Cognitive/Neuropsychiatric Adverse Events 

Adverse events most often associated with the use of tiagabine HCl were related to the central nervous system. The most significant of these can be classified into 2 general categories: 1) impaired concentration, speech or language problems, and confusion (effects on thought processes); and 2) somnolence and fatigue (effects on level of consciousness). The majority of these events were mild to moderate. In controlled clinical trials, these events led to discontinuation of treatment with tiagabine HCl in 6% (31 of 494) of patients compared to 2% (5 of 275) of the placebo-treated patients. A total of 1.6% (8 of 494) of the tiagabine HCl treated patients in the controlled trials were hospitalized secondary to the occurrence of these events compared to 0% of the placebo treated patients. Some of these events were dose related and usually began during initial titration. 

Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity (see PRECAUTIONS, Laboratory Tests, EEG). In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment. 

Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of tiagabine HCl. 

Status Epilepticus 

In the three double-blind, placebo-controlled, parallel-group studies (Studies 1, 2, and 3), the incidence of any type of status epilepticus (simple, complex, or generalized tonic-clonic) in patients receiving tiagabine HCl was 0.8% (4 of 494 patients) versus 0.7% (2 of 275 patients) receiving placebo. Among the patients treated with tiagabine HCl across all epilepsy studies (controlled and uncontrolled), 5% had some form of status epilepticus. Of the 5%, 57% of patients experienced complex partial status epilepticus. A critical risk factor for status epilepticus was the presence of a previous history; 33% of patients with a history of status epilepticus had recurrence during tiagabine HCl treatment. Because adequate information about the incidence of status epilepticus in a similar population of patients with epilepsy who have not received treatment with tiagabine HCl is not available, it is impossible to state whether or not treatment with tiagabine HCl is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with tiagabine HCl. 

Sudden Unexpected Death In Epilepsy (SUDEP) 

There have been as many as 10 cases of sudden unexpected deaths during the clinical development of tiagabine among 2,531 patients with epilepsy (3,831 patient-years of exposure). 

This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving tiagabine HCl (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populations similar to that in the clinical development program for tiagabine HCl, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving tiagabine HCl are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to tiagabine HCl, that underwent clinical testing in similar populations at about the same time. This evidence suggests that the SUDEP rates reflect population rates, not a drug effect.