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GABITRIL®
(tiagabine hydrochloride)
Tablets
DESCRIPTION
GABITRIL (tiagabine HCl) 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 C20H25NO2S2 HCl, and its molecular weight is 412.0. Tiagabine HCl 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
GABITRIL tablets contain the following inactive ingredients: Ascorbic acid, colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil wax, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, stearic acid, and titanium dioxide. In addition, individual tablets contain:
- 2 mg tablets: FD&C Yellow No. 6.
- 4 mg tablets: D&C Yellow No. 10.
- 12 mg tablets: D&C Yellow No. 10 and FD&C Blue No. 1.
- 16 mg tablets: FD&C Blue No. 2.
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 ED50 and ED85 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 5HT1A, 5HT2, and 5HT3, beta-1 and 2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A1 and A2, opiate µ and K1, NMDA glutamate, and GABAA receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT1B, 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 phenobarbital). The pharmacokinetic profile in induced patients is significantly different from the non-induced population (see PRECAUTIONS - Use in Non-Induced Patients). The systemic clearance of tiagabine in induced patients is approximately 60% greater resulting in considerably lower plasma concentrations and an elimination half-life of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population.
SPECIAL POPULATIONS
CLINICAL STUDIES
The effectiveness of GABITRIL as adjunctive therapy (added to other antiepilepsy drugs) was examined in three multi-center, double-blind, placebo-controlled, parallel-group, clinical trials in 769 patients with refractory partial seizures who were taking at least one hepatic enzyme-inducing antiepilepsy drug (AED), and two placebo-controlled cross-over studies in 90 patients. In the parallel-group trials, patients had a history of at least six complex partial seizures (Study 1 and Study 2, U.S. studies), or six partial seizures of any type (Study 3, European study), occurring alone or in combination with any other seizure type within the 8-week period preceding the first study visit in spite of receiving one or more AEDs at therapeutic concentrations.
In the first two studies, the primary protocol-specified outcome measure was the median reduction from baseline in the 4-week complex partial seizure (CPS) rates during treatment. In the third study, the protocol-specified primary outcome measure was the proportion of patients achieving a 50% or greater reduction from baseline in the 4-week seizure rate of all partial seizures during treatment. The results given below include data for complex partial seizures and all partial seizures for the intent-to-treat population (all patients who received at least one dose of treatment and at least one seizure evaluation) in each study.
Study 1 was a double-blind, placebo-controlled, parallel-group trial comparing GABITRIL 16 mg/day, GABITRIL 32 mg/day, GABITRIL 56 mg/day, and placebo. Study drug was given as a four times a day regimen. After a prospective Baseline Phase of 12 weeks, patients were randomized to one of the four treatment groups described above. The 16-week Treatment Phase consisted of a 4-week Titration Period, followed by a 12-week Fixed-Dose Period, during which concomitant AED doses were held constant. The primary outcome was assessed for the combined 32 and 56 mg/day groups compared to placebo.
Study 2 was a double-blind, placebo-controlled, parallel-group trial consisting of an 8-week Baseline Phase and a 12-week Treatment Phase, the first 4 weeks of which constituted a Titration Period and the last 8 weeks a Fixed-Dose Period. This study compared GABITRIL 16 mg BID and 8 mg QID to placebo. The protocol-specified primary outcome measure was assessed separately for each group treated with GABITRIL.
