TIAGABINE HYDROCHLORIDE_- tiagabine hydrochloride_tablet

CLINICAL PHARMACOLOGY
Mechanism of Action in vitro 50 85 in vitro 1A 2 3 1 2 1 A 1B Pharmacokinetics PRECAUTIONS, General, Use in Non-Induced Patients Absorption and Distribution: max max Metabolism and Elimination: in vivo in vitro in vitro min Special Populations Renal Insufficiency: Hepatic Insufficiency: PRECAUTIONS Geriatric: Pediatric: Gender, Race and Cigarette Smoking: Interactions with other Antiepilepsy Drugs: PRECAUTIONS, Drug Interactions Interactions with Other Drugs: See PRECAUTIONS, Drug Interactions.
ANIMAL TOXICOLOGY
In repeat dose toxicology studies, dogs receiving daily oral doses of 5 mg/kg/day or greater experienced unexpected CNS effects throughout the study. These effects occurred acutely and included marked sedation and apparent visual impairment which was characterized by a lack of awareness of objects, failure to fix on and follow moving objects, and absence of a blink reaction. Plasma exposures (AUCs) at 5 mg/kg/day were equal to those in humans receiving the maximum recommended daily human dose of 56 mg/day. The effects were reversible upon cessation of treatment and were not associated with any observed structural abnormality. The implications of these findings for humans are unknown. Medication Guides available at www.northstarrxllc.com/products Manufactured by: MSN Laboratories Private Limited Manufactured for: Issued on:

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

General: Tiagabine hydrochloride tablet is given orally and should be taken with food. Do not use a loading dose of tiagabine hydrochloride tablets. Dose titration: Rapid escalation and/or large dose increments of tiagabine hydrochloride tablets should not be used. Missed dose(s): If the patient forgets to take the prescribed dose of tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets 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: Table7: 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 Week 3 Increase total daily dose by 4 mg 12 mg/day Week 4 Increase total daily dose by 4 mg 16 mg/day Week 5 Increase total daily dose by 4 to 8 mg 20 to 24 mg/day Week 6 Increase total daily dose by 4 to 8 mg 24 to 32 mg/day 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: CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non-Induced Patients.

The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of tiagabine hydrochloride 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. Adverse Event Incidence in Controlled Clinical Trials: Table 5: Treatment-Emergent Adverse Event1 Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with Tiagabine Hydrochloride and numerically more frequent than in the placebo group) Body System/COSTART Tiagabine Hydrochloride N=494 % Placebo N=275 % Body as a Whole Abdominal Pain 7 3 Pain (Unspecified) 5 3 Cardiovascular Vasodilation 2 1 Digestive Nausea 11 9 Diarrhea 7 3 Vomiting 7 4 Increased Appetite 2 0 Mouth Ulceration 1 0 Musculoskeletal Myasthenia 1 0 Nervous System Dizziness 27 15 Asthenia 20 14 Somnolence 18 15 Nervousness 10 3 Tremor 9 3 Difficulty with Concentration/Attention* 6 2 Insomnia 6 4 Ataxia 5 3 Confusion 5 3 Speech Disorder 4 2 Difficulty with Memory* 4 3 Paresthesia 4 2 Depression 3 1 Emotional Lability 3 2 Abnormal Gait 3 2 Hostility 2 1 Nystagmus 2 1 Language Problems* 2 0 Agitation 1 0 Respiratory System Pharyngitis 7 4 Cough Increased 4 3 Skin and Appendages Rash 5 4 Pruritus 2 0 1 Table 6: Treatment-Emergent Adverse Event Incidence in Study 1 dagger Body System/COSTART Term Tiagabine Hydrochloride 56 mg (N=57) % Tiagabine Hydrochloride 32 mg (N=88) % Placebo (N=91) % Body as Whole Accidental Injury 21 15 20 Infection 19 10 12 Flu Syndrome 9 6 3 Pain 7 2 3 Abdominal Pain 5 7 4 Digestive System Diarrhea 2 10 6 Hemic and Lymphatic System Ecchymosis 0 6 1 Musculoskeletal System Myalgia 5 2 3 Nervous System Dizziness 28 31 12 Asthenia 23 18 15 Tremor 21 14 1 Somnolence 19 21 17 Nervousness 14 11 6 Difficulty with Concentration/Attention* 14 7 3 Ataxia 9 6 6 Depression 7 1 0 Insomnia 5 6 3 Abnormal Gait 5 5 3 Hostility 5 5 2 Respiratory System Pharyngitis 7 8 6 Special Senses Amblyopia 4 9 8 Urogenital System Urinary Tract Infection 5 0 2 dagger Other Adverse Events Observed During All Clinical Trials: 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: Postmarketing Reports Skin and subcutaneous tissue disorders: Eye disorders:

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

Pregnancy:
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. 2 2 2 2 http://www.aedpregnancyregistry.org/. Use in Nursing Mothers:
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 tiagabine hydrochloride during its clinical evaluation, no specific statements about the safety or effectiveness of tiagabine hydrochloride in this age group could be made.

