Tiagabine Hydrochloride
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Questions & Answers
Side Effects & Adverse Reactions
Seizures in Patients Without Epilepsy: Postmarketing reports have shown that tiagabine hydrochloride use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of tiagabine hydrochloride as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.
The tiagabine hydrochloride dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of tiagabine hydrochloride by inducing its metabolism. Use of tiagabine hydrochloride without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based (see DOSAGE AND ADMINISTRATION).
Safety and effectiveness of tiagabine hydrochloride have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.
In nonepileptic patients who develop seizures while on tiagabine hydrochloride treatment, tiagabine hydrochloride should be discontinued and patients should be evaluated for an underlying seizure disorder.
Seizures and status epilepticus are known to occur with tiagabine hydrochloride overdosage (see OVERDOSAGE).
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including tiagabine hydrochloride, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 4 shows absolute and relative risk by indication for all evaluated AEDs.
| Indication |
Placebo Patients with Events per 1000 Patients |
Drug Patients with Events per 1000 Patients |
Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients |
Risk Difference: Additional Drug Patients with Events per 1000 Patients |
| Epilepsy |
1 |
3.4 |
3.5 |
2.4 |
| Psychiatric |
5.7 |
8.5 |
1.5 |
2.9 |
| Other |
1 |
1.8 |
1.9 |
0.9 |
| Total |
2.4 |
4.3 |
1.8 |
1.9 |
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing tiagabine hydrochloride or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Withdrawal Seizures: As a rule, antiepilepsy drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In a placebo-controlled, double-blind, dose-response study (Study 1 described in CLINICAL STUDIES) designed, in part, to investigate the capacity of tiagabine hydrochloride to induce withdrawal seizures, study drug was tapered over a 4-week period after 16 weeks of treatment. Patients’ seizure frequency during this 4-week withdrawal period was compared to their baseline seizure frequency (before study drug). For each partial seizure type, for all partial seizure types combined, and for secondarily generalized tonic-clonic seizures, more patients experienced increases in their seizure frequencies during the withdrawal period in the three tiagabine hydrochloride groups than in the placebo group. The increase in seizure frequency was not affected by dose. tiagabine hydrochloride should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Cognitive/Neuropsychiatric Adverse Events: Adverse events most often associated with the use of tiagabine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride.
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 hydrochloride was 0.8% (4 of 494 patients) versus 0.7% (2 of 275 patients) receiving placebo. Among the patients treated with tiagabine hydrochloride 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 hydrochloride 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 hydrochloride is not available, it is impossible to state whether or not treatment with tiagabine hydrochloride 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 hydrochloride.
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 2531 patients with epilepsy (3831 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 hydrochloride (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 hydrochloride, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving tiagabine hydrochloride are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to tiagabine hydrochloride, 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.
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Manufacturer Warnings
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FDA Labeling Changes
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Uses
Tiagabine hydrochloride tablets are indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.
History
There is currently no drug history available for this drug.
Other Information
Tiagabine hydrochloride, USP is an antiepilepsy drug available as 2 mg and 4 mg tablets for oral administration. Its chemical name is (-)-(R)-1-[4,4-Bis(3- methyl-2-thienyl)-3-butenyl]nipecotic acid hydrochloride, its molecular formula is C20H25NO2S2 HCl, and its molecular weight is 412. Tiagabine hydrochloride is a white to off-white, odorless, crystalline powder. It is insoluble in heptane, sparingly soluble in water, and soluble in aqueous base. The structural formula is:
Inactive Ingredients
Tiagabine hydrochloride tablets contain the following inactive ingredients: Hydrogenated vegetable oil, anhydrous lactose, butylated hydroxyanisole, pregelatinized maize starch, colloidal silicon dioxide, talc, crospovidone, titanium dioxide, hypromellose, polyethylene glycol.
In addition, individual tablets contain:
2 mg tablets: FD&C Yellow No. 6 and polysorbate 80.
4 mg tablets: Lactose monohydrate and D&C Yellow No. 10.
Sources
Tiagabine Hydrochloride Manufacturers
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Sun Pharmaceutical Industries Limited
![Tiagabine Hydrochloride Tablet, Film Coated [Sun Pharmaceutical Industries Limited ]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Tiagabine Hydrochloride | Sun Pharmaceutical Industries Limited
General:
Tiagabine hydrochloride tablets are given orally and should be taken with food. Do not use a loading dose of tiagabine hydrochloride tablets Dose titration: Rapid escalation and/or large dose increments of tiagabine hydrochloride tablets should not be used. Missed dose(s): If the patient forgets to take the prescribed dose of tiagabine hydrochloride tablets at the scheduled time, the patient should not attempt to make up for the missed dose by increasing the next dose. If a patient has missed multiple doses, patient should refer back to his or her physician for possible re-titration as clinically indicated. Dosage adjustment of tiagabine hydrochloride tablets should be considered whenever a change in patient's enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent.
The blood level of tiagabine obtained after a given dose depends on whether the patient also is receiving a drug that induces the metabolism of tiagabine. The presence of an inducer means that the attained blood level will be substantially reduced. Dosing should take the presence of concomitant medications into account.
Tiagabine hydrochloride tablets are recommended as adjunctive therapy for the treatment of partial seizures in patients 12 years and older.
