Gabitril Information
Gabitril () 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 CHNOS 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:
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:
Gabitril () Clinical Pharmacology
The precise mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability, documented in 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 and ED 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 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, 5HT, and 5HT, beta-1 and 2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A and A, opiate µ and K, NMDA glutamate, and GABA receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT, benzodiazepine, and chloride channel receptors at concentrations 20 to 400 times those inhibiting the uptake of GABA.
Gabitril () 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.
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):
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.
Gabitril () 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.
Gabitril () Contraindications
Gabitril () is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
Gabitril () Precautions
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. Gabitril () is considered to be a non-enzyme inducing AED (see ).
The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy.
Carcinogenesis:
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Impairment of Fertility:
Pregnancy Category C: Tiagabine has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, when administered to pregnant rats and rabbits at doses greater than the human therapeutic dose.
An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) and decreased fetal weights were observed following oral administration of 100 mg/kg/day to pregnant rats during the period of organogenesis. This dose is approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m). Maternal toxicity (transient weight loss/reduced maternal weight gain during gestation) was associated with this dose, but there is no evidence to suggest that the teratogenic effects were secondary to the maternal effects. No adverse maternal or embryo-fetal effects were seen at a dose of 20 mg/kg/day (3 times the MRHD on a mg/m basis).
Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m basis).
When female rats were given tiagabine 100 mg/kg/day during late gestation and throughout parturition and lactation, decreased maternal weight gain during gestation, an increase in stillbirths, and decreased postnatal offspring viability and growth were found. There are no adequate and well-controlled studies in pregnant women. Tiagabine should be used during pregnancy only if clearly needed.
To provide additional information regarding the effects of in utero exposure to Gabitril () , physicians are advised to recommend that pregnant patients taking Gabitril () enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website .
Gabitril () 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%).
Gabitril () Drug Abuse And Dependence
The abuse and dependence potential of Gabitril () have not been evaluated in human studies.
Gabitril () Overdosage
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 context of seizures.
Gabitril () Dosage And Administration
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 () :
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 Gabitril () .
In adolescents 12 to 18 years old, Gabitril () should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of Gabitril () 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, Gabitril () should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of Gabitril () 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.
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 Gabitril () , 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 Gabitril () . These patients may also require a slower titration of Gabitril () compared to that of induced patients (see and ).
Gabitril () 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 30 ( 63459-402-30).
• 4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 63459-404-30).
• 12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 63459-412-30).
• 16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 63459-416-30).
Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.
Gabitril () 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.
Gabitril ()
Gabitril () Medication Guide
Read this Medication Guide before you start taking Gabitril () and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Stopping Gabitril () suddenly can cause serious problems.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
Gabitril () is a prescription medicine used with other medicines to treat partial seizures in adults and children age 12 and older.
Do not take Gabitril () if you are allergic to tiagabine hydrochloride or any of the other ingredients in Gabitril () . See the end of this Medication Guide for a complete list of ingredients in Gabitril () .
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Always tell your healthcare provider if there are any changes in any other medicines that you take.
If you take too much Gabitril () , call your healthcare provider or local Poison Control Center right away.
Call your healthcare provider right away if you have any of the serious side effects listed above.
These are not all the possible side effects of Gabitril () . For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Gabitril () for a condition for which it was not prescribed. Do not give Gabitril () to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Gabitril () . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Gabitril () that is written for health professionals
For more information, go to www.Gabitril () .com or call 1-800-896-5855.
In addition:
This Medication Guide has been approved by the U.S. Food and Drug Administration.
GABMG-001
September 2010
U.S. Patent Nos. 5,354,760; 5,866,590; 5,958,951
©2010 Cephalon, Inc., or its affiliates. All rights reserved.
Printed in U.S.A.
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