Safety of Long-Term Treatment with Tiagabine

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Seizure 2000; 9: 431–435 doi: 10.1053/seiz.2000.0433, available online at http://www.idealibrary.com on

Safety of long-term treatment with tiagabine

† ‡ § TOUFIC FAKHOURY , BASIM UTHMAN & BASSEL ABOU-KHALIL

† Department of Neurology, University of Kentucky Medical Center, Lexington, KY, USA; ‡Departments of Neurology and Neuroscience, University of Florida College and Department of Veterans Affairs Medical Center, Gainesville, FL, USA; §Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence to: Touﬁc Fakhoury, MD, Department of Neurology, University of Kentucky Medical Center, Ken- tucky clinic- Rm L445, Lexington, KY 40536-0284, USA. E-mail: [email protected]

The aim of this study was to evaluate the safety of long-term treatment with tiagabine. We reviewed the case report forms of patients with refractory partial epilepsy who took tiagabine for longer than 6 months in two long-term studies. We classified all adverse events based on severity and persistence, and recorded the dose at onset of each adverse event. We then divided patients into those treated for 6–12 months, 12–24 months and >24 months. We compared the adverse event profile and change in seizure frequency among the three groups. Forty-two patients took tiagabine for longer than 6 months. The mean duration of treatment was 22.6 months. The mean monthly seizure frequency was 12.7 at baseline and 8.1 at study termination (36% decrease). The most common adverse events were: tiredness (56%), headache (46%), dizziness (44%), visual symptoms (blurring, difficulty focusing, diplopia) (39%), altered mentation (32%), and tremor (31%). The adverse event profile was comparable among the three groups. Seizure frequency was significantly more improved in the >24 months group. Long-term treatment with tiagabine is well tolerated. The most important predictor of long-term therapy with tiagabine was the degree of seizure improvement. c 2000 BEA Trading Ltd

Key words: tiagabine; epilepsy; long term; safety.

INTRODUCTION in two centers. We concentrated on patients who took the medication for 6 months or longer and re- Tiagabine (Gabitril) is a novel antiepileptic agent ap- viewed their case-report forms and medical records. proved for use in the USA since 19971. It is a nipecotic We recorded age, gender, type(s) of seizures and num- acid derivative with high bioavailability (90–95%), ber of antiepileptic drugs (AEDs) previously tried. We dose-independent absorption, high protein binding recorded the baseline AED(s) and noted any change in (96%), first-order elimination pharmacokinetics, and these medications during the studies. We noted seizure it is metabolized extensively through the hepatic cy- frequency at baseline and at study termination. We tochrome P450 enzyme system2, 3. The mechanism of also recorded the duration of treatment with tiagabine action is through selective binding to a GABA up- and the dose used for the longest period of time. We take carrier (GAT-1), therefore inhibiting the reuptake looked at the maximum dose of tiagabine achieved of GABA to neurons and glia4, 5. Its efficacy against for each patient and the reason for its discontinuation partial seizures and its side-effect profile have been when applicable. well detailed in several reports6–13. Less has been pub- We evaluated all adverse events encountered dur- lished about the long-term use of tiagabine8–10. We ing the studies. We divided adverse events into ma- report our experience with the safety of long-term jor categories based on symptoms reported. The cate- tiagabine therapy in patients with refractory epilepsy. gory of ‘tiredness’, for example, included sleepiness, drowsiness, decreased energy, and sluggishness. The term ‘dizziness’ encompassed vertigo, unsteadiness, MATERIALS AND METHODS and a ‘drugged feeling’. Visual symptoms included We reviewed the results of two long-term, open- blurred vision, diplopia, and decreased visual focus. label studies of tiagabine in refractory partial epilepsy Gastrointestinal symptoms included nausea, vomit-