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 hydrochloride is considered to be a non-enzyme inducing AED (see PRECAUTIONS, General, Use in Non-Induced Patients Effects of Tiagabine Hydrochloride on other Antiepilepsy Drugs (AEDs): Phenytoin: Carbamazepine: Valproate: Phenobarbital or Primidone: Effects of other Antiepilepsy Drugs (AEDs) on Tiagabine Hydrochloride: Carbamazepine: Phenytoin: Phenobarbital (Primidone): Valproate: in vitro in vitro Interaction of Tiagabine Hydrochloride with Other Drugs: Cimetidine: Theophylline: Warfarin: Digoxin: Ethanol or Triazolam: Oral Contraceptives: Antipyrine: St. John’s wort: Interaction of Tiagabine Hydrochloride with Highly Protein Bound Drugs: In vitro

CLINICAL STUDIES
The effectiveness of tiagabine hydrochloride as adjunctive therapy (added to other antiepilepsy drugs) was examined in three multi-center, double-blind, placebo-controlled, parallel-group, clinical trials in 769 patients with refractory partial seizures who were taking at least one hepatic enzyme-inducing antiepilepsy drug (AED), and two placebo-controlled cross-over studies in 90 patients. In the parallel-group trials, patients had a history of at least six complex partial seizures (Study 1 and Study 2, U. studies), or six partial seizures of any type (Study 3, European study), occurring alone or in combination with any other seizure type within the 8-week period preceding the first study visit in spite of receiving one or more AEDs at therapeutic concentrations. Table 1: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 1 Placebo (N=91) Tiagabine Hydrochloride 16 mg/day (N=61) Tiagabine Hydrochloride 32 mg/day (N=87) Tiagabine Hydrochloride 56 mg/day (N=56) Combined 32 and 56 mg/day (N=143) Complex Partial Median Reduction 0. 6* Median % Reduction dagger 9% 13% 25% 32% 29% All Partial Median Reduction 0. 9* Median % Reduction dagger 3% 12% 24% 36% 27% * p< 0. 05 Table 2: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 2 Placebo (N=107) Tiagabine Hydrochloride 16 mg BID (N=106) Tiagabine Hydrochloride 8 mg QID (N=104) Complex Partial Median Reduction 0. 3* Median % Reduction dagger 4% 22% 15% All Partial Median Reduction 0. 3 Median % Reduction dagger 5% 19% 13% * p <0. 027, necessary for statistical significance due to multiple comparisons. Figure 2 also displays the results for Study 1, which was a dose-response study, by treatment group, without combining tiagabine hydrochloride dosage groups. Figure 2 indicates a dose-response relationship across the three tiagabine hydrochloride groups. The proportion of patients achieving any particular level of reduction in all partial seizure rates was consistently higher as the dose of tiagabine hydrochloride was increased. For example, Figure 2 indicates that approximately 4% of patients in the placebo group experienced a 50% or greater reduction in all partial seizure rate, compared to approximately 10% of the tiagabine hydrochloride 16 mg/day group, 21% of the tiagabine hydrochloride 32 mg/day group, and 30% of the tiagabine hydrochloride 56 mg/day group. Figure 3 indicates that the proportion of patients achieving any particular level of reduction in partial seizure rate was consistently greater in patients taking tiagabine hydrochloride than in those taking placebo in Study 2 (Study 2 compared placebo to tiagabine hydrochloride 32 mg/day; one of the tiagabine hydrochloride groups received 8 mg QID, while the other tiagabine hydrochloride group received 16 mg BID). For example, Figure 3 indicates that approximately 7% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate, compared to approximately 23% of patients in the tiagabine hydrochloride 8 mg QID group and 28% of patients in the tiagabine hydrochloride 16 mg BID group. Study 3 was a double-blind, placebo-controlled, parallel-group trial that compared tiagabine hydrochloride 10 mg TID (N=77) with placebo (N=77). In this trial, patients were followed prospectively during a 12-week Baseline Phase and then randomized to receive study drug during an 18-week Treatment Phase. During the first 6 weeks of treatment (Titration Period), patients were titrated to 30 mg/day, after which they were maintained on this dose during the 12-week Fixed-Dose Period. The protocol-specified primary outcome measure (proportion of patients who achieved at least a 50% reduction from baseline in partial seizure rate) did not reach statistical significance. However, analyses of the median reduction from baseline in 4-week partial seizure rate (the analyses presented above for Study 1 and Study 2) were performed and showed a statistically significant improvement compared to placebo in all partial and complex partial seizure rates (Table 3): Table 3: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 3 Placebo (N=77) Tiagabine Hydrochloride 30 mg/day (N=77) Complex Partial double dagger Median Reduction -0. 3* Median % Reduction dagger -1% 14% All Partial Median Reduction -0. 1* Median % Reduction dagger -7% 11% * p <0. 