Gabitril

Tiagabine comes as a tablet to take by mouth. It usually is taken with food two to four times a day. However, for the first week of treatment you will only take tiagabine once a day. Your doctor will slowly increase your dose (not more often than once each week) until you reach the dose of tiagabine you are to take regularly. To help you remember to take tiagabine, take it around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tiagabine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take tiagabine even if you feel well. Do not stop taking tiagabine without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. Abruptly stopping this medication can cause seizures. Your doctor will probably decrease your dose gradually.

Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with tiagabine and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs) or the manufacturer's website to obtain the Medication Guide.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

>10%

Dizziness (26-30%)

Asthenia (16-20%)

Somnolence (16-20%)

Nausea (11-15%)

1-10%

Abdominal pain (6-10%)

Diarrhea (6-10%)

Vomiting (6-10%)

Nervousness (6-10%)

Pharyngitis (6-10%)

Tremor (6-10%)

Insomnia (6-10%)

Rash (1-5%)

Pruritis (1-5%)

Ataxia (1-5%)

Confusion (1-5%)

Speech d/o (1-5%)

Paresthesia (1-5%)

Depr'n (1-5%)

Pain (1-5%)

Increased appetite (1-5%)

Hostility (1-5%)

Nystagmus (1-5%)

Postmarketing Reports

Bullous dermatitis

Vision blurred

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, reports of overdose involving GABITRIL 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 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, 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

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.

Gabitril is a prescription medicine used with other medicines to treat partial seizures in adults and children age 12 and older.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

 

See “Drug Precautions”.

Gabitril may cause other serious side effects including:

• seizures that can happen more often or become worse
• trouble concentrating, problems with speech and language, feeling confused, feeling sleepy and tired, and problems thinking
• weakness all over your body
• eye and vision problems
• serious rash

Call your healthcare provider right away if you have any of the serious side effects listed above.

The most common side effects of Gabitril include:

• dizziness
• lack of energy
• drowsiness
• nausea
• nervousness
• tremor
• stomach pain
• abnormal thinking
• difficulty with concentration or attention

These are not all the possible side effects of Gabitril. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Pain Management Medication Types
• Prescription Anxiety Medications
• Seizure (Epilepsy)

Contraindications

Known hypersensitivity to tiagabine or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Seizures in Nonepileptic Patients

New-onset seizures and status epilepticus reported in patients without epilepsy; may be dose-related and may occur in patients using concomitant drugs that lower seizure threshold (e.g., antidepressants, antipsychotics, stimulants, narcotics).1 14

Safety and efficacy not established for any indication other than the management of partial seizures.1 Use of tiagabine for unlabeled indications is strongly discouraged.14

Discontinue therapy if seizures develop in nonepileptic patients and evaluate patient for underlying seizure disorder.1

Discontinuance of Therapy

Abrupt withdrawal may result in increased seizure frequency; withdraw gradually and reduce dosage slowly unless safety concerns require a more rapid withdrawal.1 13

Cognitive/Neuropsychiatric Effects

Possible somnolence and fatigue, impaired concentration, speech or language problems, and confusion; usually mild to moderate in severity, may be dose-related, and usually begins during initial dosage titration.1

Cognitive/neuropsychiatric events may be accompanied by EEG abnormalities (e.g., generalized spike and wave activity). 1 May be a manifestation of underlying seizure activity; dosage adjustment may be required.1

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).20 21 24 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.20 21 24 Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.20

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.20 21 24 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.20

Balance risk of suicidality with risk of untreated illness.20 24 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.23 24 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.23 24 (See Advice to Patients.)