1059–1311/00/060431 + 05 $35.00/0 c 2000 BEA Trading Ltd

432 T. Fakhoury et al. ing, diarrhea, constipation, and abdominal discom- The mean duration of treatment with tiagabine fort. Nervousness also referred to shakiness and jitters, was 22.5 months for all patients. The mean dose whereas emotional lability included feeling ‘high’ as of tiagabine that patients took for the longest time 1 well as depression. The term ‘altered mentation’ in- was 49 mg d− . The dose of tiagabine taken for the cluded complaints of a ‘blank feeling’, confusion, longest period of time did not necessarily represent and/or disorientation. We then classified all adverse the highest dose achieved; the mean maximal dose was 1 events based on severity (mild–moderate–severe) and 59 mg d− . The mean monthly seizure frequency was persistence (transient–persistent). We also recorded 12.7 at baseline and 8.1 at the end of follow-up, this the dose of tiagabine at the onset of each adverse event. represented a 36% decrease in seizure frequency. The We then divided the patients into three groups based median monthly seizure frequency was seven at base- on the duration of treatment with tiagabine; patients line and four at the end of follow-up (43% decrease). who took the drug for 6–12 months (19 patients, mean The most common adverse events were tiredness, duration of treatment 8 months), patients who took headache, dizziness, visual symptoms, altered menta- the drug for 12–24 months= (6, mean duration of treat- tion, tremor, memory problems, gastrointestinal symp- ment 15 months), and those who took the drug for toms, nervousness, paresthesias, and emotional labil- greater= than 24 months (17, mean duration of treat- ity (Table 1). Less common adverse events were in- ment 43 months). The two largest groups were somnia (four patients), decreased concentration (three those who= took the drug for 6–12 months and greater patients), tinnitus (three patients), auditory hallucina- than 24 months. We compared these two groups for tions (one patient), generalized stiffness (one patient), age, gender, number of AEDs previously tried, num- and speech disturbance (one patient). Adverse events ber of AEDs at baseline, and change in AEDs dur- were mostly mild to moderate in intensity and tran- ing the studies as well as seizure frequency at baseline sient in nature. Reducing tiagabine or concomitant and study termination. We also compared the adverse AED doses relieved most adverse events. Only three event profile among the two groups, including the dose patients discontinued the medication because of ad- at onset, frequency, and persistence. verse events. We used the chi-squared method and Fisher’s exact One particular adverse event, altered mentation, oc- test for statistical analysis. curred in 13 patients (32%). This was generally de- scribed as episodes of confusion or a blank feeling. RESULTS Four patients had associated decreased responsive- ness and subtle twitching of one or more limbs, which 1 A total of 59 patients in two centers received tiagabine started at a mean dose of 51 mg d− . An EEG ob- as a part of various studies of the treatment of partial tained in two of these patients showed concomitant seizures. Four patients who participated in the double- generalized bisynchronous rhythmic slow wave activ- blind phase of a dose–response trial exited without en- ity. No patient acutely responded to repeated doses rollment in the long-term, open-label extension of the of benzodiazepines. One patient consequently discon- study. The other 55 patients participated in two long- tinued tiagabine. The others had significant reduction term studies of tiagabine in the treatment of refrac- in seizure frequency and as a result only reduced the tory partial seizures. Forty-two of those 55 patients dose of tiagabine (two patients) or the concomitant (76%) took tiagabine for longer than 6 months and AED (one patient) with improvement or resolution of constituted the study population. There were 24 fe- symptoms. males and 18 males; the mean age was 36 years (range: Comparison of the two largest groups of patients 13–70). They had previously tried an average of 5.5 (6–12 months and greater than 24 months) revealed AEDs prior to enrollment in a tiagabine study. The similar demographic data (Table 2). The only major most common baseline AEDs were carbamazepine difference was the degree of improvement in seizure (21 patients), phenytoin (16 patients) and divalproex control, which was significantly in favor of the greater sodium (ten patients). At baseline, 26 patients were on than 24 months groups. The adverse event profile was one AED, 14 were on two AEDs, and one patient was also generally comparable among the two groups (Ta- on three AEDs. Twenty-nine of 42 patients remained ble 3). Only emotional lability occurred significantly on the same baseline AEDs during the course of the more frequently in the greater than 24 months group. study. Of these 29 patients, 19 were on one AED, nine were on two AEDs, and one was on three. Among the other 12 patients, five were on two AEDs and reduced DISCUSSION to one drug, four were on one AED and changed to a different drug, one was on one AED and changed to a We report our experience with long-term treatment of different drug and two patients were on one AED and refractory epilepsy with tiagabine. In our series, 76% added another drug. of patients with refractory epilepsy who were exposed Safety of long-term treatment with tiagabine 433

Table 1: Adverse events with long-term tiagabine therapy.

Adverse event Number of Severity Persistence Mean onset 1 patients Mild Moderate Severe Transient Persistent dose (mg d− ) Tiredness 23 17 5 1 18 5 40 Headache 19 11 7 1 11 8 30 Dizziness 18 12 6 0 14 4 43 Visual symptoms 16 13 3 0 13 3 36 Altered mentation 13 7 5 1 11 2 50 Tremor 13 11 2 0 8 5 36 Memory problems 9 6 3 0 2 7 41 GI symptoms 8 8 0 0 7 1 42 Nervousness 8 4 3 1 7 1 37 Paresthesias 7 5 1 1 4 3 30 Emotional lability 6 6 0 0 5 1 47

Table 2: Comparison of the three treatment groups for age, seizure control and tiagabine (TGB) dose.

