英文药名: Gabitril(Tiagabine Tablets)
中文药名: 噻加宾片
药品名称
药物类别：神经系统用药
所属类别：抗癫痫药
药物名称：噻加宾
英文名称：Tiagabine
药理作用
本品通过对神经元及神经胶质细胞对γ-氨基丁酸(GABA)再摄取的阻滞，增加突触部位GABA的水平，而达到抗惊厥作用。
药动学
本品口服吸收快，O.5～2小时可达血药浓度峰值，生物利用度为90％～95％，血浆蛋白结合率为96％，平均消除半衰期为5～8小时。本品通过肝脏细胞色素P㈣酶系统代谢，合并使用酶诱导剂可增加本品的消除，使其半衰期缩短。肝功能不全者，其代谢降低。约63％经粪便排出，25％经尿排出。
适应症
一般作为辅助治疗，用于成人及12岁以上儿童难治性部分性癫痫发作。
用法用量
初始剂量为12mg／d，分两次服用，每周可增加剂量12～24mg。通常有效剂量为24～60mg／d，分2～4次服用。 或遵医嘱！
不良反应
不良反应可见困倦、头晕、头痛、疲乏、咽炎、呕吐、腹泻、易怒、注意力不集中。少见有弱视、日炎、肌无力、肌痛、失眠、精神紊乱、抑郁、瘙痒、共济失调、感觉障碍。罕见有健忘、情绪不稳、兴奋、眼震、皮疹等。
药物相互作用
本品不影响其他抗癫痫药的浓度，与红霉素、地高辛、三吐仑无药动学相互作用。
注意事项
1.禁用于有肝脏疾病的患者。
2.慎用于孕妇及哺乳期妇女。
禁示
美国FDA和美国赛法隆（Cephalon）公司联合通告医务人员噻加宾盐酸盐（tiagabine，商品名为Gabitril）可能会引起癫痫发作。Gabitril是Cephalon 公司生产的用于治疗12岁以上局部发作与继发全身发作的抗癫痫补充药物，于1997年9月批准上市。Gabitril治疗癫痫的确切机制不明确，其可能机制是与神经突触细胞膜上的GABA转运蛋白结合，阻断了GABA的再摄取，使GABA停留在神经突触间隙继续发挥抑制神经元活动的功能。美国FDA收到至少30例因精神疾病服用Gabitril而导致癫痫发作或癫痫状态的病例，这些患者均没有癫痫病史。
Gabitril诱发癫痫可能与剂量有一定关系。因为多数病例同时合用了其他一些可能降低癫痫发作阈值的药物（如抗抑郁药物、抗精神病药物和麻醉药物），还有一些病例发生癫痫发作出现在调高Gabitril的使用剂量的情况下。
为此，Cephalon公司在说明书中用粗体字标明Gabitril可能引起癫痫的不良反应并进一步开展其机制研究。另外，Cephalon公司表示，Gabitril用于治疗除癫痫以外的精神疾病的安全性和有效性还有待进一步了解和评价，因此不提倡扩大Gabitril的使用适应症。
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原产地英文商品名:
GABITRIL 2mg/tablet 100tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 2毫克/片 100片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
---------------------------------------------------------------
原产地英文商品名:
GABITRIL 2mg/tablet 30tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 2毫克/片 30片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
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原产地英文商品名:
GABITRIL 4mg/tablet 30tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 4毫克/片 30片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
---------------------------------------------------------------
原产地英文商品名:
GABITRIL 4mg/tablet 100tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 4毫克/片 100片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
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原产地英文商品名:
GABITRIL 12mg/tablet 30tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 12毫克/片 30片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
---------------------------------------------------------------
原产地英文商品名:
GABITRIL 12mg/tablet 100tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 12毫克/片 100片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
---------------------------------------------------------------
原产地英文商品名:
GABITRIL 16mg/tablet 30tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 16毫克/片 30片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
---------------------------------------------------------------
原产地英文商品名:
GABITRIL 16mg/tablet 100tablets/bottle
原产地英文药品名:
TIAGABINE HCL
中文参考商品译名:
GABITRIL 16毫克/片 100片/瓶
中文参考药品译名:
盐酸噻加宾
生产厂家中文参考译名:
CEPHALON
生产厂家英文名:
CEPHALON
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GABITRIL®;
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DRUG DESCRIPTION
GABITRIL® (tiagabine HCl) is an antiepilepsy drug available as 2 mg, 4 mg, 12 mg, and 16mg 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.
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INDICATIONS
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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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.
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 wellcontrolled clinical trials.
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 noninduced patients requires lower doses of GABITRIL. These patients may also require a slower titration of GABITRIL compared to that of induced patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non- Induced Patients).
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HOW SUPPLIED
GABITRIL tablets are available in four dosage strengths.
2 mg orange-peach, round tablets, debossed with C 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 C on one side and 404 on the opposite side, are available in bottles of 100 (NDC 63459-404-01).
12 mg green, ovaloid tablets, debossed with C on one side and 412 on the opposite side, are available in bottles of 100 (NDC 63459-412-01).
16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 100 (NDC 63459-416-01).
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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SIDE EFFECTS
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/lightheadedness, 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 5 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 relative contribution 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 6 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.
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 of events 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.
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DRUG INTERACTIONS
In evaluating the potential for interactions among co-administered antiepilepsy drugs(AEDs),whether or not an AED induces or does not induce metabolic enzymes is an important consideration. Carbamazepine, phenytoin, primidone, and phenobarbital are generally classified as enzyme inducers; valproate and gabapentin are not. GABITRIL is considered to be a nonenzyme inducing AED (see PRECAUTIONS, General, Use in Non-Induced Patients).
The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy.
Effects of 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.
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.
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 Rwarfarin 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.
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.
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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).
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including GABITRIL, 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.
Anyone considering prescribing GABITRIL or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
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 (Study 1 described in CLINICAL STUDIES) 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 (see PRECAUTIONS, Laboratory Tests, EEG). 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 populations similar 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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PRECAUTIONS
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 (see DOSAGE AND ADMINISTRATION). 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.
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, 10 th and 90th percentiles 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 (see WARNINGS, Cognitive/Neuropsychiatric Adverse Events). In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 Leydig cell 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/m² basis).
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/m²). 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/m² basis).
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/m²). 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/m² 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/m² 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/m² 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 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 (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric).
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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OVERDOSE
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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CONTRAINDICATIONS
GABITRIL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.