Status Epilepticus

Not established whether incidence of status epilepticus (5% in controlled and uncontrolled trials of tiagabine) is higher or lower than would be expected to occur in patients with epilepsy not treated with the drug.1

Seizures and status epilepticus may occur with tiagabine overdosage.1

Sudden, Unexpected Death In Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.1

Sensitivity Reactions

Dermatologic Reactions

Serious rash (i.e., Stevens-Johnson syndrome, maculopapular rash, vesiculobullous rash), potentially fatal, reported rarely.1

General Precautions

Generalized Weakness

Generalized weakness (moderately severe to incapacitating) reported; resolves after a reduction in dose or discontinuance of tiagabine.1

Binding to Melanin-rich Tissues

Possible long-term ophthalmologic effects.1 Accumulation of tiagabine in melanin-containing cells in the eye observed in dogs; however ophthalmologic changes were not noted in long-term studies in these animals.1

Manufacturer makes no specific recommendations for periodic ophthalmologic monitoring.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use only if potential benefits outweigh the risks.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1 Pharmacokinetics evaluated in a limited number of children 3–10 years of age.1 (See Special Populations under Pharmacokinetics.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether safety and efficacy of tiagabine in geriatric patients differ from safety and efficacy in younger adults.1 The pharmacokinetic profile in healthy geriatric adults does not appear to differ from that in younger adults.1 11

Hepatic Impairment

Decreased clearance in patients with moderate hepatic impairment (Child-Pugh class B); dosage adjustments recommended.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Pharmacokinetics not altered in patients with mild, moderate, or severe renal impairment or in those undergoing hemodialysis.1

Common Adverse Effects

Dizziness/light-headedness, asthenia, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, abnormal thinking/difficulty with concentration or attention.1

Storage

Oral

Tablets

20–25°C.1 Protect from light and moisture.1

In the U.S.

• Gabitril

Available Dosage Forms:

• Tablet
• Capsule

Therapeutic Class: Anticonvulsant

Pharmacologic Class: Gamma Aminobutyric Acid Uptake Inhibitor

Tiagabine is used to help control some types of seizures in the treatment of epilepsy. This medicine cannot cure epilepsy and will only work to control seizures for as long as you continue to take it.

Tiagabine is available only with your doctor's prescription.

Take this medicine only as directed by your doctor, to help your condition as much as possible. Do not take more or less of it, and do not take it more or less often than your doctor ordered.

Tiagabine should be taken with food or on a full stomach.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For epilepsy:
    • Adults and teenagers 12 years of age and older—At first, 4 milligrams (mg) once a day. Your doctor may increase your dose slowly as needed and tolerated. However, the dose usually is not greater than 56 mg a day.
    • Children up to 12 years of age—Use and dose must be determined by the doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Blue or purple spots on skin
• difficulty in concentrating or paying attention

Less common

• Burning, numbness, or tingling sensations
• clumsiness or unsteadiness
• confusion
• itching
• mental depression
• speech or language problems

Rare

• Agitation
• bloody or cloudy urine
• burning, pain, or difficulty in urinating
• frequent urge to urinate
• generalized weakness
• hostility
• memory problems
• quick to react or overreact emotionally
• rash
• uncontrolled back-and-forth and/or rolling eye movements
• walking in unusual manner

Symptoms of overdose

• Agitation (severe)
• clumsiness or unsteadiness (severe)
• coma
• confusion (severe)
• drowsiness (severe)
• increase in seizures
• mental depression
• severe muscle twitching or jerking
• sluggishness
• speech problems (severe)
• weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Chills
• diarrhea
• dizziness
• drowsiness
• fever
• headache
• muscle aches or pain
• nervousness
• sore throat
• tremor
• unusual tiredness or weakness
• vomiting

Less common

• Abdominal pain
• flushing
• impaired vision
• increased appetite
• increased cough
• mouth ulcers
• muscle weakness
• nausea
• pain
• trouble in sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat seizures.

Mechanism of Action

The precise mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability, documented in in vitro experiments, to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. In rat-derived hippocampal slices, tiagabine has been shown to prolong GABA-mediated inhibitory post-synaptic potentials. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus, ventral palladum, and substantia nigra in rats at the ED50 and ED85 doses for inhibition of pentylenetetrazol (PTZ)-induced tonic seizures. This suggests that tiagabine prevents the propagation of neural impulses that contribute to seizures by a GABA-ergic action.