The following tables display the results of the analyses of these two trials.
| * p < 0.05 | ||||||
| †Statistical significance was not assessed for median % reduction. | ||||||
Placebo (N=91) | GABITRIL 16 mg/day (N=61) | GABITRIL 32 mg/day (N=87) | GABITRIL 56 mg/day (N=56) | Combined 32 + 56 mg/day (N=143) | ||
|---|---|---|---|---|---|---|
| Complex | Median Reduction | 0.6 | 0.8 | 2.2* | 2.9* | 2.6* |
| Partial | Median % Reduction† | 9% | 13% | 25% | 32% | 29% |
| All | Median Reduction | 0.2 | 1.2 | 2.7* | 3.5* | 2.9* |
| Partial | Median % Reduction† | 3% | 12% | 24% | 36% | 27% |
| * p < 0.027, necessary for statistical significance due to multiple comparisons | ||||
| †Statistical significance was not assessed for median % reduction. | ||||
Placebo (N=107) | GABITRIL 16 mg BID (N=106) | GABITRIL 8 mg QID (N=104) | ||
|---|---|---|---|---|
| Complex Partial | Median Reduction | 0.3 | 1.6 | 1.3* |
| Median % Reduction† | 4% | 22% | 15% | |
| All Partial | Median Reduction | 0.5 | 1.6 | 1.3 |
| Median % Reduction† | 5% | 19% | 13% | |
Figures 1 to 4 present the proportion of patients (X-axis) whose percent reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y axis in the three placebo-controlled adjunctive studies (Studies 1, 2, and 3). A positive value on the Y axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo.
Figure 1 indicates that the proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the combined GABITRIL 32 mg and 56 mg groups compared to the placebo group in Study 1. For example, Figure 1 indicates that approximately 24% of patients treated with GABITRIL experienced a 50% or greater reduction, compared to 4% in the placebo group.
Figure 2 also displays the results for Study 1, which was a dose-response study, by treatment group, without combining GABITRIL dosage groups. Figure 2 indicates a dose-response relationship across the three GABITRIL groups. The proportion of patients achieving any particular level of reduction in all partial seizure rates was consistently higher as the dose of GABITRIL was increased. For example, Figure 2 indicates that approximately 4% of patients in the placebo group experienced a 50% or greater reduction in all partial seizure rate, compared to approximately 10% of the GABITRIL 16 mg/day group, 21% of the GABITRIL 32 mg/day group, and 30% of the GABITRIL 56 mg/day group.
Figure 3 indicates that the proportion of patients achieving any particular level of reduction in partial seizure rate was consistently greater in patients taking GABITRIL than in those taking placebo in Study 2. (Study 2 compared placebo to GABITRIL 32 mg/day; one of the GABITRIL groups received 8 mg QID, while the other GABITRIL group received 16 mg BID). For example, Figure 3 indicates that approximately 7% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate, compared to approximately 23% of patients in the GABITRIL 8 mg QID group and 28% of patients in the GABITRIL 16 mg BID group.
Study 3 was a double-blind, placebo-controlled, parallel-group trial that compared GABITRIL 10 mg TID (N=77) with placebo (N=77). In this trial, patients were followed prospectively during a 12-week Baseline Phase and then randomized to receive study drug during an 18-week Treatment Phase. During the first 6 weeks of treatment (Titration Period), patients were titrated to 30 mg/day, after which they were maintained on this dose during the 12-week Fixed-Dose Period. The protocol-specified primary outcome measure (proportion of patients who achieved at least a 50% reduction from baseline in partial seizure rate) did not reach statistical significance. However, analyses of the median reduction from baseline in 4-week partial seizure rate (the analyses presented above for Study 1 and Study 2) were performed and showed a statistically significant improvement compared to placebo in all partial and complex partial seizure rates (Table 3):
| * p < 0.05 | |||
| †Statistical significance was not assessed for median % reduction. | |||
| ‡N=72 and 75 for placebo and GABITRIL, respectively. | |||
Placebo (N=77) | GABITRIL 30 mg/day (N=77) | ||
|---|---|---|---|
| Complex Partial‡ | Median Reduction | -0.1 | 1.3* |
| Median % Reduction† | -1% | 14% | |
| All Partial | Median Reduction | -0.5 | 1.1* |
| Median % Reduction† | -7% | 11% | |
Figure 4 indicates that the proportion of patients achieving any particular level of reduction in seizure activity was consistently higher in those taking GABITRIL than those taking placebo in Study 3. For example, Figure 4 indicates that approximately 5% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate compared to approximately 10% of patients in the GABITRIL group.
