Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3553
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GABITRIL (Tablet)
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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: 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 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 6. Non-Induced Adults and Adolescents 12 Years or Older: 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 .
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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 CHNOSHCl, 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:<br/>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:
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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 EDand EDdoses 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, 5HT, and 5HT, beta-1 and 2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine Aand A, opiate��and K, NMDA glutamate, and GABAreceptors at 100��M. 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.<br/>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 . 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 exposureafter 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. Absorption and Distribution: Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed (>95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean Twas prolonged to 2.5 hours, and mean Cwas reduced by about 40%) but not the extent (AUC) of tiagabine absorption. In all clinical trials, tiagabine was given with meals. The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days. Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and��1-acid glycoprotein over the concentration range of 10 ng/mL to 10,000 ng/mL. While the relationship between tiagabine plasma concentrations and clinical response is not currently understood, trough plasma concentrations observed in controlled clinical trials at doses from 30 to 56 mg/day ranged from<1 ng/mL to 234 ng/mL. Metabolism and Elimination: Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine. Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP 3A), although contributions to the metabolism of tiagabine from CYP 1A2, CYP 2D6 or CYP 2C19 have not been excluded. Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites, at least 2 of which have not been identified. The mean systemic plasma clearance is 109 mL/min (CV = 23%) and the average elimination half-lifefor tiagabine in healthy subjects ranged from 7 to 9 hours. The elimination half-life decreased by 50 to 65% in hepatic enzyme-induced patients with epilepsy compared to uninduced patients with epilepsy. A diurnal effect on the pharmacokinetics of tiagabine was observed. Mean steady-state Cvalues were 40% lower in the evening than in the morning. Tiagabine steady-state AUC values were also found to be 15% lower following the evening tiagabine dose compared to the AUC following the morning dose.<br/>SPECIAL POPULATIONS:
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GABITRIL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
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GABITRIL tablets are available in four dosage strengths. Recommended Storage: Store tablets at controlled room temperature, between 20-25��C (68-77��F). See USP. Protect from light and moisture.
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dailymed-ingredient:FD&C_Yellow_#6,
dailymed-ingredient:ascorbic_acid,
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:crospovidone,
dailymed-ingredient:hydrogenated_vegetable_oil_wax,
dailymed-ingredient:hydroxypropyl_cellulose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:lactose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:pregelatinized_starch,
dailymed-ingredient:stearic_acid,
dailymed-ingredient:titanium_dioxide
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General: Use in Non-Induced Patients: Virtually all experience with GABITRIL 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 GABITRIL. These patients may also require a slower titration of GABITRIL compared to that of induced patients . 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 GABITRIL in 28 of 2531 (approximately 1%) patients with epilepsy. The weakness resolved in all cases after a reduction in dose or discontinuation of GABITRIL. 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 GABITRIL. 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 instructed to take GABITRIL only as prescribed. Patients should be advised that GABITRIL 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 GABITRIL 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 GABITRIL. Because teratogenic effects were seen in the offspring of rats exposed to maternally toxic doses of tiagabine and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Because of the possibility that tiagabine may be excreted in breast milk, patients should be advised to notify those providing care to themselves and their children if they intend to breast-feed or are breast-feeding an infant.<br/>Laboratory Tests: Therapeutic Monitoring of Plasma Concentrations of Tiagabine: A therapeutic range for tiagabine plasma concentrations has not been established. In controlled trials, trough plasma concentrations observed among patients randomized to doses of tiagabine that were statistically significantly more effective than placebo ranged from<1 ng/mL to 234 ng/mL (median, 10and 90percentiles are 23.7 ng/mL, 5.4 ng/mL, and 69.8 ng/mL, respectively). Because of the potential for pharmacokinetic interactions between GABITRIL and drugs that induce or inhibit hepatic metabolizing enzymes, it may be useful to obtain plasma levels of tiagabine before and after changes are made in the therapeutic regimen. Clinical Chemistry and Hematology: During the development of GABITRIL, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his/her care. EEG: Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity . In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment.<br/>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 . The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy.<br/>Effects of GABITRIL 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.<br/>Effects of other Antiepilepsy Drugs (AEDs) on GABITRIL:: 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.<br/>Interaction of GABITRIL 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 microsomal enzyme systems responsible for the metabolism of antipyrine.