Tiagabine Hydrochloride 4 mg Tablet, Film Coated, 30-count — NDC 0093-5031-56 (Billing 00093-5031-56)

WARNINGS Seizures in Patients Without Epilepsy: Post-marketing reports have shown that tiagabine HCl 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 HCl 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 HCl 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 HCl by inducing its metabolism. Use of tiagabine HCl 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 HCl 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 HCl treatment, tiagabine HCl should be discontinued and patients should be evaluated for an underlying seizure disorder. Seizures and status epilepticus are known to occur with tiagabine HCl overdosage (see OVERDOSAGE ).

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including tiagabine HCl, 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 (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis 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: Ad… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of tiagabine HCl in combination with other antiepilepsy drugs not seen at an equivalent frequency among placebo-treated patients were dizziness/light-headedness, asthenia/lack of energy, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, and thinking abnormal/difficulty with concentration or attention. Approximately 21% of the 2531 patients who received tiagabine HCl in clinical trials of epilepsy discontinued treatment because of an adverse event.

The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%). In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with tiagabine HCl and 6% for the placebo group. The most common adverse events considered the primary reason for discontinuation were confusion (1.2%), somnolence (1.0%), and ataxia (1.0%).

Adverse Event Incidence in Controlled Clinical Trials: Table 5 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients treated with tiagabine HCl for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the tiagabine HCl group. In these studies, either tiagabine HCl or placebo was added to the patient’s current antiepilepsy drug therapy. Adverse events were usually mild or moderate in intensity.

The prescriber should be aware that these figures, obtained when tiagabine HCl was added to concurrent antiepilepsy drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Table 5: Treatment-Emergent Adverse Event 1 Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with tiagabine HCl and numerically more frequent than in the placebo group) Body System/COSTART Tiagabine HCl N=494 % Placebo N=275 % Body as a Whole Abdominal Pain 7 3 Pain (unspecified) 5 3 Cardiovascular Vasodilation 2 1 Digestive Nausea 11 9 Diarrhea 7 3 Vomiting 7 4 Increased Appetite 2 0 Mouth Ulceration 1 0 Musculoskeletal Myasthenia 1 0 Nervous System Dizziness 27 15 Asthenia 20 14 Somnolence 18 15 Nervousness 10 3 Tremor 9 3 Difficulty with Concentration/Attention* 6 2 Insomnia 6 4 Ataxia 5 3 Confusion 5 3 Speech Disorder 4 2 Difficulty with Memory* 4 3 Paresthesia 4 2 Depression 3 1 Emotional Lability 3 2 Abnormal Gait 3 2 Hostility 2 1 Nystagmus 2 1 Language Problems* 2 0 Agitation 1 0 Respiratory System Pharyngitis 7 4 Cough Increased 4 3 Skin and Appendages Rash 5 4 Pruritus 2 0 1 Patients in these add-on studies were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to tiagabine HCl or placebo.

Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. * COSTART term substituted with a more clinically descriptive term. Other events reported by 1% or more of patients treated with tiagabine HCl but equally or more frequent in the placebo group were: accidental injury, chest pain, constipation, flu syndrome, rhinitis, anorexia, back pain, dry mouth, flatulence, ecchymosis, twitching, fever, amblyopia, conjunctivitis, urinary trac… [Excerpted — this section continues on DailyMed.]

Drug Interactions In evaluating the potential for interactions among co-administered antiepilepsy drugs (AEDs), whether or not an AED induces or does not induce metabolic enzymes is an important consideration. Carbamazepine, phenytoin, primidone, and phenobarbital are generally classified as enzyme inducers; valproate and gabapentin are not. Tiagabine HCl is considered to be a non-enzyme inducing AED (see PRECAUTIONS, General, Use in Non-Induced Patients ).

The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy. Effects of Tiagabine HCl on other Antiepilepsy Drugs (AEDs): Phenytoin : Tiagabine had no effect on the steady-state plasma concentrations of phenytoin in patients with epilepsy. Carbamazepine : Tiagabine had no effect on the steady-state plasma concentrations of carbamazepine or its epoxide metabolite in patients with epilepsy.

Valproate : Tiagabine causes a slight decrease (about 10%) in steady-state valproate concentrations. Phenobarbital or Primidone : No formal pharmacokinetic studies have been performed examining the addition of tiagabine to regimens containing phenobarbital or primidone. The addition of tiagabine in a limited number of patients in three well-controlled studies caused no systematic changes in phenobarbital or primidone concentrations when compared to placebo.

