Tiagabine Hydrochloride

INDICATIONS AND USAGE Tiagabine hydrochloride tablet is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.

DOSAGE AND ADMINISTRATION 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 hydrochloride tablet 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 hydrochloride tablets: Tiagabine hydrochloride tablet is 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. 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. 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. Table7: 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-indu …

CONTRAINDICATIONS Tiagabine hydrochloride is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

ADVERSE REACTIONS The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of tiagabine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the tiagabine hydrochloride group. In these studies, either tiagabine hydrochloride 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 hydrochloride 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 Event1 Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with Tiagabine Hydrochloride and numerically more frequent than in the placebo group) Body System/COSTART Tiagabine Hydrochloride 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 hydrochloride 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 hydrochloride but equally or more frequent in the placebo group were: accidental injury, chest pain, constipation, flu syndrome, rhinitis, anor …

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 hydrochloride 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 Hydrochloride 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 Hydrochloride: 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 Hydrochloride 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 …

DESCRIPTION Tiagabine hydrochloride USP is an antiepilepsy drug available as 2 mg, 4 mg, 12 mg, and 16 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 C 20 H 25 NO 2 S 2 HCl, and its molecular weight is 412.01. Tiagabine HCl, USP is a white to off-white powder. It is freely soluble in methanol and in alcohol, soluble in 5% Water in isopropanol, very slightly soluble in chloroform, sparingly soluble in water and practically insoluble in n-Heptane. The structural formula is: Inactive Ingredients Tiagabine hydrochloride tablets contain the following inactive ingredients: Butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil (cottonseed oil), hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, pregelatinized starch, stearic acid and titanium dioxide. In addition, individual tablets contain: 2 mg tablets: FD&C yellow No. 6 aluminum lake 4 mg tablets: D&C yellow No. 10 aluminum lake 12 mg tablets: D&C yellow No. 10 aluminum lake and FD&C Blue No. 1 aluminum lake 16 mg tablets: FD&C blue No. 2 aluminum lake tia-str

OVERDOSAGE Human Overdose Experience: Human experience of acute overdose with tiagabine hydrochloride is limited. Eleven patients in clinical trials took single doses of tiagabine hydrochloride up to 800 mg. All patients fully recovered, usually within one day. The most common symptoms reported after overdose included somnolence, impaired consciousness, agitation, confusion, speech difficulty, hostility, depression, weakness, and myoclonus. One patient who ingested a single dose of 400 mg experienced generalized tonic-clonic status epilepticus, which responded to intravenous phenobarbital. From post-marketing experience, reports of overdose involving tiagabine hydrochloride alone have included cases in which patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including tiagabine hydrochloride, have resulted in fatal outcomes. Symptoms most often accompanying tiagabine hydrochloride overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, respiratory arrest, coma, loss of consciousness, ataxia, dizziness, confusion, somnolence, drowsiness, impaired speech, aggression, agitation, lethargy, myoclonus, spike wave stupor, encephalopathy, amnesia, dyskinesia, tremors, disorientation, psychotic disorder, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. Management of Overdose: There is no specific antidote for overdose with tiagabine hydrochloride. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of clinical status of the patient. Since tiagabine is mostly metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial. A Certified Poison Control Center should be consulted for up to date information on the management of overdose with tiagabine hydrochloride.

HOW SUPPLIED Tiagabine hydrochloride tablets are available in four dosage strengths. 2 mg light orange-peach colored, round shaped, biconvex film-coated tablets debossed with “MT” on one side and “3” on the other side, are available in bottles of 30 (NDC 72205-084-30). 4 mg yellow colored, round shaped, biconvex film-coated tablets debossed with “MT” on one side and “4” on the other side, are available in bottles of 30 (NDC 72205-085-30). 12 mg green colored, capsule shaped, biconvex film-coated tablets debossed with “MT” on one side and “5” on the other side, are available in bottles of 30 (NDC 72205-086-30). 16 mg blue colored, capsule shaped, biconvex film-coated tablets debossed with “MT” on one side and “6” on the other side, are available in bottles of 30 (NDC 72205-087-30). Recommended Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from light and moisture.