05 The two other placebo-controlled trials that examined the effectiveness of tiagabine hydrochloride were small cross-over trials (N=46 and 44). Both trials included an open Screening Phase during which patients were titrated to an optimal dose and then treated with this dose for an additional 4 weeks. After this Open Phase, patients were randomized to one of two blinded treatment sequences (tiagabine hydrochloride followed by placebo or placebo followed by tiagabine hydrochloride). The Double-Blind Phase consisted of two Treatment Periods, each lasting 7 weeks (with a 3 week washout between periods). The outcome measures were median with-in patient differences between placebo and tiagabine hydrochloride Treatment Periods in 4-week complex partial and all partial seizure rates. The reductions in seizure rates were statistically significant in both studies. fig-1 fig-2 fig-3 fig-4.
WARNINGS
Seizures in Patients Without Epilepsy: Post-marketing reports have shown that tiagabine hydrochloride 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 hydrochloride 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. Suicidal Behavior and Ideation: Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 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. Withdrawal Seizures: CLINICAL STUDIES Cognitive/Neuropsychiatric Adverse Events: PRECAUTIONS, Laboratory Tests, EEG Status Epilepticus: Sudden Unexpected Death In Epilepsy (SUDEP):
Carcinogenesis,Mutagenesis, Impairment of Fertility
Carcinogenesis: 2 Mutagenesis: in vitro in vitro in vitro in vivo Impairment of Fertility: 2 2
OVERDOSAGE
Human Overdose Experience: Management of Overdose:
Medication Guide
TIAGABINE HYDROCHLORIDE Read this Medication Guide before you start taking tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets? Tiagabine hydrochloride tablets can cause serious side effects, including: 1. Call your healthcare provider right away if you have a seizure and you are not taking tiagabine hydrochloride tablets for epilepsy. 2. Like other antiepileptic drugs, tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets without first talking to a healthcare provider. Stopping tiagabine hydrochloride tablets 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 are tiagabine hydrochloride tablets? Who should not take tiagabine hydrochloride tablets? What should I tell my healthcare provider before taking tiagabine hydrochloride tablets? 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 tiagabine hydrochloride tablets can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking tiagabine hydrochloride tablets. You and your healthcare provider will decide if you should take tiagabine hydrochloride tablets while you are pregnant. If you become pregnant while taking tiagabine hydrochloride tablets, 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 tiagabine hydrochloride 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 tiagabine hydrochloride tablets. Tell your healthcare provider about all the medicines you take, How should I take tiagabine hydrochloride tablets? Take tiagabine hydrochloride tablets exactly as your healthcare provider tells you. Your healthcare provider may change your dose. Tiagabine hydrochloride tablets should be taken with food. Do not stop taking tiagabine hydrochloride tablets without talking to your healthcare provider. Stopping tiagabine hydrochloride tablets suddenly can increase your chances of having a seizure or cause seizures that will not stop. If you miss a dose of tiagabine hydrochloride tablets, do not take 2 doses of tiagabine hydrochloride tablets at the same time. Contact your healthcare provider if you miss more than one dose. If you take too much tiagabine hydrochloride tablets, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking tiagabine hydrochloride tablets? Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking tiagabine hydrochloride tablets without first talking to your healthcare provider. Taking tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets affects you. Tiagabine hydrochloride tablets can slow your thinking and motor skills. What are possible side effects of tiagabine hydrochloride tablets? Tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets. 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. How should I store tiagabine hydrochloride tablets? Store tiagabine hydrochloride tablets between 68°F to 77°F (20°C to 25°C) Keep tiagabine hydrochloride tablets out of light Keep tiagabine hydrochloride tablets dry Keep tiagabine hydrochloride tablets and all medicines out of the reach of children. What are the ingredients in tiagabine hydrochloride tablets? Active Ingredient: Inactive Ingredients: the 2 mg tablets contain FD&C yellow No. 6 aluminum lake the 4 mg tablets contain D&C yellow No. 10 aluminum lake the 12 mg tablets contain D&C yellow No. 10 aluminum lake and FD&C Blue No.1 aluminum lake the 16 mg tablets contain FD&C blue No. 2 aluminum lake This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guides available at www.northstarrxllc.com/products Rx only Manufactured by: Manufactured for: Issued on:

Northstar Rx LLC

TIAGABINE HYDROCHLORIDE_- tiagabine hydrochloride_tablet Product manual source documgent