TIAGABINE HYDROCHLORIDE

Tiagabine hydrochloride, USP is an antiepilepsy drug available as 2 mg and 4 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 C 20 H 25 NO 2 S 2 HCl, and its molecular weight is 412. Tiagabine hydrochloride is a white to off-white, odorless, crystalline powder. It is insoluble in heptane, sparingly soluble in water, and soluble in aqueous base. The structural formula is: Inactive Ingredients Tiagabine hydrochloride tablets contain the following inactive ingredients: Hydrogenated vegetable oil, anhydrous lactose, butylated hydroxyanisole, pregelatinized maize starch, colloidal silicon dioxide, talc, crospovidone, titanium dioxide, hypromellose, polyethylene glycol. In addition, individual tablets contain: 2 mg tablets: FD&C Yellow No. 6 and polysorbate 80. 4 mg tablets: Lactose monohydrate and D&C Yellow No. 10. chemical-structure

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

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. Tiagabine hydrochloride tablets are 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 tiagabine hydrochloride tablets: Tiagabine hydrochloride tablets are 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: 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 tiagabine hydrochloride tablets. In adolescents 12 to 18 years old, tiagabine hydrochloride tablets should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of tiagabine hydrochloride tablets 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, tiagabine hydrochloride tablets should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of tiagabine hydrochloride tablets 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 tiagabine hydrochloride tablets, 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 tiagabine hydrochloride tablets. These patients may also require a slower titration of tiagabine hydrochloride tablets compared to that of induced patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non-Induced Patients ).

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

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. Approximately 21% of the 2531 patients who received tiagabine hydrochloride 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 hydrochloride and 6% for the placebo group. The most common adverse events considered the primary reason for discontinuation were confusion (1.2%), somnolence (1%), and ataxia (1%). Adverse Event Incidence in Controlled Clinical Trials: Table 5 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients treated with tiagabine hydrochloride for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the tiagabine hydrochloride group. In these studies, either tiagabine hydrochloride or placebo was added to the patient’s current antiepilepsy drug therapy. Adverse events were usually mild or moderate in intensity. The prescriber should be aware that these figures, obtained when tiagabine hydrochloride 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. Table 5: Treatment-Emergent Adverse Event Patients in these add-on studies were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to tiagabine hydrochloride or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. 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 COSTART term substituted with a more clinically descriptive term. 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 Other events reported by 1% or more of patients treated with tiagabine hydrochloride 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 hydrochloride 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. Table 6: Treatment-Emergent Adverse Event Incidence in Study 1 Patients in this study were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to tiagabine hydrochloride or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. (events in at least 5% of patients treated with Tiagabine Hydrochloride 32 or 56 mg and numerically more frequent than in the placebo group) Body System/ COSTART Term Tiagabine Hydrochloride 56 mg (N=57) % Tiagabine Hydrochloride 32 mg (N=88) % Placebo (N=91) % Body as a Whole Accidental Injury 21 15 20 Infection 19 10 12 Flu Syndrome 9 6 3 Pain 3 7 2 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 COSTART term substituted with a more clinically descriptive term. 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 The effects of tiagabine hydrochloride 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: Tiagabine hydrochloride has been administered to 2531 patients during all phase 2/3 clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 2531 patients exposed to tiagabine hydrochloride who experienced events of the type cited on at least one occasion while receiving tiagabine hydrochloride. All reported events are included except those already listed above, events seen only three times or fewer (unless potentially important), events very unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to tiagabine. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole: Frequent : Allergic reaction, chest pain, chills, cyst, neck pain, and malaise. Infrequent : Abscess, cellulitis, facial edema, halitosis, hernia, neck rigidity, neoplasm, pelvic pain, photosensitivity reaction, sepsis, sudden death, and suicide attempt. Cardiovascular System: Frequent : Hypertension, palpitation, syncope, and tachycardia. Infrequent : Angina pectoris, cerebral ischemia, electrocardiogram abnormal, hemorrhage, hypotension, myocardial infarct, pallor, peripheral vascular disorder, phlebitis, postural hypotension, and thrombophlebitis. Digestive System : Frequent : Gingivitis and stomatitis. Infrequent: Abnormal stools, cholecystitis, cholelithiasis, dysphagia, eructation, esophagitis, fecal incontinence, gastritis, gastrointestinal hemorrhage, glossitis, gum hyperplasia, hepatomegaly, increased salivation, liver function tests abnormal, melena, periodontal abscess, rectal hemorrhage, thirst, tooth caries, and ulcerative stomatitis. Endocrine System : Infrequent : Goiter and hypothyroidism. Hemic and Lymphatic System: Frequent : Lymphadenopathy. Infrequent: Anemia, erythrocytes abnormal, leukopenia, petechia, and thrombocytopenia. Metabolic and Nutritional: Frequent : Edema, peripheral edema, weight gain, and weight loss. Infrequent: Dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, and hyponatremia. Musculoskeletal System: Frequent : Arthralgia. Infrequent: Arthritis, arthrosis, bursitis, generalized spasm, and tendinous contracture. Nervous System: Frequent : Depersonalization, dysarthria, euphoria, hallucination, hyperkinesia, hypertonia, hypesthesia, hypokinesia, hypotonia, migraine, myoclonus, paranoid reaction, personality disorder, reflexes decreased, stupor, twitching, and vertigo. Infrequent : Abnormal dreams, apathy, choreoathetosis, circumoral paresthesia, CNS neoplasm, coma, delusions, dry mouth, dystonia, encephalopathy, hemiplegia, leg cramps, libido increased, libido decreased, movement disorder, neuritis, neurosis, paralysis, peripheral neuritis, psychosis, reflexes increased, and urinary retention. Respiratory System: Frequent : Bronchitis, dyspnea, epistaxis, and pneumonia. Infrequent : Apnea, asthma, hemoptysis, hiccups, hyperventilation, laryngitis, respiratory disorder, and voice alteration. Skin and Appendages: Frequent : Alopecia, dry skin, and sweating. Infrequent : Contact dermatitis, eczema, exfoliative dermatitis, furunculosis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, psoriasis, skin benign neoplasm, skin carcinoma, skin discolorations, skin nodules, skin ulcer, subcutaneous nodule, urticaria, and vesiculobullous rash. Special Senses: Frequent : Abnormal vision, ear pain, otitis media, and tinnitus. Infrequent : Blepharitis, blindness, deafness, eye pain, hyperacusis, keratoconjunctivitis, otitis externa, parosmia, photophobia, taste loss, taste perversion, and visual field defect. Urogenital System: Frequent : Dysmenorrhea, dysuria, metrorrhagia, urinary incontinence, and vaginitis. Infrequent : Abortion, amenorrhea, breast enlargement, breast pain, cystitis, fibrocystic breast, hematuria, impotence, kidney failure, menorrhagia, nocturia, papanicolaou smear suspicious, polyuria, pyelonephritis, salpingitis, urethritis, urinary urgency, and vaginal hemorrhage. Postmarketing Reports The following adverse reactions have been identified during postapproval use of tiagabine hydrochloride. 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: bullous dermatitis Eye disorders: vision blurred

In evaluating the potential for interactions among coadministered 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 ). The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy. Effects of Tiagabine Hydrochloride 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 Tiagabine Hydrochloride: 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 Tiagabine Hydrochloride with Other Drugs: Cimetidine : Coadministration 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 Tiagabine Hydrochloride 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.