BOXED WARNING SECTION.

WARNING: DEPRESSION AND SUICIDALITY. Tetrabenazine tablet can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntingtons disease. Anyone considering the use of Tetrabenazine tablet must balance the risks of depression and suicidality with the clinical need for control of chorea. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behavio rs of concern promptly to the treating physician.Particular caution should be exercised in treating patients with history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntingtons disease. Tetrabenazine tablet is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4), Warnings and Precautions (5.2)] . WARNING: DEPRESSION AND SUICIDALITYSee full prescribing information for complete boxed warning.Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntingtons disease 5.2). Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of Tetrabenazine tablet (5.1) Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior 5.2). Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician 5.2). Exercise caution when treating patients with history of depression or prior suicide attempts or ideation 5.2). Tetrabenazine tablet is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression 4, 5.2). Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntingtons disease 5.2). Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of Tetrabenazine tablet (5.1) Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior 5.2). Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician 5.2). Exercise caution when treating patients with history of depression or prior suicide attempts or ideation 5.2). Tetrabenazine tablet is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression 4, 5.2).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with Tetrabenazine tablet have been reported in the literature. The dose of Tetrabenazine tablet in these patients ranged from 100 mg to 1g. Adverse reactions associated with Tetrabenazine tablet overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting poison control center on the treatment of any overdose.

ABUSE SECTION.

9.2 Abuse. Clinical trials did not reveal patients developed drug seeking behaviors, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where Tetrabenazine tablet has been marketed.As with any CNS-active drug, prescribers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of Tetrabenazine tablet misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).Abrupt discontinuation of Tetrabenazine tablet from patients did not produce symptoms of withdrawal or discontinuation syndrome; only symptoms of the original disease were observed to re-emerge [see Dosage and Administration (2.4)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below and elsewhere in the labeling:Depression and suicidality [see Warnings and Precautions (5.2)] Akathisia, restlessness, and agitation [see Warnings and Precautions (5.5)] Parkinsonism [see Warnings and Precautions (5.6)] Dysphagia [see Warnings and Precautions (5.7)] Sedation and somnolence [see Warnings and Precautions (5.8)] Depression and suicidality [see Warnings and Precautions (5.2)] Akathisia, restlessness, and agitation [see Warnings and Precautions (5.5)] Parkinsonism [see Warnings and Precautions (5.6)] Dysphagia [see Warnings and Precautions (5.7)] Sedation and somnolence [see Warnings and Precautions (5.8)] Most common adverse reactions (>10% and at least 5% greater than placebo) were: Sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety, nausea 6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.During its development, Tetrabenazine tablet was administered to 773 unique subjects and patients. The conditions and duration of exposure to Tetrabenazine tablet varied greatly, and included single and multiple dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients.In randomized, 12-week, placebo-controlled clinical trial of HD subjects, adverse reactions were more common in the Tetrabenazine tablet group than in the placebo group. Forty-nine of 54 (91%) patients who received Tetrabenazine tablet experienced one or more adverse reactions at any time during the study. The most common adverse reactions (over 10%, and at least 5% greater than placebo) were sedation/ somnolence, fatigue, insomnia, depression, akathisia, anxiety and nausea.. Adverse Reactions Occurring in >=4% PatientsThe number and percentage of the most common adverse reactions that occurred at any time during the study in >=4% of Tetrabenazine tablet-treated patients, and with greater frequency than in placebo-treated patients, are presented in Table 1.Table 1. Adverse Reactions in 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntingtons Disease. Adverse ReactionTetrabenazine tablet = 54 (%) Placebo = 30 (%) Sedation/somnolence313Insomnia220Depression190Anxiety/anxiety aggravated153Irritability93Decreased appetite40Obsessive reaction40Akathisia190Balance difficulty90Parkinsonism/bradykinesia90Dizziness40Dysarthria40Unsteady gait40Headache43Nausea137Vomiting63Fatigue2213Fall1513Laceration (head)60Ecchymosis60Upper respiratory tract infection117Shortness of breath40Bronchitis40Dysuria40Dose escalation was discontinued or dosage of study drug was reduced because of one or more adverse reactions in 28 of 54 (52%) patients randomized to Tetrabenazine tablet. These adverse reactions consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one adverse reaction and are, therefore, counted more than once.. Adverse Reactions Due to Extrapyramidal SymptomsTable describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at greater frequency in Tetrabenazine tablet -treated patients compared to placebo-treated patients.Table 2. Adverse Reactions Due to Extrapyramidal Symptons in 12-Week, Double-Blind, Placebo-Controlled Trial with Huntingtons disease.Tetrabenazine tablet = 54 Placebo = 30 Akathisia Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. 190Extrapyramidal event Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia. 150Any extrapyramidal event330Patients may have had events in more than one category. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Tetrabenazine tablet. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Nervous system disorders: tremorPsychiatric disorders: confusion, worsening aggressionRespiratory, thoracic and mediastinal disorders: pneumoniaSkin and subcutaneous tissue disorders: hyperhidrosis, skin rash To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafetyavkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo increase in tumors was observed in p53 +/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15 and 30 mg/kg/day for 26 weeks. When compared to humans receiving 50 mg dose of TETRABENAZINE, mice dosed with 30 mg/kg dose of tetrabenazine produce about one sixth the levels of 9-desmethyl-beta-DHTBZ, major human metabolite. Therefore, this study may not have adequately characterized the potential of tetrabenazine to be carcinogenic in people. MutagenesisTetrabenazine and metabolites -HTBZ and -HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. -HTBZ and -HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus tests were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats. Because the bioactivation system used in the in vitro studies was hepatic S9 fraction prepared from rat, species that, when dosed with tetrabenazine, does not produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately assessed the potential of TETRABENAZINE to be mutagenic in humans. Furthermore, since the mouse produces very low levels of this metabolite when dosed with tetrabenazine, the in vivo study may not have adequately assessed the potential of TETRABENAZINE to be mutagenic in humans. Impairment of FertilityOral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day of gestation resulted in disrupted estrous cyclicity at doses greater than mg/kg/day (less than the MRHD on mg/m basis). No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (doses of 5, 15 or 30 mg/kg/day; up to times the MRHD on mg /m basis) prior to and throughout mating with untreated females. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately assessed the potential of TETRABENAZINE to impair fertility in humans.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The precise mechanism by which TETRABENAZINE exerts its anti-chorea effects is unknown but is believed to be related to its effect as reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type (VMAT 2) (K 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), mixture of -HTBZ and -HTBZ, -and -HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (K = 2100 nM). 12.2 Pharmacodynamics. QTc ProlongationThe effect of single 25 or 50 mg dose of Tetrabenazine tablet on the QT interval was studied in randomized, double-blind, placebo controlled crossover study in healthy male and female subjects with moxifloxacin as positive control. At 50 mg, TETRABENAZINE caused an approximately msec mean increase in QTc (90 CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given single 50 mg dose of TETRABENAZINE does not further increase the effect on the QTc interval. Effects at higher exposures to either TETRABENAZINE or its metabolites have not been evaluated [see Warnings and Precautions (5.9), Drug Interactions (7.5)]. Melanin BindingTetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing [see Warnings and Precautions (5.13)]. 12.3 Pharmacokinetics. AbsorptionFollowing oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites -HTBZ and -HTBZ. -HTBZ and -HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (C max) of -HTBZ and -HTBZ are reached within to 1/2 hours post-dosing. -HTBZ is subsequently metabolized to minor metabolite, 9-desmethyl--DHTBZ. -HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl--DHTBZ, for which Cmax is reached approximately hours post-dosing. Food EffectsThe effects of food on the bioavailability of Tetrabenazine tablet were studied in subjects administered single dose with and without food. Food had no effect on mean plasma concentrations, max, or the area under the concentration time course (AUC) of -HTBZ or -HTBZ [see Dosage and Administration (2.1)]. DistributionResults of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-labeled tetrabenazine or -HTBZ, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein binding of tetrabenazine, -HTBZ, and -HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, -HTBZ binding ranged from 60% to 68%, and -HTBZ binding ranged from 59% to 63%. MetabolismAfter oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. -HTBZ, -HTBZ and 9-desmethyl--DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. -HTBZ and -HTBZ are formed by carbonyl reductase that occurs mainly in the liver. -HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl--DHTBZ, minor metabolite. -HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl--DHTBZ.The results of in vitro studies do not suggest that tetrabenazine, -HTBZ, or -HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its or -HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its or -HTBZ metabolites is likely to be substrate or inhibitor of P-glyco- protein at clinically relevant concentrations in vivo. No in vitro metabolism studies have been conducted to evaluate the potential of the 9-desmethyl-- DHTBZ metabolite to interact with other drugs. The activity of this metabolite relative to the parent drug is unknown. EliminationAfter oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. -HTBZ, -HTBZ and 9-desmethyl--DHTBZ have half-lives of hours, hours and 12 hours respectively. In mass balance study in healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of -HTBZ or HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.. Specific Populations. GenderThere is no apparent effect of gender on the pharmacokinetics of -HTBZ or -HTBZ.. Hepatic ImpairmentThe disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of -HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to -HTBZ. The mean tetrabenazine max in subjects with hepatic impairment was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (t max) of -HTBZ and -HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half-lives of the -HTBZ and -HTBZ were prolonged to approximately 10 and hours, respectively. The exposure to -HTBZ and -HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, Tetrabenazine tablet is contraindicated in