<br/>Interaction of GABITRIL with Highly Protein Bound Drugs:: In vitro data showed that tiagabine is 96% bound to human plasma protein and therefore has the potential to interact with other highly protein bound compounds. Such an interaction can potentially lead to higher free fractions of either tiagabine or the competing drug. Carcinogenesis:In rats, a study of the potential carcinogenicity associated with tiagabine HCl administration showed that 200 mg/kg/day (plasma exposure [AUC] 36 to 100 times that at the maximum recommended human dosage [MRHD] of 56 mg/day) for 2 years resulted in small, but statistically significant increases in the incidences of hepatocellular adenomas in females and Leydigcell tumors of the testis in males. The significance of these findings relative to the use of GABITRIL in humans is unknown. The no effect dosage for induction of tumors in this study was 100 mg/kg/day (17 to 50 times the exposure at the MRHD). No statistically significant increases in tumor formation were noted in mice at dosages up to 250 mg/kg/day (20 times the MRHD on a mg/mbasis). Mutagenesis: Tiagabine produced an increase in structural chromosome aberration frequency in human lymphocytes in vitro in the absence of metabolic activation. No increase in chromosomal aberration frequencies was demonstrated in this assay in the presence of metabolic activation. No evidence of genetic toxicity was found in the in vitro bacterial gene mutation assays, the in vitro HGPRT forward mutation assay in Chinese hamster lung cells, the in vivo mouse micronucleus test, or an unscheduled DNA synthesis assay. Impairment of Fertility: Studies of male and female rats administered dosages of tiagabine HCl prior to and during mating, gestation, and lactation have shown no impairment of fertility at doses up to 100 mg/kg/day. This dose represents approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m). Lowered maternal weight gain and decreased viability and growth in the rat pups were found at 100 mg/kg, but not at 20 mg/kg/day (3 times the MRHD on a mg/mbasis). Pregnancy: 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/mbasis). 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/mbasis) 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/mbasis). 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. Use in Nursing Mothers: Studies in rats have shown that tiagabine HCl and/or its metabolites are excreted in the milk of that species. Levels of excretion of tiagabine and/or its metabolites in human milk have not been determined and effects on the nursing infant are unknown. GABITRIL should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established. The pharmacokinetics of tiagabine were evaluated in pediatric patients age 3 to 10 years . Geriatric Use: Because few patients over the age of 65 (approximately 20) were exposed to GABITRIL during its clinical evaluation, no specific statements about the safety or effectiveness of GABITRIL in this age group could be made.
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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 context 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.
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tiagabine hydrochloride
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GABITRIL (Tablet)
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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%). Adverse Event Incidence in Controlled Clinical Trials: Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients treated with GABITRIL for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the GABITRIL group. In these studies, either GABITRIL 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 GABITRIL 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 relativecontribution of drug and non-drug factors to the adverse event incidences in the population studied. Other events reported by 1% or more of patients treated with GABITRIL 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 tract infection, urinary frequency, infection, dyspepsia, gastroenteritis, nausea and vomiting, myalgia, diplopia, headache, anxiety, acne, sinusitis, and incoordination. Study 1 was a dose-response study including doses of 32 mg and 56 mg. Table 5 shows adverse events reported at a rate of���5% in at least one GABITRIL group and more frequent than in the placebo group. Among these events, depression, tremor, nervousness, difficulty with concentration/attention, and perhaps asthenia exhibited a positive relationship to dose. The effects of GABITRIL in relation to those of placebo on the incidence of adverse events and the types of adverse events reported were independent of age, weight, and gender. Because only 10% of patients were non-Caucasian in parallel-group, placebo-controlled trials, there is insufficient data to support a statement regarding the distribution of adverse experience reports by race. Other Adverse Events Observed During All Clinical Trials: GABITRIL has been administered to 2531 patients during all phase 2/3 clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types ofevents were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 2531 patients exposed to GABITRIL who experienced events of the type cited on at least one occasion while receiving GABITRIL. All reported events are included except those already listed above, events seen only three times or fewer (unless potentially important), events very unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to tiagabine. