Antiepileptic Drugs, 5th Edition

Tiagabine

74

Clinical Efficacy and Use in Epilepsy

Reetta Kälviäinen MD, PhD

Head of the Outpatient Clinic, Leader of the Clinical Epilepsy Research Project, Department of Neurology, Kuopio University Hospital and University of Kuopio, Kuopio, Finland

SPECTRUM OF EFFICACY

Evidence from Randomized Controlled Trials

Tiagabine has proven effective as add-on therapy in patients with refractory partial seizures with or without secondary generalization (Table 74.1). The primary clinical evidence of this efficacy is based on five controlled add-on trials in adults with epilepsy unsatisfactorily controlled with current antiepileptic drugs (AEDs).

The first phase II multicenter trials were two small, placebo-controlled, crossover studies. In an initial titration period lasting ≤8 weeks, patients started with a tiagabine dose of 8 mg/day, and the dose was titrated either to reduce seizures sufficiently or to produce unacceptable adverse events. Patients then entered a 4-week fixed-dose period on the dose attained in titration. The maximal dose allowed in the first study was 52 mg/day (1). Patients were eligible to enter the double-blind crossover phase if their seizure frequency had been reduced by ≥25% during the fixed-dose period. In this two-period crossover study, patients were randomized to placebo or tiagabine or to their previously determined dose of tiagabine or placebo, and they remained on each of these two regimens for 7 weeks. The 7-week treatment periods were separated by a 3-week washout period. The median daily dose of tiagabine in the doubleblind phase was 32 mg/day. Of the total 42 patients who contributed data for both periods of the crossover phase, 26% of those with complex partial seizures and 63% with secondarily generalized tonic-clonic seizures (n = 27) experienced a reduction of ≥50% in seizure frequency during the tiagabine period compared with the placebo period. The median seizure rate during the tiagabine treatment period was significantly lower than during the placebo treatment period for complex partial seizures (p = .05) and for secondarily generalized tonic-clonic seizures (p = .009).

The second phase II study used the same design but allowed a maximal dose of 64 mg/day (2). The intent-to-treat group comprised 36 patients who received a mean total daily dose of 46 mg in the tiagabine treatment periods. Tiagabine was significantly better than placebo in reducing all partial seizures (p = .002), complex partial seizures (p < .001), and partial seizures with secondary generalization (p = .030). A total of 46% of patients with complex partial seizures had a ≥50% reduction in weekly seizure rates.

Altogether, 769 patients took part in the three multicenter, parallel-group, double-blind add-on studies in which tiagabine was compared with placebo: the dose-response study, the dose-frequency study, and the thrice-a-day dosing study (3, 4, 5). The dose-ranging multicenter study in the United States had a fixed-dose, placebo-controlled parallel-group design (n = 297) (3). During a 4-week period, tiagabine-treated patients were given increasing doses until the dose level to which they had been randomized was reached (16, 32, or 56 mg/day divided in four equal doses). They then remained on a fixed dose for 12 weeks of double-blind treatment. Median decreases in 4-week complex partial seizure frequency for 32 mg (-2.2) and 56 mg (-2.8) tiagabine groups were significantly greater than for placebo (-0.7) group (p = .03 and p < .03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a ≥50% reduction in the frequency of complex partial seizures compared with 4% in the placebo group (p = .002 and p < .001, respectively).

The dose-frequency study was also a randomized, double-blind, placebo-controlled United States multicenter study with a parallel-group, add-on design (n = 318) (4). The study lasted for 24 weeks and consisted of an 8-week baseline, a 12-week double-blind treatment phase, and a 4-week termination period. During the first month of treatment, doses were increased weekly to 32 mg/day. The treatment groups were placebo, 16 mg tiagabine twice a day (b.i.d.), and 8 mg tiagabine four times a day (q.i.d.). The

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median changes in 4-week complex partial seizure rates were -1.6 (p = .055) for the 16 mg b.i.d. group and -1.2 (p < .05) for the 8 mg q.i.d. group versus -0.2 for placebo. Statistically significant differences between placebo and two tiagabine groups occurred in the proportion of patients experiencing a >50% rate reduction for complex partial, simple partial, and all partial seizure rates.

TABLE 74.1. DATA FROM FIVE DOUBLE-BLIND PLACEBO-CONTROLLED TRIALS AND FROM AN INTEGRATED ANALYSIS OF THESE STUDIES SHOWING THE EFFICACY OF TIAGABINE AS ADD-ON THERAPY IN PARTIAL EPILEPSY

Reference

Number of Patients

Daily Dose (mgday)

Responder Rate (>50% Seizure Reduction) for All Partial Seizures

Tiagabine

Placebo

Richens et al., 1995

42

33

52%

24%a

Crawford et al., 1993

36

46

40%

14%b

Uthman et al., 1998

297

16

10%

4%

   

32

20%

4%a

   

56

31%

4%a

Sachdeo et al., 1997

318

32 (16 mg b.i.d.)