Tiagabine has shown efficacy in several animal models of seizures. It is effective against the tonic phase of subcutaneous PTZ-induced seizures in mice and rats, seizures induced by the proconvulsant DMCM in mice, audiogenic seizures in genetically epilepsy-prone rats (GEPR), and amygdala-kindled seizures in rats. Tiagabine has little efficacy against maximal electroshock seizures in rats and is only partially effective against subcutaneous PTZ-induced clonic seizures in mice, picrotoxin-induced tonic seizures in the mouse, bicuculline-induced seizures in the rat, and photic seizures in photosensitive baboons. Tiagabine produces a biphasic dose-response curve against PTZ- and DMCM-induced convulsions, with attenuated effectiveness at higher doses.

Based on in vitro binding studies, tiagabine does not significantly inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline and shows little or no binding to dopamine D1 and D2, muscarinic, serotonin 5HT1A, 5HT2, and 5HT3, beta-1 and 2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A1 and A2, opiate µ and K1, NMDA glutamate, and GABAA receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT1B, benzodiazepine, and chloride channel receptors at concentrations 20 to 400 times those inhibiting the uptake of GABA.

Pharmacokinetics

Tiagabine is well absorbed, with food slowing absorption rate but not altering the extent of absorption. The elimination half-life of tiagabine is 7 to 9 hours in normal volunteers. In epilepsy clinical trials, most patients were receiving hepatic enzyme-inducing agents (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). The pharmacokinetic profile in induced patients is significantly different from the non-induced population (see PRECAUTIONS, General, Use in Non-Induced Patients). The systemic clearance of tiagabine in induced patients is approximately 60% greater resulting in considerably lower plasma concentrations and an elimination half-life of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population.

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 Tmax was prolonged to 2.5 hours, and mean Cmax was 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 α1-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-life for 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 Cmin values 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.

Special Populations

Renal Insufficiency: The pharmacokinetics of total and unbound tiagabine were similar in subjects with normal renal function (creatinine clearance >80 mL/min) and in subjects with mild (creatinine clearance 40 to 80 mL/min), moderate (creatinine clearance 20 to 39 mL/min), or severe (creatinine clearance 5 to 19 mL/min) renal impairment. The pharmacokinetics of total and unbound tiagabine were also unaffected in subjects with renal failure requiring hemodialysis.

Hepatic Insufficiency: In patients with moderate hepatic impairment (Child-Pugh Class B), clearance of unbound tiagabine was reduced by about 60%. Patients with impaired liver function may require reduced initial and maintenance doses of tiagabine and/or longer dosing intervals compared to patients with normal hepatic function (see PRECAUTIONS).

Geriatric: The pharmacokinetic profile of tiagabine was similar in healthy elderly and healthy young adults.

Pediatric: Tiagabine has not been investigated in adequate and well-controlled clinical trials in patients below the age of 12. The apparent clearance and volume of distribution of tiagabine per unit body surface area or per kg were fairly similar in 25 children (age: 3 to 10 years) and in adults taking enzyme-inducing antiepilepsy drugs ([AEDs] e.g., carbamazepine or phenytoin). In children who were taking a non-inducing AED (e.g., valproate), the clearance of tiagabine based upon body weight and body surface area was 2 and 1.5-fold higher, respectively, than in non-induced adults with epilepsy.

Gender, Race and Cigarette Smoking: No specific pharmacokinetic studies were conducted to investigate the effect of gender, race and cigarette smoking on the disposition of tiagabine. Retrospective pharmacokinetic analyses, however, suggest that there is no clinically important difference between the clearance of tiagabine in males and females, when adjusted for body weight. Population pharmacokinetic analyses indicated that tiagabine clearance values were not significantly different in Caucasian (N=463), Black (N=23), or Hispanic (N=17) patients with epilepsy, and that tiagabine clearance values were not significantly affected by tobacco use.

