Tiagabine Hydrochloride

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Overview

What is Tiagabine Hydrochloride?

Tiagabine hydrochloride 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:

What does Tiagabine Hydrochloride look like?

What are the available doses of Tiagabine Hydrochloride?

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What should I talk to my health care provider before I take Tiagabine Hydrochloride?

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How should I use Tiagabine Hydrochloride?

Tiagabine HCl is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.

What interacts with Tiagabine Hydrochloride?

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

What are the warnings of Tiagabine Hydrochloride?

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Seizures in Patients Without Epilepsy: Post-marketing reports have shown that tiagabine HCl use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of tiagabine HCl as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.

The tiagabine HCl dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of tiagabine HCl by inducing its metabolism. Use of tiagabine HCl without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based (see ).

Safety and effectiveness of tiagabine HCl have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.

In nonepileptic patients who develop seizures while on tiagabine HCl treatment, tiagabine HCl should be discontinued and patients should be evaluated for an underlying seizure disorder.

Seizures and status epilepticus are known to occur with tiagabine HCl overdosage (see ).

Suicidal Behavior and Ideation:

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing tiagabine HCl 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.

Cognitive/Neuropsychiatric Adverse Events:

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 ). 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 tiagabine HCl.

Status Epilepticus:

Sudden Unexpected Death In Epilepsy (SUDEP):

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 tiagabine HCl (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 tiagabine HCl, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving tiagabine HCl are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to tiagabine HCl, 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.

What are the precautions of Tiagabine Hydrochloride?

General

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Generalized Weakness:

Binding in the Eye and Other Melanin-Containing Tissues:

Use in Hepatically-Impaired Patients:

Serious Rash:

Information for Patients

Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking tiagabine HCl. The complete text of the Medication Guide is provided at the end of this labeling.

Suicidal Thinking and Behavior

Patients should be advised that tiagabine HCl 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 tiagabine HCl 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 tiagabine HCl.

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.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see ).

Laboratory Tests

Therapeutic Monitoring of Plasma Concentrations of Tiagabine:

Clinical Chemistry and Hematology:

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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. Tiagabine HCl 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.

Effects of Tiagabine HCl on other Antiepilepsy Drugs (AEDs):

Phenytoin:

Carbamazepine:

Valproate:

Phenobarbital or Primidone:

Effects of other Antiepilepsy Drugs (AEDs) on Tiagabine HCl:

Carbamazepine:

Phenytoin:

Phenobarbital (Primidone):

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Interaction of Tiagabine HCl with Other Drugs:

Cimetidine:

Theophylline:

Warfarin:

Digoxin:

Ethanol or Triazolam:

Oral Contraceptives:

Antipyrine:

St. John’s wort

Interaction of Tiagabine HCl with Highly Protein Bound Drugs:

In vitro

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

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Impairment of Fertility:

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/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 tiagabine HCl, physicians are advised to recommend that pregnant patients taking tiagabine HCl 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 .

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. Tiagabine HCl 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 ).

Geriatric Use:

Because few patients over the age of 65 (approximately 20) were exposed to tiagabine HCl during its clinical evaluation, no specific statements about the safety or effectiveness of tiagabine HCl in this age group could be made.

What are the side effects of Tiagabine Hydrochloride?

The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of tiagabine HCl in combination with other antiepilepsy drugs not seen at an equivalent frequency among placebo-treated patients were dizziness/light-headedness, asthenia/lack of energy, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, and thinking abnormal/difficulty with concentration or attention.

Approximately 21% of the 2531 patients who received tiagabine HCl in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%).

In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with tiagabine HCl 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:

The prescriber should be aware that these figures, obtained when tiagabine HCl 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 tiagabine HCl 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 tiagabine HCl 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 tiagabine HCl 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:

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:

Infrequent:

Cardiovascular System:

Frequent:

Infrequent:

Digestive System:

Frequent:

Infrequent:

Endocrine System:

Infrequent:

Hemic and Lymphatic System:

Frequent:

Infrequent:

Metabolic and Nutritional:

Frequent:

Infrequent:

Musculoskeletal System:

Frequent:

Infrequent:

Nervous System:

Frequent:

Infrequent:

Respiratory System:

Frequent:

Infrequent:

Skin and Appendages:

Frequent:

Infrequent:

Special Senses:

Frequent:

Infrequent:

Urogenital System:

Frequent:

Infrequent:

Table 5: Treatment-Emergent Adverse Event Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with tiagabine HCl and numerically more frequent than in the placebo group)

Postmarketing Reports

The following adverse reactions have been identified during postapproval use of tiagabine HCl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders:

Eye disorders:

What should I look out for while using Tiagabine Hydrochloride?

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

Seizures in Patients Without Epilepsy: Post-marketing reports have shown that tiagabine HCl use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of tiagabine HCl as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.

The tiagabine HCl dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of tiagabine HCl by inducing its metabolism. Use of tiagabine HCl without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based (see ).

Safety and effectiveness of tiagabine HCl have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.

In nonepileptic patients who develop seizures while on tiagabine HCl treatment, tiagabine HCl should be discontinued and patients should be evaluated for an underlying seizure disorder.

Seizures and status epilepticus are known to occur with tiagabine HCl overdosage (see ).

Suicidal Behavior and Ideation:

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing tiagabine HCl 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:

Cognitive/Neuropsychiatric Adverse Events:

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 ). 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 tiagabine HCl.