28%

8%a

   

32 (8 mg q.i.d.)

23%

8%a

Kälviäinen et al., 1998

154

30

10%

5%

Ben-Menachem, 1995

951

16-56

23%

9%

b.i.d., twice daily; q.i.d., four times daily.

a p < .01.

b p < .05.

The thrice-a-day dosing study was a Northern-European multicenter parallel-group study that compared a dose of 30 mg/day tiagabine with placebo as add-on therapy (n = 154) (5). The study included 12-week baseline, an 18-week double-blind treatment phase, and a 4-week termination period. The median change from baseline in complex partial seizure rates was -1.3 for patients receiving tiagabine, whereas placebo-treated patients had a median increase of 0.1 in complex partial seizure rates (p < .05). Tiagabine was significantly more effective than placebo in patients with simple partial seizures with respect to the proportion of patients achieving a seizure reduction of ≥50% (21% versus 6%; p < .05).

The meta-analysis across all these three trials for 50% responders showed an odds ratio of 3.03 (95% confidence interval [CI], 2.01 to 4.58) (6). The summary odds ratios for each dose indicate increasing efficacy with increasing doses, with no suggestion of a plateauing of effect at the doses examined in these studies. A 16-mg dose has a fairly small effect of 2.40 (95% CI, 0.65 to 8.87). There is a substantial increase with doses of 30 or 32 mg to an odds ratio of 3.17 (95% CI, 2.03 to 4.96) and a smaller additional gain for a dose level 56 mg, with an odds ratio of 7.95 (95% CI, 3.09 to 20.49).

A multicenter, open-label, randomized, parallel group study compared the efficacy, tolerability, and safety of thrice-a-day and twice-a-day administration dosing of tiagabine as adjunctive therapy for the treatment of refractory patients with partial seizures (7). A total of 347 patients were randomized and treated: 175 thrice daily (t.i.d.) and 172 b.i.d. Each group was administered the same daily dose of tiagabine incremented stepwise during a 12-week fixed-schedule titration period to a target 40 mg/day. The patients were followed for a further 12-week flexible continuation phase. A significantly greater number of patients in the thrice-a-day group completed the fixed schedule titration period (81.4% versus 73.1%; 95% CI, .331, .970; p = .038). The proportion of responders (patients showing a ≥50% decrease in all-seizure frequency from baseline) was similar for both groups (44% for twice-daily and 48% for thrice-daily groups) during last 8 weeks of treatment, and seven (4%) patients in the twice-daily group were seizure free compared with 14 (8%) patients in the thrice-daily group.

A multicenter trial was also performed to determine whether the combination of AEDs with different mechanisms of action was be superior to the combination of AEDs with similar mechanism of action. In this study, patients taking carbamazepine or phenytoin monotherapy with inadequately controlled complex partial seizures were randomized to add-on tiagabine or phenytoin (if previously receiving carbamazepine) or add-on tiagabine or carbamazepine (if previously receiving phenytoin) and were titrated to an optimal dose in a double-blind trial (8). In this trial, tiagabine (n = 170) showed similar efficacy to traditional AED (carbamazepine or phenytoin) (n = 175) adjunctive therapy for complex partial seizures at low average doses of 24 to 28 mg/day. The study also suggested that tiagabine may be better tolerated when it is added to phenytoin or carbamazepine than when carbamazepine and phenytoin are added to each other.

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Evidence from Other Studies

Data are available from six long-term open-label trials. More than half the 2,248 patients were treated with tiagabine for > 1 year. For each type of partial seizure, 30% to 40% of the patients obtained considerable treatment effect, which was maintained after 12 months of treatment (9). Daily doses in the long-term studies were between 24 and 60 mg in most patients, and mean and median doses were 45 mg/day for most studies. However, ≤15% of patients received a dose of between 80 and 120 mg/day after their first year of treatment (10).