The following dosing recommendations apply to all patients taking tiagabine hydrochloride tablets:Induced Adults and Adolescents 12 Years or Older: The following dosing recommendations apply to patients who are already taking enzyme-inducing antiepilepsy drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). Such patients are considered induced patients when administering tiagabine hydrochloride tablets.
Table 7: Typical Dosing Titration Regimen for Patients Already Taking Enzyme-Inducing AEDs Initiation and Titration Schedule Total Daily Dose Week 1
In adolescents 12 to 18 years old, tiagabine hydrochloride tablets should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of tiagabine hydrochloride tablets may be increased by 4 mg at the beginning of Week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration.
In adults, tiagabine hydrochloride tablets should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of tiagabine hydrochloride tablets may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 56 mg/day have not been systematically evaluated in adequate and well-controlled clinical trials.
Experience is limited in patients taking total daily doses above 32 mg/day using twice daily dosing. A typical dosing titration regimen for patients taking enzyme-inducing AEDs (induced patients) is provided in Table 7.
Initiate at 4 mg once daily
4 mg/day
Week 2
Increase total daily dose by 4 mg
8 mg/day
(in two divided doses)
Week 3
Increase total daily dose by 4 mg
12 mg/day
(in three divided doses)
Week 4
Increase total daily dose by 4 mg
16 mg/day
(in two to four divided doses)
Week 5
Increase total daily dose by 4 to 8 mg
20 to 24 mg/day
(in two to four divided doses)
Week 6
Increase total daily dose by 4 to 8 mg
24 to 32 mg/day
(in two to four divided doses)
Usual Adult Maintenance Dose in Induced Patients:
32 to 56 mg/day in two to four divided doses
Non-Induced Adults and Adolescents 12 Years or Older: The following dosing recommendations apply to patients who are taking only non-enzyme-inducing AEDs. Such patients are considered non-induced patients:
Following a given dose of tiagabine hydrochloride tablets, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of tiagabine hydrochloride tablets. These patients may also require a slower titration of tiagabine hydrochloride tablets compared to that of induced patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non-Induced Patients). -
Cima Laboratories, Inc.
Tiagabine Hydrochloride | Cima Laboratories, Inc.
General:The blood level of tiagabine obtained after a given dose depends on whether the patient also is receiving a drug that induces the metabolism of tiagabine. The presence of an inducer means that the attained blood level will be substantially reduced. Dosing should take the presence of concomitant medications into account.
Tiagabine HCl is recommended as adjunctive therapy for the treatment of partial seizures in patients 12 years and older.
The following dosing recommendations apply to all patients taking tiagabine HCl:
Tiagabine HCl is given orally and should be taken with food. Do not use a loading dose of tiagabine HCl. Dose titration: Rapid escalation and/or large dose increments of tiagabine HCl should not be used. Missed dose(s): If the patient forgets to take the prescribed dose of tiagabine HCl at the scheduled time, the patient should not attempt to make up for the missed dose by increasing the next dose. If a patient has missed multiple doses, patient should refer back to his or her physician for possible re-titration as clinically indicated. Dosage adjustment of tiagabine HCl should be considered whenever a change in patient’s enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent. Induced Adults and Adolescents 12 Years or Older:The following dosing recommendations apply to patients who are already taking enzyme-inducing antiepilepsy drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). Such patients are considered induced patients when administering tiagabine HCl.
In adolescents 12 to 18 years old, tiagabine HCl should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of tiagabine HCl may be increased by 4 mg at the beginning of Week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration.
In adults, tiagabine HCl should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of tiagabine HCl may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 56 mg/day have not been systematically evaluated in adequate and well-controlled clinical trials.
Experience is limited in patients taking total daily doses above 32 mg/day using twice daily dosing. A typical dosing titration regimen for patients taking enzyme-inducing AEDs (induced patients) is provided in Table 7.
Table 7: Typical Dosing Titration Regimen for Patients Already Taking Enzyme-Inducing AEDs Initiation and Titration Schedule Total Daily Dose Week 1 Initiate at 4 mg once daily 4 mg/day Week 2 Increase total daily dose by 4 mg 8 mg/day
(in two divided doses) Week 3 Increase total daily dose by 4 mg 12 mg/day
(in three divided doses) Week 4 Increase total daily dose by 4 mg 16 mg/day
(in two to four divided doses) Week 5 Increase total daily dose by 4 to 8 mg 20 to 24 mg/day
(in two to four divided doses) Week 6 Increase total daily dose by 4 to 8 mg 24 to 32 mg/day
(in two to four divided doses) Usual Adult Maintenance Dose in Induced Patients: 32 to 56 mg/day in two to four divided doses Non-Induced Adults and Adolescents 12 Years or Older:The following dosing recommendations apply to patients who are taking only non-enzyme-inducing AEDs. Such patients are considered non-induced patients:
Following a given dose of tiagabine HCl, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of tiagabine HCl. These patients may also require a slower titration of tiagabine HCl compared to that of induced patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non-Induced Patients).
![Tiagabine Hydrochloride Tablet [Cima Laboratories, Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=25225511-70b8-4377-ad4f-6629025ac75f&name=25225511-70b8-4377-ad4f-6629025ac75f-08.jpg)
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