Status Epilepticus:

Sudden Unexpected Death In Epilepsy (SUDEP):

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 tiagabine HCl (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 tiagabine HCl, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving tiagabine HCl are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to tiagabine HCl, 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.

What might happen if I take too much Tiagabine Hydrochloride?

Human Overdose Experience:

From post-marketing experience, reports of overdose involving tiagabine HCl alone have included cases in which patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including tiagabine HCl, have resulted in fatal outcomes. Symptoms most often accompanying tiagabine HCl overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, respiratory arrest, coma, loss of consciousness, ataxia, dizziness, confusion, somnolence, drowsiness, impaired speech, aggression, agitation, lethargy, myoclonus, spike wave stupor, encephalopathy, amnesia, dyskinesia, tremors, disorientation, psychotic disorder, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures.

Management of Overdose:

How should I store and handle Tiagabine Hydrochloride?

Store at 20° to 25°C (68° to 77°F)Protect from moisture.Store at 20° to 25°C (68° to 77°F)Protect from moisture.Tiagabine HCl 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 ( 0093-5030-56).4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 0093-5031-56).12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 0093-8072-56).16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 0093-8076-56).Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.Tiagabine HCl 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 ( 0093-5030-56).4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 0093-5031-56).12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 0093-8072-56).16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 0093-8076-56).Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.Tiagabine HCl 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 ( 0093-5030-56).4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 0093-5031-56).12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 0093-8072-56).16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 0093-8076-56).Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.Tiagabine HCl 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 ( 0093-5030-56).4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 0093-5031-56).12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 0093-8072-56).16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 0093-8076-56).Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.Tiagabine HCl 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 ( 0093-5030-56).4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 0093-5031-56).12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 0093-8072-56).16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 0093-8076-56).Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.Tiagabine HCl 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 ( 0093-5030-56).4 mg yellow, round tablets, debossed with on one side and 404 on the opposite side, are available in bottles of 30 ( 0093-5031-56).12 mg green, ovaloid tablets, debossed with on one side and 412 on the opposite side, are available in bottles of 30 ( 0093-8072-56).16 mg blue, ovaloid tablets, debossed with on one side and 416 on the opposite side, are available in bottles of 30 ( 0093-8076-56).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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Clinical Information

Chemical Structure

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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.

Non-Clinical Toxicology

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

Seizures in Patients Without Epilepsy: Post-marketing reports have shown that tiagabine HCl use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of tiagabine HCl as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.

The tiagabine HCl dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of tiagabine HCl by inducing its metabolism. Use of tiagabine HCl without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based (see ).

Safety and effectiveness of tiagabine HCl have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.

In nonepileptic patients who develop seizures while on tiagabine HCl treatment, tiagabine HCl should be discontinued and patients should be evaluated for an underlying seizure disorder.

Seizures and status epilepticus are known to occur with tiagabine HCl overdosage (see ).

Suicidal Behavior and Ideation:

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing tiagabine HCl 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:

Cognitive/Neuropsychiatric Adverse Events:

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 ). 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 tiagabine HCl.

Status Epilepticus:

Sudden Unexpected Death In Epilepsy (SUDEP):

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 tiagabine HCl (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 tiagabine HCl, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving tiagabine HCl are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to tiagabine HCl, 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.

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. Tiagabine HCl 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.

Effects of Tiagabine HCl on other Antiepilepsy Drugs (AEDs):

Phenytoin:

Carbamazepine:

Valproate:

Phenobarbital or Primidone:

Effects of other Antiepilepsy Drugs (AEDs) on Tiagabine HCl:

Carbamazepine:

Phenytoin:

Phenobarbital (Primidone):

Interaction of Tiagabine HCl with Other Drugs:

Cimetidine:

Theophylline:

Warfarin:

Digoxin:

Ethanol or Triazolam:

Oral Contraceptives:

Antipyrine:

St. John’s wort

Interaction of Tiagabine HCl with Highly Protein Bound Drugs:

In vitro

Use in Non-Induced Patients:

Generalized Weakness:

Binding in the Eye and Other Melanin-Containing Tissues:

Use in Hepatically-Impaired Patients:

Serious Rash:

The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of tiagabine HCl in combination with other antiepilepsy drugs not seen at an equivalent frequency among placebo-treated patients were dizziness/light-headedness, asthenia/lack of energy, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, and thinking abnormal/difficulty with concentration or attention.

Approximately 21% of the 2531 patients who received tiagabine HCl in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%).

In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with tiagabine HCl 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:

The prescriber should be aware that these figures, obtained when tiagabine HCl 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 tiagabine HCl 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 tiagabine HCl 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 tiagabine HCl 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:

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:

Infrequent:

Cardiovascular System:

Frequent:

Infrequent:

Digestive System:

Frequent:

Infrequent:

Endocrine System:

Infrequent:

Hemic and Lymphatic System:

Frequent:

Infrequent:

Metabolic and Nutritional:

Frequent:

Infrequent:

Musculoskeletal System:

Frequent:

Infrequent:

Nervous System:

Frequent:

Infrequent:

Respiratory System:

Frequent:

Infrequent:

Skin and Appendages:

Frequent:

Infrequent:

Special Senses:

Frequent:

Infrequent:

Urogenital System:

Frequent:

Infrequent:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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