Antiepileptic Drugs, 5th Edition

Tiagabine

76

Adverse Effects

Steven C. Schachter MD

Associate Professor, Department of Neurology, Harvard Medical School; and Director of Clinical Trials, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Controlling seizures without intolerable or disabling side effects is the primary goal of seizure therapy. In 1985, Mattson and colleagues found that the development of side effects was often responsible for medication failure in patients with new-onset partial seizures (1). Subsequently, an unprecedented number of antiepileptic drugs (AEDs) as well as a device were developed for treating partial seizures, thus giving renewed hope to patients with suboptimal quality of life resulting from seizures or medication side effects (2, 3, 4). This chapter reviews the adverse effects of tiagabine (TGB).

RELEVANT PHARMACOKINETICS

The maximum serum concentration of TGB is reached within 1 to 1.5 hours when the drug is taken without food compared with a mean of 2.6 hours when it is taken with food (5). For this reason, patients should be instructed to take TGB with food, thereby reducing the possibility of peak concentration side effects.

TGB is extensively oxidized in the liver by CYP3A isoform (6). Dosage reductions and less frequent dosing intervals are recommended for patients with hepatic dysfunction to prevent excessive total and unbound TGB concentrations, resulting in symptoms and signs of neurotoxicity (7). However, because only 2% of TGB is excreted unchanged in the urine (8,9), the tolerability of TGB is unchanged in renally impaired patients (10).

Whereas an inducible enzyme metabolizes TGB, concurrently administered drugs that induce CYP3A increase the clearance of TGB, reduce the area under the curve, and decrease its half-life (11, 12, 13). Consequently, serum concentrations of TGB are likely to rise if a concomitant enzyme-inducing AED is tapered (14), possibly resulting in side effects.

TGB had no pharmacodynamic interactions with ethanol or triazolam in healthy volunteers (15,16), but a pharmacodynamic interaction with the benzodiazepines diazepam and zolpidem was seen in rats, manifested as behavioral changes (17). The human correlate, if any, has not been well characterized.

CLINICAL STUDIES OF SAFETY AND TOLERABILITY

Controlled Adjunctive Trials

Five multicenter, double-blind, randomized, placebo-controlled studies, including two crossover studies, evaluated TGB for the adjunctive treatment of partial-onset seizures. A total of 951 patients (675 randomly assigned to receive TGB) were enrolled (8,18, 19, 20).

Study subjects in the three parallel-design studies received one to three concomitant enzyme-inducing AEDs: carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (21, 22, 23). The dose-response study compared the efficacy, safety, and tolerability of three different daily doses of TGB—16, 32, and 56 mg/day—with placebo (21). The dose-frequency study compared two different TGB dosing schedules of TGB—16 mg twice daily and 8 mg four times daily—with placebo (22). The third trial, a thrice-daily dosing study, compared TGB, 10 mg given three times daily, with placebo (23). Patients in both the treatment and placebo groups were well matched in all three studies, they had epilepsy for a median of 23 years, and they had taken a median of six AEDs in the past.

Overall, 90% of TGB-treated patients in the parallel-group, placebo-controlled, add-on trials experienced at least one side effect compared with 86% of patients who received placebo. The side effects that occurred significantly more often with TGB than with placebo were dizziness, asthenia (fatigue or generalized muscle weakness), nervousness, tremor, abnormal thinking (difficulty in concentrating, mental lethargy, or slowness of thought), depression, aphasia (dysarthria, difficulty speaking, or speech arrest), and abdominal pain (24) (Figure 76.1). Most of the side effects were mild or moderate, occurred during titration, and resolved spontaneously.

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FIGURE 76.1. Tiagabine adverse effects in double-blind, placebo-controlled add-on studies: adverse effects that emerged during treatment with tiagabine and statistically higher than placebo. All patients were also concomitantly receiving one to three enzyme-inducing antiepileptic drugs. Dark bar, placebo; light bar, tiagabine.

More pronounced side effects were recorded for 9% of patients who received TGB and for 5% of patients who received placebo. The most common of these were somnolence, asthenia, and headache (25). A total of 13% of patients who received TGB withdrew from studies prematurely because of side effects, compared with 5% of those who received placebo. The most common reasons for premature withdrawal were confusion (1.4%), somnolence (1.2%), ataxia (<1%), and dizziness (<1%) (24).

A total of 12% of TGB-treated patients and 13% of placebo-treated patients in the three double-blind, parallel, add-on studies had an increase of ≥50% in their partial seizures (26). Complex or simple partial status epilepticus occurred in 4 of 494 (0.8%) of the TGB recipients and in 4 of 275 (1.5%) of the placebo recipients, findings similar to the expected incidence for the population studied. Convulsive status did not occur (27).