Pragmatic trials use larger patient numbers and a longer follow-up than the trials required for drug registration and more closely mimic routine clinical practice. Three such pragmatic studies—in Germany, Poland, and Spain—were conducted with add-on tiagabine in patients with refractory partial epilepsy (11, 12, 13). All had a longer follow-up than that of the pivotal studies, and together these studies included considerably more patients than the studies submitted in the registration dossier. These trials used the newly recommended titration schedule in a total of 1,151 patients, 3 to 93 years old, who were followed-up for ≤6 months. Tiagabine was given thrice daily, at an initial dose of 5 mg/day and following the new titration schedule, with increases of 5 mg/wk. The maintenance dose was titrated individually according to the labeling. The average dose was 30 mg (range, 5 to 90 mg) per day. Rates for 50% responders varied from 41% to 61%, and 8% to 22% of patients became seizure free.

MONOTHERAPY

The efficacy of tiagabine monotherapy in patients with chronic partial epilepsy not satisfactorily controlled by other drugs was studied. A dose-ranging double-blind parallel-group study in 198 patients with refractory epilepsy compared 6 mg/day tiagabine with 36 mg/day after gradual withdrawal of other AEDs over 29 weeks (14). Altogether, 33% of the patients receiving the lower dose completed the study compared with 47% taking the higher dose. For both dose groups, the median complex partial seizure rates decreased significantly during the study compared with baseline (p < .05). However, a higher proportion of patients in the 36 mg/day group experienced a reduction in complex partial seizures of ≥50% compared with the 6 mg/day group (31% versus 18%, p < .05). In addition to showing a dose-response relationship, this study suggested that even a dose of tiagabine as low as 6 mg/day may be effective when used as monotherapy or with noninducing AEDs.

The second study was a double-blind, randomized comparison of slow and fast switching to tiagabine monotherapy from another type of monotherapy, followed by an open-label evaluation of the safety and efficacy of tiagabine as monotherapy for chronic partial epilepsy (15). When a patient did not tolerate the double-blind titration scheme for tiagabine, even slower open uptitration of tiagabine was used. Thirty-four (85%) of the 40 patients were successfully switched to tiagabine monotherapy in either the doubleblind or open-label drug switching scheme. According to this trial, it seems that the open-label uptitration with 5 mg/day, with weekly increments of 5 mg/day, should also be recommended in clinical practice. The retention rate in the study for 12 weeks of tiagabine monotherapy was 63% (25 of 40), and it was 48% for 48 weeks (19 of 40). The initial target dose of tiagabine monotherapy was 10 mg b.i.d., but in the open-label phase, tiagabine could be adjusted upward or downward in individual patients according to clinical adjustment of the investigator up to a maximum daily dose of 70 mg. The median dose was 20 mg/day, and the range was 7.5 to 42.5 mg/day during the first 48 weeks.

Monotherapy in newly diagnosed partial epilepsy was studied by comparing the efficacy and safety of tiagabine versus carbamazepine as monotherapy in a double-blind, randomized, parallel group trial (n = 290) (16). During the 6-week titration, patients were titrated from tiagabine 5 mg/day or carbamazepine 200 mg/day to tiagabine 10 or 15/mg/day or carbamazepine 400 or 600 mg/day in a stepwise fashion. During the 44-week assessment period, the dose could be adjusted within the ranges tiagabine 10 to 20 mg/day or carbamazepine 400 to 800 mg/day. All doses were administered twice daily. The study has so far been published only in abstract form showing a significant difference between the study groups with regard to the end point “time to meeting the exit criterion” (p < .05). An exit criterion was either status epilepticus or the occurrence of the second seizure at maximum tolerated or maximum allowed dose level. In the tiagabine-treated group, 41% (77 of 144), and in the carbamazepine-treated group, 53% (77 of 144) completed the assessment period either seizure free or with a single seizure (p < .05). Failure of tiagabine monotherapy to show efficacy in this trial may relate to the relatively low maximum dose of tiagabine that was allowed to be used.

PEDIATRIC USE

Use of tiagabine in children was studied as adjunctive therapy in >200 pediatric patients. A European study were carried out at two centers in Denmark and at one center in France (17). This 4-month, single-blind study evaluated the tolerability, safety, and preliminary efficacy of ascending doses (0.25 to 1.5 mg/kg/day) of tiagabine add-on therapy in 52 children over 2 years with different syndromes of refractory epilepsy. Tiagabine appeared to reduce seizures more in localization-related epilepsy syndromes than generalized epilepsy syndromes. Seventeen of the 23 patients

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with localization-related epilepsy syndromes entered the fourth dosing period. The 17 patients had a median reduction of seizure rate in the fourth month of treatment of 33% compared with baseline. In comparison, 13 of 22 children with seven different generalized epilepsy syndromes entered the fourth dosing period with a median change of seizure rate of 0%. Among generalized seizures, tonic seizures and atypical absences responded best, with median percentage reductions in the weekly seizure rate of 77% and 63%. The overall maximum daily tiagabine dose level received and tolerated (mean ± standard deviation) was 0.65±0.37 mg/kg.