Length of Number of Mean age Mean Prior # Baseline End seizure % change Maximum Longest TGB 1 treatment patients (years) duration of AEDs seizure frequency TGB dose dose (mg d− ) 1 (months) (months) treatment frequency (mg d− ) 6–12 19 41 8 5 10.2 9.1 10.9 52 44 12–24 6 32 15 6.5 9.3 4.8 47.8 70 61 >24 17 32 43 6.3 16.6 8 52 64 49 P value NS NS NS NS NS 0.006 NS NS

1 to tiagabine and entered an extension study continued range (32–56 mg d− ) for patients on concurrent hep- the medication for longer than 6 months. The most atic enzyme-inducing AEDs15. common adverse events related to the central nervous One specific adverse event, altered mentation, has system and were tiredness, headache, dizziness, vi- received particular attention with some reports sug- sual symptoms, altered mentation, tremor, and mem- gesting that it may represent a form of non-convulsive ory problems. They were, therefore, generally com- status epilepticus (NCSE)16–19. The evidence for parable to previous reports6–13. All but one of our NCSE was given in some case reports of NCSE in patients were on at least one other AED, and one of the association with TGB therapy16–19. In some instances disadvantages of add-on trials is the tendency to over- there was no EEG confirmation of the suspected di- estimate adverse events14. However, the safety profile agnosis16, and where the EEG was performed during of tiagabine has been similar in both add-on6, 8–13 and the episode the published figures can be interpreted as monotherapy studies7. Overall, in the clinical trials, showing bisynchronous slow wave activity consistent 21% of patients discontinued the medication because with encephalopathy17–19. NCSE may be a rare occur- of adverse events, most commonly dizziness, somno- rence with TGB therapy20 comparable in incidence lence, depression, confusion, and asthenia2. Our find- to other cohorts of patients with epilepsy followed ings are somewhat similar, with dizziness, decreased over a long period of time21. Our experience sug- memory, altered mentation and headache causing dis- gests that in the majority of patients this adverse event continuation of the drug after long-term therapy in may represent a dose-related encephalopathic state three patients (7%). The smaller number of patients due to intolerance of tiagabine itself or in combination discontinuing the drug because of adverse events in with other AEDs rather than NCSE. Abou-Khalil22 our series may reflect the open-label nature of the reported two patients with prolonged episodes of al- trials where frequent adjustments of doses of medi- tered mental status, twitching of upper extremities and cations are possible. In addition, only patients who concomitant EEG showing rhythmic generalized slow were treated for 6 months or more were included in waves intermixed with sharp waves and no response this study, and adverse effects resulting in discontin- to lorazepam in one. Both patients were then mon- uation may be more likely early in therapy. Adverse itored with continuous video-EEG following with- events were mostly mild to moderate in severity, tran- drawal of their AEDs; both had only non-epileptic sient in nature, and occurred at relatively large doses spells and no evidence for epilepsy. This further sug- of tiagabine. In fact, the mean daily dose of tiagabine gests that the manifestations reported represent an en- used for the longest period of times was 49 mg, which cephalopathic state induced by tiagabine rather than approaches the higher end of the recommended dose NCSE. 434 T. Fakhoury et al.

Table 3: Comparison of the three treatment groups for adverse events.

Length of Tiredness Headache Dizziness Vis Alt Tremor Memory GI Paresthesias Emotional Nervousness treatment sxs MS sxs lability 6–12 months 53 37 37 32 32 32 32 11 11 0 5 12–24 months 67 50 83 50 0 33 0 33 33 33 33 >24 months 53 53 35 35 35 29 18 24 18 24 29 P value NS NS NS NS NS NS NS NS NS 0.04 NS

Results are expressed as percentage of patients experiencing side-effects. Vis sxs, visual symptoms; Alt MS, altered mentation; GI sxs, gastrointestinal symptoms.