patients with hepatic impairment [see Contraindications (4), Use in Specific Populations (8.6)]. Poor CYP2D6 MetabolizersAlthough the pharmacokinetics of TETRABENAZINE and its metabolites in patients who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to -HTBZ and -HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively) [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Use in Specific Populations (8.7)]. Drug Interactions. CYP2D6 InhibitorsIn vitro studies indicate that -HTBZ and -HTBZ are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of tetrabenazine and its metabolites was studied in 25 healthy subjects following single 50 mg dose of tetrabenazine given after 10 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. There was an approximately 30% increase in max and an approximately 3-fold increase in AUC for -HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For -HTBZ, the max and AUC were increased 2.4- and 9-fold, respectively, in subjects given paroxetine prior to tetrabenazine given alone. The elimination half-life of -HTBZ and -HTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure to TETRABENAZINE and its metabolites has not been evaluated [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Drug Interactions (7.1), Use in Specific Populations (8.7)]. DigoxinDigoxin is substrate for P-glycoprotein. study in healthy volunteers showed that Tetrabenazine tablet (25 mg twice daily for days) did not affect the bioavailability of digoxin, suggesting that at this dose, TETRABENAZINE does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that TETRABENAZINE or its metabolites are P-glycoprotein inhibitors.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Study 1The efficacy of Tetrabenazine tablet as treatment for the chorea of Huntingtons disease was established primarily in randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with diagnosis of HD. The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including 7-week dose titration period and 5-week maintenance period followed by 1-week washout. Tetrabenazine tablet was started at dose of 12.5 mg per day, followed by upward titration at weekly intervals, in 12.5 mg increments until satisfactory control of chorea was achieved, intolerable side effects occurred, or until maximal dose of 100 mg per day was reached.The primary efficacy endpoint was the Total Chorea Score, an text of the Unified Huntingtons Disease Rating Scale (UHDRS). On this scale, chorea is rated from to (with representing no chorea) for different parts of the body. The total score ranges from to 28.As shown in Figure 1, Total Chorea Scores for patients in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study (1 week after discontinuation of the study medication), the Total Chorea Scores of patients receiving TETRABENAZINE returned to baseline.Figure 1. Mean +- s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Patients Treated with Tetrabenazine tablet (n=54) or Placebo (n=30)Figure illustrates the cumulative percentages of patients from the Tetrabenazine tablet and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the axis. The left-ward shift of the curve (toward greater improvement) for the Tetrabenazine tablet-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. For example, about 7% of placebo patients had 6-point or greater improvement compared to 50% of Tetrabenazine tablet treated patients. The percentage of patients achieving reductions of at least 10, 6, and 3-points from baseline to Week 12 are shown in the inset table.Figure 2. Cumulative Percentage of Patients with Specified Changes from Baseline in Total Chorea Score. The Percentages of Randomized Patients within each treatment group who completed Study were: Placebo 97%, Tetrabenazine 91%.A Physician-rated Clinical Global Impression (CGI) favored Tetrabenazine tablet statistically. In general, measures of functional capacity and cognition showed no difference between Tetrabenazine tablet and placebo. However, one functional measure (Part of the UHDRS), 25-text scale assessing the capacity for patients to perform certain activities of daily living, showed decrement for patients treated with Tetrabenazine tablet compared to placebo, difference that was nominally statistically significant. 3-text cognitive battery specifically developed to assess cognitive function in patients with HD (Part of the UHDRS) also showed decrement for patients treated with Tetrabenazine tablet compared to placebo, but the difference was not statistically significant.. Image. Image. Study 2A second controlled study was performed in patients who had been treated with open-label Tetrabenazine tablet for at least months (mean duration of treatment was years). They were randomized to continuation of Tetrabenazine tablet at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared. Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study (about 3.5 units).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Tetrabenazine tablet is contraindicated in patients:Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.2)]. With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablet should not be used in combination with an MAOI, or within minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3)]. Taking reserpine. At least 20 days should elapse after stopping reserpine before starting Tetrabenazine tablet [see Drug Interactions (7.2)]. Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.2)]. With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablet should not be used in combination with an MAOI, or within minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3)]. Taking reserpine. At least 20 days should elapse after stopping reserpine before starting Tetrabenazine tablet [see Drug Interactions (7.2)]. Actively suicidal, or who have depression which is untreated or undertreated 4, 5.2) Hepatic impairment 4, 8.6, 12.3) Taking MAOIs or reserpine 4, 7.2, 7.3) Actively suicidal, or who have depression which is untreated or undertreated 4, 5.2) Hepatic impairment 4, 8.6, 12.3) Taking MAOIs or reserpine 4, 7.2, 7.3).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance. TETRABENAZINE is not controlled substance.

DESCRIPTION SECTION.