Effects of other Antiepilepsy Drugs (AEDs) on Tiagabine HCl: Carbamazepine : Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking carbamazepine with or without other enzyme-inducing AEDs. Phenytoin : Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking phenytoin with or without other enzyme-inducing AEDs. Phenobarbital (Primidone) : Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking phenobarbital (primidone) with or without other enzyme-inducing AEDs.

Valproate : The addition of tiagabine to patients taking valproate chronically had no effect on tiagabine pharmacokinetics, but valproate significantly decreased tiagabine binding in vitro from 96.3 to 94.8%, which resulted in an increase of approximately 40% in the free tiagabine concentration. The clinical relevance of this in vitro finding is unknown. Interaction of Tiagabine HCl with Other Drugs: Cimetidine : Co-administration of cimetidine (800 mg/day) to patients taking tiagabine chronically had no effect on tiagabine pharmacokinetics.

Theophylline : A single 10 mg dose of tiagabine did not affect the pharmacokinetics of theophylline at steady state. Warfarin : No significant differences were observed in the steady-state pharmacokinetics of R-warfarin or S-warfarin with the addition of tiagabine given as a single dose. Prothrombin times were not affected by tiagabine.

Digoxin : Concomitant administration of tiagabine did not affect the steady-state pharmacokinetics of digoxin or the mean daily trough serum level of digoxin. Ethanol or Triazolam : No significant differences were observed in the pharmacokinetics of triazolam (0.125 mg) and tiagabine (10 mg) when given together as a single dose. The pharmacokinetics of ethanol were not affected by multiple-dose administration of tiagabine.

Tiagabine has shown no clinically important potentiation of the pharmacodynamic effects of triazolam or alcohol. Because of the possible additive effects of drugs that may depress the nervous system, ethanol or triazolam should be used cautiously in combination with tiagabine. Oral Contraceptives : Multiple dose administration of tiagabine (8 mg/day monotherapy) did not alter the pharmacokinetics of oral contraceptives in healthy women of child-bearing age.

Antipyrine : Antipyrine pharmacokinetics were not significantly different before and after tiagabine multiple-dose regimens. This indicates that tiagabine does not cause induction or inhibition of the hepatic microsoma… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Use in Non-Induced Patients: Virtually all experience with tiagabine HCl has been obtained in patients with epilepsy receiving at least one concomitant enzyme-inducing antiepilepsy drug (AED), which lowers the plasma levels of tiagabine. 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 DOSAGE AND ADMINISTRATION ).

Patients taking a combination of inducing and non-inducing agents (e.g., carbamazepine and valproate) should be considered to be induced. Patients not receiving hepatic enzyme-inducing agents are referred to as non-induced patients. Generalized Weakness: Moderately severe to incapacitating generalized weakness has been reported following administration of tiagabine HCl in 28 of 2531 (approximately 1%) patients with epilepsy.

The weakness resolved in all cases after a reduction in dose or discontinuation of tiagabine HCl. Binding in the Eye and Other Melanin-Containing Tissues: When dogs received a single dose of radiolabeled tiagabine, there was evidence of residual binding in the retina and uvea after 3 weeks (the latest time point measured). Although not directly measured, melanin binding is suggested.

The ability of available tests to detect potentially adverse consequences, if any, of the binding of tiagabine to melanin-containing tissue is unknown and there was no systematic monitoring for relevant ophthalmological changes during the clinical development of tiagabine HCl. However, long-term (up to one year) toxicological studies of tiagabine in dogs showed no treatment-related ophthalmoscopic changes and macro- and microscopic examinations of the eye were unremarkable. Accordingly, although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Use in Hepatically-Impaired Patients: Because the clearance of tiagabine is reduced in patients with liver disease, dosage reduction may be necessary in these patients. Serious Rash: Four patients treated with tiagabine during the product’s premarketing clinical testing developed what were considered to be serious rashes. In two patients, the rash was described as maculopapular; in one it was described as vesiculobullous; and in the 4th case, a diagnosis of Stevens Johnson syndrome was made.

In none of the 4 cases is it certain that tiagabine was the primary, or even a contributory, cause of the rash. Nevertheless, drug associated rash can, if extensive and serious, cause irreversible morbidity, even death. Information for Patients Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking tiagabine HCl.

The complete text of the Medication Guide is provided at the end of this labeling. Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled that AEDs, including tiagabine HCl, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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.

Patients should be advised that tiagabine HCl may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, patients should be advised neither to drive nor to operate other complex machinery until they have gained sufficient experience on tiagabine HCl to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive depressive effects, caution should also be used when patients are taking other CNS depressants in combination with tiagabine HCl.

Because teratogenic effects were seen in the offspring of rats exposed t… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of tiagabine HCl have not been evaluated in human studies.