Interactions with other Antiepilepsy Drugs: The clearance of tiagabine is affected by the co-administration of hepatic enzyme-inducing antiepilepsy drugs. Tiagabine is eliminated more rapidly in patients who have been taking hepatic enzyme-inducing drugs, e.g., carbamazepine, phenytoin, primidone and phenobarbital than in patients not receiving such treatment (see PRECAUTIONS, Drug Interactions).

Interactions with Other Drugs: See PRECAUTIONS, Drug Interactions.

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

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.

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 Gabitril. The complete text of the Medication Guide is provided at the end of this labeling.

Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled that AEDs, including Gabitril, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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.

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.

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 PRECAUTIONS, Pregnancy).

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.

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 non-enzyme 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 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.

St. John’s wort: Concomitant use of St. John’s wort may enhance the metabolism of tiagabine.

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, 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 http://www.aedpregnancyregistry.org/.

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 (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.

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 well-controlled clinical trials.

Experience is limited in patients taking total daily doses above 32 mg/day using twice daily dosing. A typical dosing titration regimen for patients taking enzyme-inducing AEDs (induced patients) is provided in Table 7.

Table 7: Typical Dosing Titration Regimen for Patients Already Taking Enzyme-Inducing AEDs

	Initiation and Titration Schedule	Total Daily Dose
Week 1	Initiate at 4 mg once daily	4 mg/day
Week 2	Increase total daily dose by 4 mg	8 mg/day (in two divided doses)
Week 3	Increase total daily dose by 4 mg	12 mg/day (in three divided doses)
Week 4	Increase total daily dose by 4 mg	16 mg/day (in two to four divided doses)
Week 5	Increase total daily dose by 4 to 8 mg	20 to 24 mg/day (in two to four divided doses)
Week 6	Increase total daily dose by 4 to 8 mg	24 to 32 mg/day (in two to four divided doses)
Usual Adult Maintenance Dose in Induced Patients:	32 to 56 mg/day in two to four divided doses

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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non-Induced Patients).

Gabitril® (găb-ĭ-trĭl)

(tiagabine hydrochloride)

Tablets

Read this Medication Guide before you start taking Gabitril and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Gabitril?

Do not stop taking Gabitril without first talking to your healthcare provider.

Stopping Gabitril suddenly can cause serious problems.

Gabitril can cause serious side effects, including:

1. Gabitril may cause seizures in people who do not have epilepsy. If you do not have a seizure disorder and you take Gabitril, you may have a seizure or seizures that do not stop (status epilepticus). Call your healthcare provider right away if you have a seizure and you are not taking Gabitril for epilepsy.

2. Like other antiepileptic drugs, Gabitril may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling agitated or restless • panic attacks • trouble sleeping (insomnia)

• new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood

  Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.   How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. • Call your healthcare provider between visits as needed, especially if you are worried about symptoms.   Do not stop Gabitril without first talking to a healthcare provider. • Stopping Gabitril suddenly can cause serious problems. If you have epilepsy and stop a seizure medicine suddenly, you may have more frequent seizures or seizures that will not stop (status epilepticus).

What is Gabitril?

Gabitril is a prescription medicine used with other medicines to treat partial seizures in adults and children age 12 and older.

Who should not take Gabitril?

Do not take Gabitril if you are allergic to tiagabine hydrochloride or any of the other ingredients in Gabitril. See the end of this Medication Guide for a complete list of ingredients in Gabitril.

What should I tell my healthcare provider before taking Gabitril?