In the United States, the long-term use of tiagabine was also studied in an open-label extension study in 152 children 2 to 11 years old from antecedent double-blind studies (18). Of the 140 evaluable patients, 10 patients were seizure free with tiagabine add-on therapy and 13 patients achieved freedom from seizures with tiagabine monotherapy for periods ranging from 9 to 109 weeks. The shortest seizure-free or monotherapy durations represented patients with recent enrollment dates at the time of the report. The dose range was from 4 to 66 mg/day, and the average dose was 23.5 mg/day. In a preliminary open trial in infantile spasms, six of 12 infants had a ≥50% seizure reduction at dosages of 0.5 to 3.1 mg/kg/day (19).

MODE OF USE

Indications

Tiagabine is recommended as add-on treatment of adults and children >12 years old with partial seizures, with or without secondary generalization, which cannot be satisfactorily controlled with other AEDs.

Dosing Recommendations

Formulation

In preclinical and clinical studies, the tiagabine dose was expressed in terms of milligrams hydrochloride. A conversion factor of 0.91 has been used to calculate the dose as tiagabine free base, which is available everywhere as 5-, 10-, 15-mg tablets, except in the United States, Canada, and Mexico, where 4-, 12-, 16-, and 20-mg tablets of tiagabine hydrochloride are used (Table 74.2).

Initial Dose and Titration Rate

The current labeling with tiagabine free base states that the initial dosage is 7.5 to 15 mg/day, followed by weekly increments of 5 to 15 mg/day. In the United States, Canada, and Mexico, labeling was already modified toward a lower initial dose of 4 mg/day tiagabine hydrochloride, followed by weekly increments of 4 to 8 mg/day. Phase IV trial and clinical experience to date would lead one to recommend to start tiagabine with 4 or 5 mg/day and to increase the dose gradually by weekly increments of 4 or 5 mg/day, to minimize side effects related to the central nervous system.

TABLE 74.2. CLINICAL USE OF TIAGABINE

Dosage of current formulation must be titrated slowly (4-5 mg/wk) and individually to avoid dizziness.

Tiagabine should always be taken at the end of the meal (food slows rate of absorption).

In case of adverse events, change easily from twice daily to three or four times daily dosing with higher doses.

The usual initial target maintenance dosage in patients taking enzyme-inducing drugs is 30-32 mg/day and in patients not taking enzyme-inducing drugs 15-16 mg/day.

Usual range of maintenance dosage in patients taking enzyme-inducing drugs is ≤50-56 mg/day and in patients not taking enzyme-inducing drugs ≤30-32 mg/day.

High daily doses of ≥70-80 mg are well tolerated for some individual patients.

After an enzyme-inducing agent is removed, tiagabine clearance will decrease, and tiagabine dosage reduction may be necessary.

From phase II and III tiagabine trials, it is clear that some central nervous system-related adverse effects are particularly common with tiagabine treatment, especially dizziness. Patients usually describe the dizziness as a lightheaded or unstable feeling. It is a very nonspecific symptom, usually occurring within 1 to 2 hours of taking a tiagabine dose, and it is usually associated with the peak concentration of the drug. Adverse events more common with tiagabine than with placebo are asthenia (lack of energy), nervousness, tremor, concentration difficulties, depressive mood, and language problems (difficulty in finding words or initiation of speech). The increased risk of central nervous system-related adverse events with tiagabine when compared with placebo is evident only in the titration period; the risk levels off during the fixed-dose period (10). Because of these adverse effects, tiagabine should be titrated slowly. Initial doses can be given twice a day, but a change to thrice-daily dosing is recommended, with doses >30 to 32 mg/day. Tiagabine should always be taken with food, and preferably at the end of meals, to avoid rapid rises in plasma concentrations. Individual doses given four times daily may also be helpful, at least with higher doses. Neither somnolence nor drowsiness was seen more frequently in patients receiving tiagabine than in patients receiving placebo.

Maintenance Dosages

Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking enzyme-inducing AEDs. The usual initial target maintenance dose in patients taking enzyme-inducing drugs is 30

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to 32 mg/day, and in patients not taking enzyme-inducing drugs, it is 15 to 16 mg/day (20). The usual range of maintenance doses in patients taking enzyme-inducing drugs is ≤50 to 56 mg/day, and in patients not taking enzyme-inducing drugs, it is ≤30 to 32 mg/day; however, high daily doses of ≥70 to 80 mg are well tolerated by some patients. Patients taking a combination of inducing and noninducing drugs (e.g., carbamazepine and valproate) should be considered to be induced.