The two other placebo-controlled trials that examined the effectiveness of GABITRIL were small cross-over trials (N=46 and 44). Both trials included an open Screening Phase during which patients were titrated to an optimal dose and then treated with this dose for an additional 4 weeks. After this Open Phase, patients were randomized to one of two blinded treatment sequences (GABITRIL followed by placebo or placebo followed by GABITRIL). The Double-Blind Phase consisted of two Treatment Periods, each lasting 7 weeks (with a 3 week washout between periods). The outcome measures were median with-in patient differences between placebo and GABITRIL Treatment Periods in 4-week complex partial and all partial seizure rates. The reductions in seizure rates were statistically significant in both studies.
INDICATIONS AND USAGE
GABITRIL (tiagabine hydrochloride) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.
CONTRAINDICATIONS
GABITRIL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
WARNINGS
Seizures in Patients Without Epilepsy: Post-marketing reports have shown that GABITRIL 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 GABITRIL 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 GABITRIL 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 GABITRIL by inducing its metabolism. Use of GABITRIL 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 GABITRIL 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 GABITRIL treatment, GABITRIL should be discontinued and patients should be evaluated for an underlying seizure disorder.
Seizures and status epilepticus are known to occur with GABITRIL overdosage (see OVERDOSAGE).
PRECAUTIONS
General
Laboratory Tests
Drug Interactions
reIn 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. GABITRIL is considered to be a non-enzyme inducing AED (see PRECAUTIONS, 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.
ADVERSE REACTIONS
The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of GABITRIL 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 GABITRIL 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 GABITRIL 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%).
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of GABITRIL have not been evaluated in human studies.
OVERDOSAGE
Human Overdose Experience: Human experience of acute overdose with GABITRIL is limited. Eleven patients in clinical trials took single doses of GABITRIL 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, there have been no reports of fatal overdoses involving GABITRIL alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including GABITRIL, have resulted in fatal outcomes. Symptoms most often accompanying GABITRIL 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, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the condiv of seizures.
Management of Overdose: There is no specific antidote for overdose with GABITRIL. 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 GABITRIL.
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.
GABITRIL (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 GABITRIL:
- GABITRIL is given orally and should be taken with food.
- Do not use a loading dose of GABITRIL.
- Dose titration: Rapid escalation and/or large dose increments of GABITRIL should not be used.
- Missed dose(s): If the patient forgets to take the prescribed dose of GABITRIL 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 GABITRIL 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.
HOW SUPPLIED
GABITRIL tablets are available in four dosage strengths.
- 2 mg orange-peach, round tablets, debossed with
on one side and 402 on the opposite side, are available in bottles of 100 (NDC 63459-402-01).
- 4 mg yellow, round tablets, debossed with
- 12 mg green, ovaloid tablets, debossed with
- 16 mg blue, ovaloid tablets, debossed with
Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.
ANIMAL TOXICOLOGY
In repeat dose toxicology studies, dogs receiving daily oral doses of 5 mg/kg/day or greater experienced unexpected CNS effects throughout the study. These effects occurred acutely and included marked sedation and apparent visual impairment which was characterized by a lack of awareness of objects, failure to fix on and follow moving objects, and absence of a blink reaction. Plasma exposures (AUCs) at 5 mg/kg/day were equal to those in humans receiving the maximum recommended daily human dose of 56 mg/day. The effects were reversible upon cessation of treatment and were not associated with any observed structural abnormality. The implications of these findings for humans are unknown.
Manufactured for:
Cephalon, Inc.
Frazer, PA 19355
Revised: March, 2006
©1997-2006 Cephalon, Inc.
All rights reserved.
U.S. Patent Nos. 5,010,090; 5,354,760; 5,866,590; 5,958,951
PRINTED IN U.S.A.