Weakness was noted in 21 of 494 (4%) of the TGB-treated patients as compared with 3 of 275 (1%) of the placebo-treated patients. This effect appeared to be dose related. There were no treatment-related differences with regard to possible psychotic events (1 of 275 placebo; 4 of 494 TGB), rash, hematologic and biochemical test results, electrocardiograms, and vital signs (25). Neuropsychologic testing did not reveal any evidence of worsening in tests of cognitive abilities, adjustment, and mood in the dose-response study (28) or in the thrice-daily dosing study (29). Finally, the incidence of sudden unexpected death resulting from epilepsy was similar among TGB-treated patients compared with incidences reported for the other new AEDs (package insert).

An adjunctive double-blind study compared the efficacy, safety, and tolerability of adding TGB to either CBZ or PHT with the combination of CBZ and PHT. TGB in combination with either CBZ or PHT was better tolerated than the combination of CBZ and PHT and had similar efficacy (30). Adjunctive TGB had no significant effects on total body weight (31) or on abilities, adjustment, and mood compared with adjunctive CBZ or PHT (32). Further, the overall health costs of add-on TGB when calculated with a cost-effectiveness clinical decision analysis model were very favorable when compared with the combination of PHT and CBZ, despite the higher acquisition cost of TGB (33).

Open Adjunctive Trials

Numerous trials have evaluated the long-term tolerability and safety of TGB, including extensions of the placebo-controlled, add-on studies and other trials that enrolled patients with uncontrolled seizures of any type. Leppik et al. reviewed the long-term exposure data for nearly 3,100 patients, including 541 patients with exposures over 36 months and 1,274 patients who had received TGB for at least 12 months (24). Daily TGB doses averaged between 24 and 60 mg. Among patients exposed for at least 12 months, 11 % took at least 80 mg daily. Side effects reported by ≥10% patients during long-term treatment included dizziness, somnolence, asthenia, headache, tremor, nervousness, difficulty with concentration or attention, confusion, ataxia, insomnia, nystagmus, depression, amnesia, speech disorder, paresthesia, and incoordination (24). These side effects tended to occur during the first 6 months of treatment and seldom caused patients to withdraw from the study (34). Further, side effects among 674 patients treated for ≤54 months tended to diminish over extended periods (35). No new side effects or laboratory abnormalities occurred in these long-term studies (24,36).

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Because of reports of fixed concentric visual field defects occurring in patients treated with vigabatrin, which is another γ-aminobutyric acid (GABA)-ergic AED, though pharmacologically different (37), the preapproval TGB safety database was scanned for adverse events that were suggestive of symptomatic visual field loss. Of the eight patients who had visual symptoms, two had field defects from fixed lesions (temporal lobe resection, cortical infarct), and six had transient visual complaints. Examination did not disclose any fixed visual defects (38).

In a series of infants with infantile spasms, TGB treatment was associated with a >50% seizure reduction in six of 11 (39). Irritability was noted in nine of 11 infants; in seven of the nine, irritability improved with time or with TGB dose reduction.

Monotherapy Trials

A dose-ranging, TGB-substitution study and a high-dose versus low-dose study evaluated the feasibility of converting to TGB monotherapy and the efficacy, safety, and tolerability of TGB as monotherapy, respectively. The dose-ranging study was designed to determine the maximum tolerated dose of TGB as monotherapy for patients with complex partial seizures (median duration, 19.5 years) not adequately controlled with one AED (40). The 31 enrolled patients had taken a mean of 5.1 AEDs in the past. Twelve patients completed the study and were taking a median TGB dose of 38.4 mg/day (range, 24 to 54 mg). Asthenia, dizziness, difficulty in concentrating, insomnia, nervousness, somnolence, and impaired memory were the most common side effects.

The high-dose versus low-dose study was a multicenter, double-blind, randomized, parallel-group trial in which patients with complex partial seizures and with or without secondarily generalized tonic-clonic seizures were randomized to TGB either 6 or 36 mg/day (14). Speech disorder, somnolence, and blurred vision (amblyopia) occurred statistically significantly more often with TGB 36 mg/day than with TGB 6 mg/day (41). Compared with baseline, the neuropsychological tests of adjustment and mood showed improvement in those patients who received TGB 6 mg/day, and tests of abilities showed improvement in patients treated with TGB 36 mg/day (42). However, the relative contributions of TGB, improved seizure control, and discontinuation of baseline AEDs to these improvements could not be determined.