Before taking Gabitril, tell your healthcare provider if you:

• have or have had depression, mood problems, or suicidal thoughts or behavior • have liver problems • have a history of seizures that do not stop (status epilepticus) • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if Gabitril can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Gabitril. You and your healthcare provider will decide if you should take Gabitril while you are pregnant. o If you become pregnant while taking Gabitril, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy. You can enroll in this registry by calling 1-888-233-2334. • are breastfeeding or plan to breastfeed. It is not known if Gabitril passes into breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Gabitril.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking Gabitril with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Always tell your healthcare provider if there are any changes in any other medicines that you take.

How should I take Gabitril?

• Take Gabitril exactly as your healthcare provider tells you. • Your healthcare provider may change your dose. • Gabitril should be taken with food. • Do not stop taking Gabitril without talking to your healthcare provider.   Stopping Gabitril suddenly can increase your chances of having a seizure or cause seizures that will not stop. • If you miss a dose of Gabitril, do not take 2 doses of Gabitril at the same time. Contact your healthcare provider if you miss more than one dose.

If you take too much Gabitril, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking Gabitril?

• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Gabitril without first talking to your healthcare provider. Taking Gabitril with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how Gabitril affects you. Gabitril can slow your thinking and motor skills.

What are possible side effects of Gabitril?

See “What is the most important information I should know about Gabitril?”

Gabitril may cause other serious side effects including:

• seizures that can happen more often or become worse • trouble concentrating, problems with speech and language, feeling confused, feeling sleepy and tired, and problems thinking • weakness all over your body • eye and vision problems • serious rash

Call your healthcare provider right away if you have any of the serious side effects listed above.

The most common side effects of Gabitril include:

• dizziness • lack of energy • drowsiness • nausea • nervousness • tremor • stomach pain • abnormal thinking • difficulty with concentration or attention

These are not all the possible side effects of Gabitril. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Gabitril?

• Store Gabitril between 68°F to 77°F (20°C to 25°C) • Keep Gabitril out of light • Keep Gabitril dry

Keep Gabitril and all medicines out of the reach of children.

General Information about Gabitril

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Gabitril for a condition for which it was not prescribed. Do not give Gabitril to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Gabitril. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Gabitril that is written for health professionals.

For more information, go to www.Gabitril.com or call 1-800-896-5855.

What are the ingredients in Gabitril?

Active Ingredient: tiagabine hydrochloride

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:

• the 2 mg tablets contain FD&C Yellow No. 6 • the 4 mg tablets contain D&C Yellow No. 10 • the 12 mg tablets contain D&C Yellow No. 10 and FD&C Blue No. 1 • the 16 mg tablets contain FD&C Blue No. 2

This Medication Guide has been approved by the U.S. Food and Drug Administration.

GABMG-002

November 2015

Rx only

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

U.S. Patent Nos. 5,354,760; 5,866,590; 5,958,951

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

Printed in U.S.A.

Gabitril® (tiagabine hydrochloride) Tablets 2 mg, 30s Label Text

NDC 63459-402-30

30 Tablets

Gabitril®

(tiagabine

hydrochloride)

Tablets

2 mg

Medication Guide

Required: Each time

Gabitril is dispensed,

give the patient a

Medication Guide

Rx only

TEVA

Summary of Use during Lactation

Monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs. Because there is very limited published experience with tiagabine during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

One mother breastfed her infant while taking tiagabine 24 mg and then 20 mg daily.[1]

No adverse effects were reported in 10 newborns who were 4 to 23 days old who were breastfed during maternal intake of levetiracetam 1000 to 3000 mg daily. One mother was also taking tiagabine 30 mg daily, clobazam 45 mg daily and oxcarbazepine 600 mg daily.[2]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1. Neppe VM. Successful tiagabine monotherapy during pregnancy and lactation: clinical and serum data. Epilepsia. 2000;41 (Suppl 7):200-1. Abstract. DOI: doi:10.1111/j.1528-1157.2000.tb01727.x

2. Tomson T, Palm R, Kallen K et al. Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilepsia. 2007;48:1111-6. PMID: 17381438