11 DESCRIPTION. TETRABENAZINE is monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43; the pKa is .51. Tetrabenazine is hexahydro-dimethoxy-benzoquinolizine derivative and has the following chemical name: cis rac -1, 3, 4, 6, 7, 11b-hexahydro-9, 10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.The empirical formula 19H 27NO is represented by the following structural formula: Tetrabenazine is white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.Each Tetrabenazine tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient.Tetrabenazine tablet contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose, magnesium stearate, maize starch, and talc. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient.Tetrabenazine tablet is supplied as yellowish-buff scored tablet containing 25 mg of TETRABENAZINE or as white non-scored tablet containing 12.5 mg of TETRABENAZINE.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Individualization of dose with careful weekly titration is required. The st weeks starting dose is 12.5 mg daily; nd week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to tolerated dose that reduces chorea 2.1, 2.2) Doses of 37.5 mg and up to 50 mg per day should be administered in three divided doses per day with maximum recommended single dose not to exceed 25 mg 2.2) Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is poor metabolizer (PM) or an extensive metabolizer (EM). 2.2, 5.3) Maximum daily dose in PMs: 50 mg with maximum single dose of 25 mg 2.2) Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with maximum single dose of 37.5mg 2.2) If serious adverse reactions occur, titration should be stopped and the dose should be reduced. If the adverse reaction(s) do not resolve, consider withdrawal of Tetrabenazine tablet 2.2) Individualization of dose with careful weekly titration is required. The st weeks starting dose is 12.5 mg daily; nd week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to tolerated dose that reduces chorea 2.1, 2.2) Doses of 37.5 mg and up to 50 mg per day should be administered in three divided doses per day with maximum recommended single dose not to exceed 25 mg 2.2) Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is poor metabolizer (PM) or an extensive metabolizer (EM). 2.2, 5.3) Maximum daily dose in PMs: 50 mg with maximum single dose of 25 mg 2.2) Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with maximum single dose of 37.5mg 2.2) If serious adverse reactions occur, titration should be stopped and the dose should be reduced. If the adverse reaction(s) do not resolve, consider withdrawal of Tetrabenazine tablet 2.2) 2.1 General Dosing Considerations. The chronic daily dose of Tetrabenazine tablet used to treat chorea associated with Huntingtons disease (HD) is determined individually for each patient. When first prescribed, Tetrabenazine tablet therapy should be titrated slowly over several weeks to identify dose of Tetrabenazine tablet that reduces chorea and is tolerated. Tetrabenazine tablet can be administered without regard to food [see Clinical Pharmacology (12.3)] . 2.2 Individualization of Dose. The dose of Tetrabenazine tablet should be individualized.. Dosing Recommendations Up to 50 mg per dayThe starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice day. Tetrabenazine tablet should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of tolerated dose that reduces chorea. If dose of 37.5 to 50 mg per day is needed, it should be given in three times day regimen. The maximum recommended single dose is 25 mg. If adverse reactions such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Tetrabenazine tablet treatment or initiating other specific treatment (e.g: antidepressants) [see Adverse Reactions (6.1)]. Dosing Recommendations Above 50 mg per dayPatients who require doses of Tetrabenazine tablet greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Tetrabenazine tablet should then be individualized accordingly to their status as PMs or EMs [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Extensive and Intermediate CYP2D6 MetabolizersGenotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetrabenazine tablet above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of tolerated dose that reduces chorea. Doses above 50 mg per day should be given in three times day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Tetrabenazine tablet treatment or initiating other specific treatment (e.g, antidepressants) [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Poor CYP2D6 MetabolizersIn PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg and the recommended daily dose should not exceed maximum of 50 mg [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.3 Dosage Adjustments with CYP2D6 Inhibitors. Strong CYP2D6 InhibitorsMedications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g, fluoxetine, paroxetine) significantly increase the exposure to -HTBZ and -HTBZ, therefore, the total dose of Tetrabenazine tablet should not exceed maximum of 50 mg and the maximum single dose should not exceed 25 mg [see Warnings and Precautions (5.3), Drug Interactions (7.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.4 Discontinuation of Treatment. Treatment with Tetrabenazine tablet can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of Tetrabenazine tablet [see Drug Abuse and Dependence (9.2)]. 2.5 Resumption of Treatment. Following treatment interruption of greater than five (5) days, Tetrabenazine tablet therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tetrabenazine tablet are available in the following strengths:The 12.5 mg Tetrabenazine tablets are white cylindrical biplanar tablets with beveled edges, debossed 707 on one side and plain on the other side.The 25 mg Tetrabenazine tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, debossed 708 on one side and scored on the other side.. Tablets: 12.5 mg non-scored and 25 mg scored 3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. TETRABENAZINE is not controlled substance.. 