted that the Epilepsy and Pregnancy Register in the United Kingdom reported an increase in prevalence of oral clefts among infants exposed in utero to topiramate monotherapy – a 16-fold increase in risk over patients without epilepsy or exposure to anti-seizure drugs. A study in Neurology in July 2008, found that 178 pregnancies exposed to topiramate resulted in 16 births with major congenital malformation. Four of these major birth defects were oral clefts.
• A large retrospective study published in the New England Journal of Medicine in 2001 indicated that pregnant women taking anti-convulsant drugs faced a greater risk of birth defects and other anomalies than did women in a control group. According to this research, which involved screening 128,409 pregnant women, the incidence of major malformations was 5.7% in babies exposed to anti-seizure medications, compared to 1.8% for the control individuals.

In addition to horrific birth defects, Topamax is associated with other dangerous conditions, including cognitive impairment in adults taking high doses. One study released in January 2011 indicates that, at very high dosages, Topamax and Topiragen can impair visual memory and language, and can delay recall and reaction time.

• Managing epilepsy during pregnancy is a serious challenge, because all anti-convulsant drugs have some potential for causing malformations and birth defects. In some cases, a condition called metabolic acidosis decreases fetal growth in the womb and can result in death of the fetus. Two anti-seizure drugs, valproic acid (Depakote) and carbamazepine (Tegretol), are linked with brain and spinal cord defects such as spina bifida – a condition in which the fetal spinal column does not close.
• Topamax can interfere with the efficacy of birth control pills and increase breakthrough bleeding. There is evidence that Topamax, Topiragen, and their generic versions may reduce the effectiveness of oral contraceptives - even as women with epilepsy are trying to prevent dangerous pregnancies. Topirimate anti-convulsants used with valproic acid cause a woman’s body to experience decreased exposure to ethinyl estradiol, a synthetic estrogen contained in many oral contraceptives. When this happens, birth control pills are rendered less effective and the risk of unintended pregnancies is increased.
• An article published in the January 11, 2011, issue of Neurology by David W. Loring, a Ph.D. at Emory University, analyzed a randomized trial of obese epilepsy patients with shocking results. Loring and his associates reported that at high doses, Topamax and Topiragen impaired cognition – affecting 35% of study participants at the highest dose tested. The most significant effects of these drugs appeared to be on visual memory, in addition to delayed recall and reaction time, and difficulties in word learning and association.

Ortho-McNeil has admitted encouraging off-label use of Topamax for psychiatric conditions such as bipolar disorder, depression, and nerve pain. There are indications that Topamax also has been used off-label for anger control, post-traumatic stress disorder-associated nightmares, metabolic disease, self-inflicted skin-pricking, essential tremors, cluster headaches, and alcoholism. Topamax and Topiragen have not been approved by the FDA for these purposes, and there is no evidence that topiramate drugs are either effective or safe for these conditions

In April 2010, the Justice Department announced an agreement with Ortho-McNeil calling for the pharmaceutical giant to pay $81 million to settle criminal and civil lawsuits related to its illegal promotion of Topamax for off-label uses. The $81 million figure included $6.4 million for a criminal fine, with the balance to resolve civil suits filed under state and federal false claims statutes. The federal charges and civil suits alleged that Ortho-McNeil paid outside doctors to speak at meetings and join company representatives in sales calls to psychiatrists, recommending Topamax for psychiatric uses not been tested or approved by the FDA.

Because of Topamax’s popularity with migraine headache sufferers and its off-label use by people with psychiatric disorders, many users – not just pregnant women with epilepsy may face serious risks. Medical scientists at the National Institutes of Health warn all patients who are taking Topamax or Topiragen to be alert for any of the following:

• Blurred or double vision
• Eye pain
• Worsening of seizures
• Slow heart rate or irregular heartbeat
• Chest pain
• Fast, shallow breathing
• Inability to respond to stimuli
• Excessive tiredness
• Stomach pain
• Loss of appetite
• Nausea or vomiting
• Intense back pain
• Constant need to urinate
• Bloody or cloudy urine
• Fever and/or chills

A good motto for Topamax users is caveat emptor, or buyers beware. This applies especially to women taking Topamax to control seizures, prevent migraine headaches, or any other off-label indication. Women taking Topamax are advised to discuss use of this medication with their doctors if they are pregnant or planning to become pregnant.