Tiagabine

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.

CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability, documented in in vitro experiments, to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. In rat-derived hippocampal slices, tiagabine has been shown to prolong GABA-mediated inhibitory post-synaptic potentials. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus, ventral palladum, and substantia nigra in rats at the ED 50 and ED 85 doses for inhibition of pentylenetetrazol (PTZ)­induced tonic seizures. This suggests that tiagabine prevents the propagation of neural impulses that contribute to seizures by a GABA-ergic action. Tiagabine has shown efficacy in several animal models of seizures. It is effective against the tonic phase of subcutaneous PTZ-induced seizures in mice and rats, seizures induced by the proconvulsant DMCM in mice, audiogenic seizures in genetically epilepsy-prone rats (GEPR), and amygdala-kindled seizures in rats. Tiagabine has little efficacy against maximal electroshock seizures in rats and is only partially effective against subcutaneous PTZ-induced clonic seizures in mice, picrotoxin-induced tonic seizures in the mouse, bicuculline-induced seizures in the rat, and photic seizures in photosensitive baboons. Tiagabine produces a biphasic dose-response curve against PTZ- and DMCM-induced convulsions, with attenuated effectiveness at higher doses. Based on in vitro binding studies, tiagabine does not significantly inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline and shows little or no binding to dopamine D1 and D2, muscarinic, serotonin 5HT 1A , 5HT 2 , and 5HT 3 , beta-1 and 2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A 1 and A 2 , opiate µ and K 1 , NMDA glutamate, and GABA A receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT 1B , benzodiazepine, and chloride channel receptors at concentrations 20 to 400 times those inhibiting the uptake of GABA. Pharmacokinetics Tiagabine is well absorbed, with food slowing absorption rate but not altering the extent of absorption. The elimination half-life of tiagabine is 7 to 9 hours in normal volunteers. In epilepsy clinical trials, most patients were receiving hepatic enzyme-inducing agents (e.g., carbamazepine, phenytoin, primidone, and pheno

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

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

WARNINGS Seizures in Patients Without Epilepsy: Post-marketing 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 (5-100 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 1,000 Patients Drug Patients with Events per 1,000 Patients R

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

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.