Another group of adverse effects that are of interest ACKNOWLEDGEMENTS are the visual symptoms. Vigabatrin, another GABA- ergic agent has been associated with visual field con- This study was supported in part by Abbott Laborato- striction, as well as other manifestations reflecting reti- ries. Drs Fakhoury and Uthman are both on the speak- nal toxicity. Our patients experienced visual symp- ers’ bureau of Abbott Laboratories. toms commonly encountered with other AEDs, mainly blurring of vision, difficulty focusing, and diplopia. There are now two reports indicating lack of occur- REFERENCES rence of visual constriction with long-term use of 22, 23 1. F-D-C Rep. The pink sheet. 1997; 59: 6–7. tiagabine . 2. Gustavson, L. E. and Mengel, H. B. Pharmacokinetics of An interesting finding in our study was the similar- tiagabine, a γ -aminobutyric acid-uptake inhibitor, in healthy ity of adverse events encountered in patients who took subjects after single and multiple doses. Epilepsia 1995; 36: tiagabine for 6–12 months and those who took it for 605–611. 3. Luer, M. S. and Rhoney, D. H. Tiagabine: a novel antiepileptic longer than 2 years. There was no significant differ- drug. Annals of Pharmacotherapy 1998; 32: 1173–1180. ence in the safety profile among the two groups both 4. Braestrup, C., Nielsen, E. B., Sonnewald, U. et al. (R)- in terms of the types and frequency of individual ad- N-[4,40-bis(3-methyl-2-thienyl)but-3-en-1-yl] nipecotic acid verse events. Emotional lability, which seemed to oc- binds with high affinity to the brain γ -aminobutyric acid uptake carrier. Journal of Neurochemistry 190; 54: 639–647. cur more frequently in the longer treated group, was 5. Borden, L. A., Dhar, T. G. M., Smith, K. E. et al. Tiagabine, mostly transient (75%). Longer duration of treatment SKF 89976-A, CI-966, and NNC-711 are selective for cloned with tiagabine, therefore, generally does not seem to GABA transport GAT-1. European Journal of Pharmacology 1994; 269: 219–224. predispose patients to greater frequency or severity of 6. Richens, A., Chadwick, D. W., Duncan, J. S. et al. Adjunc- adverse events. Patients who took the medication for tive treatment of partial seizures with tiagabine: a placebo- greater than 2 years had significantly less seizures than controlled trial. Epilepsy Research 1995; 21: 37–42. those who took it for 6–12 months (52% vs. 10.9% 7. Schachter, S. C. Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 1995; 36 (Suppl. 6): S2–6. reduction, respectively). Therefore, the degree of im- 8. Leppick, I. E. Tiagabine: the safety landscape. Epilepsia 1995; provement in seizure control and not adverse events 36 (Suppl. 6): S10–S13. was the most important predictor of long-term therapy 9. Ben-Menachem, E. International experience with tiagabine with tiagabine in our group. add-on therapy. Epilepsia 1995; 36 (Suppl. 6): S14–S21. Although the safety of tiagabine was recently re- 10. Leppick, I. E., Gram, L., Deaton, R. and Sommerville, K. W. 10 Safety of tiagabine: summary of 53 trials. Epilepsy Research ported in detail , our study adds valuable informa- 1999; 33: 235–246. tion. We emphasized long-term therapy (>6 months) 11. Sachdeo, R. C., Leroy, R. F., Krauss, G. L. et al. Tiagabine and found that it did not result in emergence of new, therapy for complex partial seizures: a dose-frequency study. unexpected adverse events. We found that long-term Archives of Neurology 1997; 54: 595–601. 12. Kalvi¨ ainen,¨ R., Brodie, M. J., Duncan, J., Chadwick, D., Ed- treatment with relatively high doses of tiagabine is wards, D. and Lyby, K. A double-blind, placebo-controlled well tolerated in patients with refractory epilepsy. We trial of tiagabine given three-times daily as add-on therapy for also compared the safety and efficacy of tiagabine refractory partial seizures. Epilepsy Research 1998; 30: 31–40. among patients with variable duration of exposure to 13. Uthman, B. M., Rowan, A. J., Ahmann, P. A. et al. Tiagabine for complex partial seizures: a randomized, add-on, dose- the agent and found that long-term therapy was mostly response trial. Archives of Neurology 1998; 55: 56–62. dependent on improvement of seizure frequency. Con- 14. Beydoun, A. Monotherapy trials of new antiepileptic drugs. tinued assessment of long-term safety is important for Epilepsia 1997; 38 (Suppl. 9): S21–S31. rd all new AEDs. The absence of cumulative or unex- 15. Gabitril. Physician’s Desk Reference. 53 Edition, Montvale, NJ, The Medical Economics Company, 1999: pp. 447–451. pected late toxicity will improve neurologists’ comfort 16. Schapel, G. and Chadwick, D. Tiagabine and status epilepti- level with the use of these agents. cus. Seizure 1996; 5: 153–156. Safety of long-term treatment with tiagabine 435

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