9.2 Abuse. Clinical trials did not reveal patients developed drug seeking behaviors, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where Tetrabenazine tablet has been marketed.As with any CNS-active drug, prescribers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of Tetrabenazine tablet misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).Abrupt discontinuation of Tetrabenazine tablet from patients did not produce symptoms of withdrawal or discontinuation syndrome; only symptoms of the original disease were observed to re-emerge [see Dosage and Administration (2.4)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 12.5 mg Tablet Bottle Label. AvKARE NDC 42291-806-30 Tetrabenazine Tablets 12.5mg 30 Tablets Rx Only Each tablet contains 12.5 mg tetrabenazine. USUAL DOSAGE: See Package Insert. MEDICATION GUIDE TO BE DISPENSED WITH EACH PRESCRIPTION. Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature]. Dispense in USP tight, light-resistant container. Do not accept if seal over bottle opening is missing or broken. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 11/2016 AV 02/17 (P) N3 4229180630 . 1.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of Tetrabenazine tablet in pediatric patients have not been established.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Strong CYP2D6 Inhibitors. In vitro studies indicate that -HTBZ and -HTBZ are substrates for CYP2D6. Strong CYPD6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. reduction in Tetrabenazine tablet dose may be necessary when adding strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on stable dose of Tetrabenazine tablet. The daily dose of Tetrabenazine tablet should not exceed 50 mg per day and the maximum single dose of Tetrabenazine tablet should not exceed 25 mg in patients taking strong CYP2D6 inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Use in Specific Population (8.7), Clinical Pharmacology (12.2)] . 7.2 Reserpine. Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering Tetrabenazine tablet to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting Tetrabenazine tablet. Tetrabenazine tablet and reserpine should not be used concomitantly [see Contraindications (4), Warnings and Precautions (5.12)]. 7.3 Monoamine Oxidase Inhibitors (MAOIs ). Tetrabenazine tablet is contraindicated in patients taking MAOIs. Tetrabenazine tablet should not be used in combination with an MAOI, or within minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4), Warnings and Precautions (5.12)]. 7.4 Alcohol. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.. 7.5 Drugs that Cause QTc Prolongation. Tetrabenazine tablet causes small prolongation of QTc (about msec), concomitant use with other drugs that are known to cause QTc prolongation should be avoided, these including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g ., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetrabenazine tablet should be avoided in patients with congenital long QT syndrome and in patients with history of cardiac arrhythmias. Certain conditions may increase the risk for torsade de pointes or sudden death such as, (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval see Warnings and Precautions (5.9), Clinical Pharmacology (12.2) ]. 7.6 Neuroleptic Drugs. The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of Tetrabenazine tablet and dopamine antagonists or antipsychotics (e.g.chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).

GERIATRIC USE SECTION.

8.5 Geriatric Use. The pharmacokinetics of Tetrabenazine tablet and its primary metabolites have not been formally studied in geriatric subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Tetrabenazine tablets are available in the following strengths and packages:Description of 12.5 mg: white cylindrical biplanar tablets with beveled edges, de-bossed 707 on one side and plain on the other side.Bottles of 30: 42291-806-30Description of 25 mg: yellowish-buff, cylindrical biplanar tablets with beveled edges, debossed 708 on one side and scored on the other side.Bottles of 30: NDC 42291-807-30. 16.2 Storage. Store at 25C (77 F); excursions permitted to 15-30 (59-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Tetrabenazine tablet is indicated for the treatment of chorea associated with Huntingtons disease.. TETRABENAZINE is vesicular monoamine transporter (VMAT) inhibitor indicated for the treatment of chorea associated with Huntingtons disease 1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Risk of SuicidalityInform patients and their families that Tetrabenazine tablet may increase the risk of suicidal thinking and behaviors. Counsel patients and their families to remain alert to the emergence of suicidal ideation and to report it immediately to the patients physician [see Contraindications (4), Warnings and Precautions (5.2)]. Risk of DepressionInform patients and their families that Tetrabenazine tablet may cause depression or may worsen pre-existing depression. Encourage patients and their families to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and to report such symptoms promptly to the patients physician [see Contraindications (4), Warnings and Precautions (5.2)]. Dosing of Tetrabenazine tabletInform patients and their families that the dose of Tetrabenazine tablet will be increased slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician and the Tetrabenazine tablet dose may need to be reduced or discontinued [see Dosage and Administration (2.2)] . Risk of Sedation and SomnolenceInform patients that Tetrabenazine tablet may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to Tetrabenazine tablet, they should be careful doing activities that require them to be alert, such as driving car or operating machinery [see Warnings and Precautions (5.8)]. Interaction with AlcoholAdvise patients and their families that alcohol may potentiate the sedation induced by Tetrabenazine tablet [see Drug Interactions (7.4)]. Usage in PregnancyAdvise patients and their families to notify the physician if the patient becomes pregnant or intends to become pregnant during Tetrabenazine tablet therapy, or is breast-feeding or intending to breast-feed an infant during therapy [see Use in Specific Populations (8.1)].

LABOR & DELIVERY SECTION.