Another randomized, parallel-group monotherapy study compared TGB and CBZ as initial monotherapy in patients with newly diagnosed partial epilepsy. Neuropsychological testing, administered at baseline and after 6 months of treatment, found no evidence of TGB-related worsening of verbal ability, memory performance, attention, or reaction times (43).

POSTMARKETING EXPERIENCE

TGB was approved in France and Denmark in 1996 and in the United States in 1997. As of December, 2000 over 80,000 people had been treated with TGB without any reports of severe, life-threatening reactions attributable to the drug. Clinical experience seems to suggest some patients can tolerate TGB better when a slow titration schedule is used (44).

Two postmarketing studies evaluated visual fields in TGB-treated patients. In one study, eight patients (mean daily dose, 56 mg) treated for at least 1 year (mean duration, 43 months) showed no changes on visual field testing with the Goldmann and Humphrey methods other than changes attributable to previous brain surgery (45). In the other study, none of 40 TGB-treated patients had abnormalities on Goldmann perimetry or ophthalmologic evaluation suggestive of concentric field constriction (44).

Several case reports of serious adverse events possibly attributable to TGB have been published, including one case each of symptomatic thrombocytopenia (46), complex partial status epilepticus (47), and absence status in a patient with a previous history of absence seizures and primary generalized tonic-clonic seizures (48). Other cases of nonconvulsive status epilepticus, with generalized spikewave electroencephalographic (EEG) abnormalities seen during some of the events, were published (49,50), as well as two cases of partial status epilepticus in a single-blind dose-escalating study (51). In two TGB-treated patients ultimately shown to have nonepileptic seizures, investigation with continuous EEG or EEG-video monitoring during prolonged episodes of stupor was consistent with toxic encephalopathy (52). The incidence of symptoms consistent with nonconvulsive status epilepticus in blinded trials was statistically equivalent among patients who received TGB and those who received placebo, so the clinical importance of isolated reports in patients with partial epilepsy is unclear. Caution appears to be warranted in patients with generalized epilepsy, however.

The safety of TGB during pregnancy is unknown. As of April, 1999, 26 pregnancies in TGB-treated women were reported (data on file, Abbott Laboratories, Abbott Park, IL). Eleven patients carried their pregnancies to term: 10 gave birth to healthy babies, and the baby of the eleventh patient had hip displacement resulting from a breech presentation. Of the 15 other patients, seven had elective abortions, five had miscarriages, one had a blighted ovum, one had an ectopic pregnancy, and one died of a cerebral neoplasm that predated the TGB therapy. The outcome of one pregnancy was not determined.

TGB overdoses ≤800 mg were reported in 47 patients as of April, 1999 (data on file, Abbott Laboratories, Abbott Park, IL). All patients recovered with supportive care; one patient who took 400 mg developed convulsive status

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epilepticus that responded to phenobarbital. Others were noted to have somnolence, impaired consciousness, confusion, agitation, hostility, lethargy, weakness, depressed mood, speech difficulty, and myoclonus. As with other AEDs, discontinuation of TGB should be undertaken slowly, although neither pharmacodynamic tolerance to TGB nor withdrawal seizures have been documented.

TGB serum concentrations can be measured by high-performance liquid chromatography (53), but their clinical utility is uncertain because of the short serum half-life of TGB in induced patients and its high protein binding, and the relationship between serum concentration and side effects has not been demonstrated. Routine monitoring of liver, renal, and bone marrow function does not appear to be necessary.

SUMMARY

Controlled studies have established the safety and tolerability of adjunctive TGB, 30 to 56 mg/day. The side effect profile is generally favorable; neurotoxic symptoms typically occur during the early phases of treatment and can be lessened by a slow titration rate and by taking TGB with food. No significant effects of TGB on systemic function or weight have been documented, and the drug has no significant cognitive, affective, and psychiatric effects. Postmarketing reports of nonconvulsive status epilepticus suggest that TGB treatment should be avoided in patients with a history of generalized epilepsy. Long-term TGB therapy does not appear to affect visual fields. There have been too few pregnancies in women treated with TGB to draw any conclusions about its effects, if any, on developing fetuses.

In the future, head-to-head trials that compare the tolerability of TGB with other AEDs as first add-on treatment should be performed to help establish the place of TGB in the overall treatment of seizures for patients who do not achieve optimum results from initial therapy. Although patients who have medically refractory epilepsy can change to TGB monotherapy, more controlled studies are necessary to confirm the side effect profile of TGB as monotherapy.

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