Seizure Activity and Off-Label Use of Tiagabine
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《新英格兰医药杂志》
To the Editor: Thirty-one case reports of new-onset seizures associated with off-label use of tiagabine (Gabitril) have prompted the addition of a boldface warning to the product label.1 (Tiagabine is approved by the Food and Drug Administration solely for adjunctive treatment of partial seizures in adults and children 12 years of age and older.) The mean duration of exposure to tiagabine before the occurrence of a seizure was three to four months, but in some cases seizures occurred within days after the initiation of the drug or an increase in the dose. Although there were no deaths, status epilepticus was reported in seven patients, of whom two had convulsions.
This experience offers several lessons. First, in this case series, many patients were prescribed tiagabine at usual doses for adjunctive therapy for epilepsy, despite the fact that they were not being treated concomitantly with hepatic-enzyme–inducing antiepileptic drugs. During the development of tiagabine as an antiepileptic drug, virtually all patients were also taking at least one hepatic-enzyme inducer. These concomitant treatments decreased the concentration of tiagabine because they induced the metabolism of tiagabine by cytochrome P-450 3A4. Patients without epilepsy who are not taking concomitant hepatic-enzyme inducers are likely to have increased plasma concentrations of tiagabine because metabolism by the cytochrome P-450 system is not induced. Second, in some cases, because tiagabine is approved for epilepsy, the dose of the drug was increased in an attempt to treat the new-onset seizure. In this setting, physicians may not have expected this paradoxical effect and therefore did not attribute a new-onset seizure to tiagabine. Third, many case reports described the addition of tiagabine to medical regimens that already had the potential to lower the seizure threshold (e.g., antidepressants and, less commonly, antipsychotics).
The FDA is concerned about the risk of seizure with tiagabine particularly because off-label use is increasing. From 1998 to 2004, the proportion of mentions of the use of tiagabine for indications other than epilepsy (i.e., bipolar disorder, anxiety, and neuropathic pain) increased from 20 percent to 94 percent. During the same period, the annual number of dispensed prescriptions for tiagabine increased by a factor of 20, from about 50,000 to about 1 million.2 The safety and efficacy of tiagabine have not been systematically evaluated for indications other than epilepsy; its off-label use should be discouraged.3
Charlene M. Flowers, R.Ph.
Judith A. Racoosin, M.D., M.P.H.
Cindy Kortepeter, Pharm.D.
Food and Drug Administration
Rockville, MD 20852
flowersc@cder.fda.gov
References
FDA public health advisory: seizures in patients without epilepsy being treated with Gabitril (tiagabine). February 18, 2005. (Accessed January 26, 2006, at http://www.fda.gov/cder/drug/advisory/gabitril.htm.)
National Disease and Therapeutic Index and National Prescription Audit Plus. January 1998–December 2004. Plymouth Meeting, Pa.: IMS Health, September 2004–April 2005.
The FDA Safety Information and Adverse Event Reporting Program. 2005 Safety alert: Gabitril (tiagabine HCI): important drug warning. February 14, 2005. (Accessed January 26, 2006, at http://www.fda.gov/medwatch/SAFETY/2005/gabitril_DHCP.htm.)
This experience offers several lessons. First, in this case series, many patients were prescribed tiagabine at usual doses for adjunctive therapy for epilepsy, despite the fact that they were not being treated concomitantly with hepatic-enzyme–inducing antiepileptic drugs. During the development of tiagabine as an antiepileptic drug, virtually all patients were also taking at least one hepatic-enzyme inducer. These concomitant treatments decreased the concentration of tiagabine because they induced the metabolism of tiagabine by cytochrome P-450 3A4. Patients without epilepsy who are not taking concomitant hepatic-enzyme inducers are likely to have increased plasma concentrations of tiagabine because metabolism by the cytochrome P-450 system is not induced. Second, in some cases, because tiagabine is approved for epilepsy, the dose of the drug was increased in an attempt to treat the new-onset seizure. In this setting, physicians may not have expected this paradoxical effect and therefore did not attribute a new-onset seizure to tiagabine. Third, many case reports described the addition of tiagabine to medical regimens that already had the potential to lower the seizure threshold (e.g., antidepressants and, less commonly, antipsychotics).
The FDA is concerned about the risk of seizure with tiagabine particularly because off-label use is increasing. From 1998 to 2004, the proportion of mentions of the use of tiagabine for indications other than epilepsy (i.e., bipolar disorder, anxiety, and neuropathic pain) increased from 20 percent to 94 percent. During the same period, the annual number of dispensed prescriptions for tiagabine increased by a factor of 20, from about 50,000 to about 1 million.2 The safety and efficacy of tiagabine have not been systematically evaluated for indications other than epilepsy; its off-label use should be discouraged.3
Charlene M. Flowers, R.Ph.
Judith A. Racoosin, M.D., M.P.H.
Cindy Kortepeter, Pharm.D.
Food and Drug Administration
Rockville, MD 20852
flowersc@cder.fda.gov
References
FDA public health advisory: seizures in patients without epilepsy being treated with Gabitril (tiagabine). February 18, 2005. (Accessed January 26, 2006, at http://www.fda.gov/cder/drug/advisory/gabitril.htm.)
National Disease and Therapeutic Index and National Prescription Audit Plus. January 1998–December 2004. Plymouth Meeting, Pa.: IMS Health, September 2004–April 2005.
The FDA Safety Information and Adverse Event Reporting Program. 2005 Safety alert: Gabitril (tiagabine HCI): important drug warning. February 14, 2005. (Accessed January 26, 2006, at http://www.fda.gov/medwatch/SAFETY/2005/gabitril_DHCP.htm.)