8.2 Labor and Delivery. The effect of Tetrabenazine tablet on labor and delivery in humans is unknown.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The precise mechanism by which TETRABENAZINE exerts its anti-chorea effects is unknown but is believed to be related to its effect as reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type (VMAT 2) (K 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), mixture of -HTBZ and -HTBZ, -and -HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (K = 2100 nM).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo increase in tumors was observed in p53 +/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15 and 30 mg/kg/day for 26 weeks. When compared to humans receiving 50 mg dose of TETRABENAZINE, mice dosed with 30 mg/kg dose of tetrabenazine produce about one sixth the levels of 9-desmethyl-beta-DHTBZ, major human metabolite. Therefore, this study may not have adequately characterized the potential of tetrabenazine to be carcinogenic in people. MutagenesisTetrabenazine and metabolites -HTBZ and -HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. -HTBZ and -HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus tests were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats. Because the bioactivation system used in the in vitro studies was hepatic S9 fraction prepared from rat, species that, when dosed with tetrabenazine, does not produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately assessed the potential of TETRABENAZINE to be mutagenic in humans. Furthermore, since the mouse produces very low levels of this metabolite when dosed with tetrabenazine, the in vivo study may not have adequately assessed the potential of TETRABENAZINE to be mutagenic in humans. Impairment of FertilityOral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day of gestation resulted in disrupted estrous cyclicity at doses greater than mg/kg/day (less than the MRHD on mg/m basis). No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (doses of 5, 15 or 30 mg/kg/day; up to times the MRHD on mg /m basis) prior to and throughout mating with untreated females. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately assessed the potential of TETRABENAZINE to impair fertility in humans.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is not known whether TETRABENAZINE or its metabolites are excreted in human milk.Since many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Tetrabenazine tablet, decision should be made whether to discontinue nursing or to discontinue Tetrabenazine tablet, taking into account the importance of the drug to the mother.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. QTc ProlongationThe effect of single 25 or 50 mg dose of Tetrabenazine tablet on the QT interval was studied in randomized, double-blind, placebo controlled crossover study in healthy male and female subjects with moxifloxacin as positive control. At 50 mg, TETRABENAZINE caused an approximately msec mean increase in QTc (90 CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given single 50 mg dose of TETRABENAZINE does not further increase the effect on the QTc interval. Effects at higher exposures to either TETRABENAZINE or its metabolites have not been evaluated [see Warnings and Precautions (5.9), Drug Interactions (7.5)]. Melanin BindingTetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing [see Warnings and Precautions (5.13)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites -HTBZ and -HTBZ. -HTBZ and -HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (C max) of -HTBZ and -HTBZ are reached within to 1/2 hours post-dosing. -HTBZ is subsequently metabolized to minor metabolite, 9-desmethyl--DHTBZ. -HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl--DHTBZ, for which Cmax is reached approximately hours post-dosing. Food EffectsThe effects of food on the bioavailability of Tetrabenazine tablet were studied in subjects administered single dose with and without food. Food had no effect on mean plasma concentrations, max, or the area under the concentration time course (AUC) of -HTBZ or -HTBZ [see Dosage and Administration (2.1)]. DistributionResults of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-labeled tetrabenazine or -HTBZ, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein binding of tetrabenazine, -HTBZ, and -HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, -HTBZ binding ranged from 60% to 68%, and -HTBZ binding ranged from 59% to 63%. MetabolismAfter oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. -HTBZ, -HTBZ and 9-desmethyl--DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. -HTBZ and -HTBZ are formed by carbonyl reductase that occurs mainly in the liver. -HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl--DHTBZ, minor metabolite. -HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl--DHTBZ.The results of in vitro studies do not suggest that tetrabenazine, -HTBZ, or -HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its or -HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its or -HTBZ metabolites is likely to be substrate or inhibitor of P-glyco- protein at clinically relevant concentrations in vivo. No in vitro metabolism studies have been conducted to evaluate the potential of the 9-desmethyl-- DHTBZ metabolite to interact with other drugs. The activity of this metabolite relative to the parent drug is unknown. EliminationAfter oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. -HTBZ, -HTBZ and 9-desmethyl--DHTBZ have half-lives of hours, hours and 12 hours respectively. In mass balance study in healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of -HTBZ or HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.. Specific Populations. GenderThere is no apparent effect of gender on the pharmacokinetics of -HTBZ or -HTBZ.. Hepatic ImpairmentThe disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of -HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to -HTBZ. The mean tetrabenazine max in subjects with hepatic impairment was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (t max) of -HTBZ and -HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half-lives of the -HTBZ and -HTBZ were prolonged to approximately 10 and hours, respectively. The exposure to -HTBZ and -HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, Tetrabenazine tablet is contraindicated in patients with hepatic impairment [see Contraindications (4), Use in Specific Populations (8.6)]. Poor CYP2D6 MetabolizersAlthough the pharmacokinetics of TETRABENAZINE and its metabolites in patients who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to -HTBZ and -HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively) [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Use in Specific Populations (8.7)]. Drug Interactions. CYP2D6 InhibitorsIn vitro studies indicate that -HTBZ and -HTBZ are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of tetrabenazine and its metabolites was studied in 25 healthy subjects following single 50 mg dose of tetrabenazine given after 10 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. There was an approximately 30% increase in max and an approximately 3-fold increase in AUC for -HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For -HTBZ, the max and AUC were increased 2.4- and 9-fold, respectively, in subjects given paroxetine prior to tetrabenazine given alone. The elimination half-life of -HTBZ and -HTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure to TETRABENAZINE and its metabolites has not been evaluated [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Drug Interactions (7.1), Use in Specific Populations (8.7)]. DigoxinDigoxin is substrate for P-glycoprotein. study in healthy volunteers showed that Tetrabenazine tablet (25 mg twice daily for days) did not affect the bioavailability of digoxin, suggesting that at this dose, TETRABENAZINE does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that TETRABENAZINE or its metabolites are P-glycoprotein inhibitors.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Tetrabenazine tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Tetrabenazine had no clear effects on embryo-fetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or times the maximum recommended human dose [MRHD] of 100 mg/day on mg/m basis). Tetrabenazine had no effects on embryo-fetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on mg/m basis). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately addressed the potential effects of tetrabenazine on embryo-fetal development in humans. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on mg/m basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, major human metabolite, this study may not have adequately assessed the potential effects of tetrabenazine on the offspring of women exposed in utero and via lactation.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Tetrabenazine (TET ra BEN Zeen) TabletsRead the Medication Guide that comes with Tetrabenazine tablet before you start taking it and each time you refill the prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. You should share this information with your family members and caregivers.What is the most important information should know about Tetrabenazine tabletTetrabenazine tablet can cause serious side effects, including:depressionsuicidal thoughtssuicidal actionsYou should not start taking Tetrabenazine tablet if you are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts or feelings. This is especially important when Tetrabenazine tablet is started and when the dose is changed.Call the doctor right away if you become depressed or have any of the following symptoms, especially if they are new, worse, or worry you:feel sad or have crying spellslose interest in seeing your friends or doing things you used to enjoysleep lot more or lot less than usual feel unimportantfeel guiltyfeel hopeless or helplessmore irritable, angry or aggressive than usualmore or less hungry than usual or notice big change in your body weighthave trouble paying attentionfeel tired or sleepy all the timehave thoughts about hurting yourself or ending your lifeWhat is Tetrabenazine tabletTetrabenazine tablet is medicine that is used to treat the involuntary movements (chorea) of Huntingtons disease. Tetrabenazine tablet does not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntingtons disease, such as problems with thinking or emotions.It is not known whether Tetrabenazine tablet is safe and effective in children.Who should not take Tetrabenazine tabletDo not take Tetrabenazine tablet if you:are depressed or have thoughts of suicide. See What is the most important information should know about Tetrabenazine tablet have liver problems.are taking monoamine oxidase inhibitor (MAOI) medicine. Ask your doctor or pharmacist if you are not sure.are taking reserpine. Do not take medicines that contain reserpine (such as Serpalan (R) and Renese (R)-R) with Tetrabenazine tablet. If your doctor plans to switch you from taking reserpine to Tetrabenazine tablet, you must wait at least 20 days after your last dose of reserpine before you start taking Tetrabenazine tablet. What should tell my doctor before taking Tetrabenazine tabletTell your doctor about all your medical conditions, including if you:have emotional or mental problems (for example, depression, nervousness, anxiety, anger, agitation, psychosis, previous suicidal thoughts or suicide attempts).have liver disease.have any allergies. See the end of this Medication Guide for complete list of the ingredients in Tetrabenazine tablet.have breast cancer or history of breast cancer.have heart disease that is not stable, have heart failure or recently had heart attack.have an irregular heartbeat (cardiac arrhythmia).are pregnant or plan to become pregnant. It is not known if Tetrabenazine tablet can harm your unborn baby.are breast-feeding. It is not known if TETRABENAZINE passes into breast milk.Tell your doctor about all the medicines you take, including prescription medicines and nonprescription medicines, vitamins and herbal products. Using Tetrabenazine tablet with certain other medicines may cause serious side effects. Do not start any new medicines while taking Tetrabenazine tablet without talking to your doctor first. How should take Tetrabenazine tabletTetrabenazine tablet is tablet that you take by mouth.Take Tetrabenazine tablet exactly as prescribed by your doctor.You may take Tetrabenazine tablet with or without food.Your doctor will increase your dose of Tetrabenazine tablet each week for several weeks, until you and your doctor find the best dose for you.If you stop taking Tetrabenazine tablet or miss dose, your involuntary movements may return or worsen in 12 to 18 hours after the last dose.Before starting Tetrabenazine tablet, you should talk to your health care provider about what to do if you miss dose. If you miss dose and it is time for your