Special Alerts:

[Posted 03/04/2011] ISSUE: 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 topiramate (Topamax) during pregnancy. Because of new human data that show an increased risk for oral clefts, topiramate is being placed in Pregnancy Category D. Pregnancy Category D means there is positive evidence of human fetal risk based on human data but the potential benefits from use of the drug in pregnant women may be acceptable in certain situations despite its risks. The patient medication guide and prescribing information for Topamax and generic topiramate will be updated with the new information.

BACKGROUND: Topiramate is an anticonvulsant medication approved for use alone or with other medications to treat patients with epilepsy who have certain types of seizures. Topiramate is also approved for use to prevent migraine headaches. The new data was from the North American Antiepileptic Drug (NAAED) Pregnancy Registry.

RECOMMENDATION: Before starting topiramate, pregnant women and women of childbearing potential should discuss other treatment options with their health care professional. Women taking topiramate should tell their health care professional immediately if they are planning to or become pregnant. Patients taking topiramate should not stop taking it unless told to do so by their health care professional. Women who become pregnant while taking topiramate should talk to their health care professional about registering with the North American Antiepileptic Drug Pregnancy Registry, a group that collects information about outcomes in infants born to women treated with antiepileptic drugs during pregnancy. For more information visit the FDA website at: [Web] and [Web].

[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.

The drugs included in the analyses include (some of these drugs are also available in generic form):

• Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
• Felbamate (marketed as Felbatol)
• Gabapentin (marketed as Neurontin)
• Lamotrigine (marketed as Lamictal)
• Levetiracetam (marketed as Keppra)
• Oxcarbazepine (marketed as Trileptal)
• Pregabalin (marketed as Lyrica)
• Tiagabine (marketed as Gabitril)
• Topiramate (marketed as Topamax)
• Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
• Zonisamide (marketed as Zonegran)

For more information visit the FDA website at: [Web] and [Web].

[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.

For more information visit the FDA website at: [Web] and [Web].

[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

The drugs included in the analyses include (some of these drugs are also available in generic form):

• Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
• Felbamate (marketed as Felbatol)
• Gabapentin (marketed as Neurontin)
• Lamotrigine (marketed as Lamictal)
• Levetiracetam (marketed as Keppra)
• Oxcarbazepine (marketed as Trileptal)
• Pregabalin (marketed as Lyrica)
• Tiagabine (marketed as Gabitril)
• Topiramate (marketed as Topamax)
• Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
• Zonisamide (marketed as Zonegran)

Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: [Web] and [Web].

REMS:

FDA approved a REMS for topiramate to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).