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole: Frequent: Allergic reaction, chest pain, chills, cyst, neck pain, and malaise. Infrequent: Abscess, cellulitis, facial edema, halitosis, hernia, neck rigidity, neoplasm, pelvic pain, photosensitivity reaction, sepsis, sudden death, and suicide attempt. Cardiovascular System: Frequent:Hypertension, palpitation, syncope, and tachycardia. Infrequent: Angina pectoris, cerebral ischemia, electrocardiogram abnormal, hemorrhage, hypotension, myocardial infarct, pallor, peripheral vascular disorder, phlebitis, postural hypotension, and thrombophlebitis. Digestive System: Frequent: Gingivitis and stomatitis. Infrequent: Abnormal stools, cholecystitis, cholelithiasis, dysphagia, eructation, esophagitis, fecal incontinence, gastritis, gastrointestinal hemorrhage, glossitis, gum hyperplasia, hepatomegaly, increased salivation, liver function tests abnormal, melena, periodontal abscess, rectal hemorrhage, thirst, tooth caries, and ulcerative stomatitis. Endocrine System: Infrequent: Goiter and hypothyroidism. Hemic and Lymphatic System: Frequent: Lymphadenopathy. Infrequent: Anemia, erythrocytes abnormal, leukopenia, petechia, and thrombocytopenia. Metabolic and Nutritional: Frequent: Edema, peripheral edema, weight gain, and weight loss. Infrequent: Dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, and hyponatremia. Musculoskeletal System: Frequent: Arthralgia. Infrequent: Arthritis, arthrosis, bursitis, generalized spasm, and tendinous contracture. Nervous System: Frequent: Depersonalization, dysarthria, euphoria, hallucination, hyperkinesia, hypertonia, hypesthesia, hypokinesia, hypotonia, migraine, myoclonus, paranoid reaction, personality disorder, reflexes decreased, stupor, twitching, and vertigo. Infrequent: Abnormal dreams, apathy, choreoathetosis, circumoral paresthesia, CNS neoplasm, coma, delusions, dry mouth, dystonia, encephalopathy, hemiplegia, leg cramps, libido increased, libido decreased, movement disorder, neuritis, neurosis, paralysis, peripheral neuritis, psychosis, reflexes increased, and urinary retention. Respiratory System: Frequent: Bronchitis, dyspnea, epistaxis, and pneumonia. lnfrequent: Apnea, asthma, hemoptysis, hiccups, hyperventilation, laryngitis, respiratory disorder, and voice alteration. Skin and Appendages: Frequent: Alopecia, dry skin, and sweating. Infrequent: Contact dermatitis, eczema, exfoliative dermatitis, furunculosis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, psoriasis, skin benign neoplasm, skin carcinoma, skin discolorations, skin nodules, skin ulcer, subcutaneous nodule, urticaria, and vesiculobullous rash. Special Senses: Frequent: Abnormal vision, ear pain, otitis media, and tinnitus. Infrequent: Blepharitis, blindness, deafness, eye pain, hyperacusis, keratoconjunctivitis, otitis externa, parosmia, photophobia, taste loss, taste perversion, and visual field defect. Urogenital System: Frequent: Dysmenorrhea, dysuria, metrorrhagia, urinary incontinence, and vaginitis. Infrequent: Abortion, amenorrhea, breast enlargement, breast pain, cystitis, fibrocystic breast, hematuria, impotence, kidney failure, menorrhagia, nocturia, papanicolaou smear suspicious, polyuria, pyelonephritis, salpingitis, urethritis, urinary urgency, and vaginal hemorrhage.
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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 . 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 . Withdrawal Seizures: As a rule, antiepilepsy drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In a placebo-controlled, double-blind, dose-response study designed, in part, to investigate the capacity of GABITRIL to induce withdrawal seizures, study drug was tapered over a 4-week period after 16 weeks of treatment. Patients' seizure frequency during this 4-week withdrawal period was compared to their baseline seizure frequency (before study drug). For each partial seizure type, for all partial seizure types combined, and for secondarily generalized tonic-clonic seizures, more patients experienced increases in their seizure frequencies during the withdrawal period in the three GABITRIL groups than in the placebo group. The increase in seizure frequency was not affected by dose. GABITRIL should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Cognitive/Neuropsychiatric Adverse Events: Adverse events most often associated with the use of GABITRIL were related to the central nervous system. The most significant of these can be classified into 2 general categories: 1) impaired concentration, speech or language problems, and confusion (effects on thought processes); and 2) somnolence and fatigue (effects on level of consciousness). The majority of these events were mild to moderate. In controlled clinical trials, these events led to discontinuation of treatment with GABITRIL in 6% (31 of 494) of patients compared to 2% (5 of 275) of the placebo-treated patients. A total of 1.6% (8 of 494) of the GABITRIL treated patients in the controlled trials were hospitalized secondary to the occurrence of these events compared to 0% of the placebo treated patients. Some of these events were dose related and usually began during initial titration. Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity . In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment. Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of GABITRIL. Status Epilepticus: In the three double-blind, placebo-controlled, parallel-group studies (Studies 1, 2, and 3), the incidence of any type of status epilepticus (simple, complex, or generalized tonic-clonic) in patients receiving GABITRIL was 0.8% (4 of 494 patients) versus 0.7% (2 of 275 patients) receiving placebo. Among the patients treated with GABITRIL across all epilepsy studies (controlled and uncontrolled),5% had some form of status epilepticus. Of the 5%, 57% of patients experienced complex partial status epilepticus. A critical risk factor for status epilepticus was the presence of a previous history; 33% of patients with a history of status epilepticus had recurrence during GABITRIL treatment. Because adequate information about the incidence of status epilepticus in a similar population of patients with epilepsy who have not received treatment with GABITRIL is not available, it is impossible to state whether or not treatment with GABITRIL is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with GABITRIL. Sudden Unexpected Death In Epilepsy (SUDEP): There have been as many as 10 cases of sudden unexpected deaths during the clinical development of tiagabine among 2531 patients with epilepsy (3831 patient-years of exposure). This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving GABITRIL (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populationssimilar to that in the clinical development program for GABITRIL, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving GABITRIL are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to GABITRIL, that underwent clinical testing in similar populations at about the same time. This evidence suggests that the SUDEP rates reflect population rates, not a drug effect.
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GABITRIL (tiagabine hydrochloride) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.
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GABITRIL
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