Stopping of Tiagabine Treatment

No AED should be withdrawn suddenly. Although no clinical data are available, it seems sensible to withdraw tiagabine gradually over ≥2 to 3 weeks (20).

Use in Special Populations

Elderly Patients

The pharmacokinetics of tiagabine in elderly patients is similar to that seen in younger patients, hence there should be no need for dosage modification (21).

Children

Tiagabine has not been investigated in adequate and well-controlled clinical trials in patients <12 years old. The apparent clearance and volume of distribution of tiagabine per unit body surface area or per kilogram were fairly similar in 25 children (age, 3 to 10 years) and in adults taking enzyme-inducing AEDs. In children who were taking a noninducing AED, the clearance of tiagabine, based on body weight and body surface area, was twofold and 1.5-fold higher, respectively, than in uninduced adults with epilepsy, a finding suggesting that dosage requirements (on the basis of milligrams per kilograms) may be higher in children (22). The maximal tolerated doses for children >2 years old used in one study were 0.65±0.37 mg/kg. Patients receiving inducing AEDs had only slightly higher doses than patients receiving noninducing AEDs, but the difference was not significant (0.73±0.44 versus 0.61±0.32 mg/kg) (17).

Patients with Renal Impairment

The pharmacokinetics of tiagabine is unaffected in patients with renal impairment or in patients with renal failure requiring hemodialysis (23).

Patients with Hepatic Impairment

Compared with normal subjects, patients with mild or moderate liver function impairment had higher and more prolonged plasma concentrations of both total and unbound tiagabine after the administration of tiagabine. The patients with hepatic impairment also had more neurologic side effects. Tiagabine should therefore be given with caution to patients with epilepsy who have impaired hepatic function. Patients with impaired liver function may require reduced initial and maintenance doses of tiagabine or longer dosing intervals compared with patients with normal hepatic function. These patients should be monitored closely because of the potential for increased incidence of neurologic side effects (24). Tiagabine should not be used in patients with severely impaired liver function.

Precautions

Pregnancy

Teratogenic effects were seen in the offspring of rats exposed to maternally toxic doses of tiagabine, but not in animals receiving nontoxic dosages. Only limited pregnancy data involving tiagabine, which show no clear teratogenicity, are available (25). Therefore, tiagabine cannot be recommended for women who are pregnant or at risk of becoming pregnant, and it should be used only if the potential benefit justifies the potential risk to the fetus.

Unclassified Seizures or Generalized Epilepsy

Tiagabine should not be used in patients with unclassified epilepsy or in patients with generalized epilepsy, especially those with a history of absence or myoclonic seizures, with a history of spike-and-wave discharges on electroencephalography (EEG), or those with nonconvulsive status epilepticus (20). Tiagabine has not yet been shown to be effective in these patients, and evidence indicates that AEDs that increase γ-aminobutyric acid (GABA)-ergic transmission may exacerbate or induce absences or myoclonus (26). Patients with history of spike-and-wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with cognitive or neuropsychiatric events. In the documented cases of spike-and-wave discharges on EEG with cognitive or neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment (10).

History of Severe Behavioral Problems and Depression

The addition of tiagabine in clinical trials was associated significantly more often with depression than the use of placebo (5% versus 2%) (27). If the patient has a history of behavioral problems or depression, treatment with tiagabine should be initiated at a low initial dose under close supervision because there may be an increased risk of

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recurrence of these symptoms during treatment with tiagabine.

CURRENT ROLE OF TIAGABINE IN EPILEPSY TREATMENT

Tiagabine, a selective GABA uptake inhibitor, is effective against all partial seizures and has a relatively favorable safety profile. The frequency of idiosyncratic drug-related reactions, particularly cutaneous reactions, is low with tiagabine, and in rare cases the relationship with tiagabine treatment has been unproven. Moreover, tiagabine has a favorable cognitive profile. The characteristic concentric visual field defect seen with vigabatrin treatment (28) was not observed in two tiagabine monotherapy trials (29,30). These features support the use of tiagabine as add-on treatment in partial epilepsy, for example, after treatment failure with a first-line sodium channel blocking AED or if a first-line AED has caused idiosyncratic reactions. Tiagabine is also suitable in patients for whom it is particularly important that the AED does not cause any deterioration in cognitive performance (31,32, 33, 34, 35). A controlled-released formulation would offset any potential clinical disadvantage stemming from tiagabine's short elimination half-life, particularly in patients receiving enzyme-inducing AEDs (36).

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