next dose, do not double the dose.Tell your doctor if you stop taking Tetrabenazine tablet for more than days. Do not take another dose until you talk to your doctor. If your doctor thinks you need to take more than 50 mg of TETRABENAZINE each day, you will need to have blood test to see if it is safe for you.What should avo id while taking Tetrabenazine tabletSleepiness (sedation) is common side effect of Tetrabenazine tablet. While taking Tetrabenazine tablet, do not drive car or operate dangerous machinery until you know how TETRABENAZINE affects you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking Tetrabenazine tablet may increase any sleepiness caused by TETRABENAZINE. What are the possible side effects of Tetrabenazine tabletTetrabenazine tablet can cause serious side effects, including:Depression, suicidal thoughts, or actions. See What is the most important information should know about Tetrabenazine Neuroleptic Malignant Syndrome (NMS). Call your doctor right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause: high feverstiff musclesproblems thinkingvery fast or uneven heartbeatincreased sweatingParkinsonism. Symptoms of Parkinsonism include: slight shaking, body stiffness, trouble moving or keeping your balance. Restlessness. You may get condition where you feel strong urge to move. This is called akathisia. Trouble swallowing. Tetrabenazine tablet may increase the chance that you will have trouble swallowing. Increased coughing may be the first sign that you are having trouble swallowing. Trouble swallowing increases your risk of pneumonia. Irregular heartbeat. Tetrabenazine tablet increases your chance of having certain changes in the electrical activity in your heart which can be seen on an electrocardiogram (EKG). These changes can lead to dangerous abnormal heartbeat. Taking Tetrabenazine tablet with certain medicines may increase this chance. Dizziness due to blood pressure changes when you change position (orthostatic hypotension). Change positions slowly from lying down to sitting up and from sitting up to standing when taking Tetrabenazine tablet. Tell your doctor right away if you get dizzy or faint while taking Tetrabenazine tablet. Your doctor may need to watch your blood pressure closely. Tardive dyskinesia (TD). TD is condition where there is repeated facial grimacing that cannot be controlled, sticking out of the tongue, smacking of the lips, puckering and pursing of the lips, and rapid eye blinking. Tetrabenazine tablet works like other drugs that can cause TD. If you get TD with Tetrabenazine tablet, it is possible that the TD will not go away. Common side effects with TETRABENAZINE include:sleepiness (sedation)trouble sleepingdepressiontiredness (fatigue)anxietyrestlessnessagitationnauseaTell your doctor if you have any side effects. Do not stop taking Tetrabenazine tablet without talking to your doctor first.Call your doctor for medical advice about side effects. You may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088.General information about Tetrabenazine tabletTetrabenazine tablet contains the active ingredient tetrabenazine. It also contains these inactive ingredients: lactose, maize starch, talc, and magnesium stearate. The 25 mg tablet, which is pale yellow, also contains yellow iron oxide.Medicines are sometimes prescribed for conditions that are not listed in Medication Guide. Do not use Tetrabenazine tablet for condition for which it was not prescribed. Do not give Tetrabenazine tablet to other people, even if they have the same symptoms that you have. It may harm them. Keep Tetrabenazine tablet out of the reach of children.This Medication Guide summarizes the most important information about Tetrabenazine tablet. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tetrabenazine tablet that is written for healthcare professionals.You can also call AvKARE, Inc. at 1-855-361-3993 or email: drugsafetyavkare.com. Trademarks are property of their respective owners.This Medication Guide has been approved by the U.S Food and Drug Administration.Manufactured for:Manufactured for: AvKARE, Inc. Pulaski, TN 38478Mfg. Rev. 11/16 AV 02/17 (P) Tetrabenazine tablet can cause serious side effects, including:depressionsuicidal thoughtssuicidal actions. depression. suicidal thoughts. suicidal actions. You should not start taking Tetrabenazine tablet if you are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts or feelings. This is especially important when Tetrabenazine tablet is started and when the dose is changed.. feel sad or have crying spells. lose interest in seeing your friends or doing things you used to enjoy. sleep lot more or lot less than usual feel unimportant. feel guilty. feel hopeless or helpless. more irritable, angry or aggressive than usual. more or less hungry than usual or notice big change in your body weight. have trouble paying attention. feel tired or sleepy all the time. have thoughts about hurting yourself or ending your life. are depressed or have thoughts of suicide. See What is the most important information should know about Tetrabenazine tablet have liver problems.. are taking monoamine oxidase inhibitor (MAOI) medicine. Ask your doctor or pharmacist if you are not sure.. are taking reserpine. Do not take medicines that contain reserpine (such as Serpalan (R) and Renese (R)-R) with Tetrabenazine tablet. If your doctor plans to switch you from taking reserpine to Tetrabenazine tablet, you must wait at least 20 days after your last dose of reserpine before you start taking Tetrabenazine tablet. have emotional or mental problems (for example, depression, nervousness, anxiety, anger, agitation, psychosis, previous suicidal thoughts or suicide attempts).. have liver disease.. have any allergies. See the end of this Medication Guide for complete list of the ingredients in Tetrabenazine tablet.. have breast cancer or history of breast cancer.. have heart disease that is not stable, have heart failure or recently had heart attack.. have an irregular heartbeat (cardiac arrhythmia).. are pregnant or plan to become pregnant. It is not known if Tetrabenazine tablet can harm your unborn baby.. are breast-feeding. It is not known if TETRABENAZINE passes into breast milk.. Tetrabenazine tablet is tablet that you take by mouth.. Take Tetrabenazine tablet exactly as prescribed by your doctor.. You may take Tetrabenazine tablet with or without food.. Your doctor will increase your dose of Tetrabenazine tablet each week for several weeks, until you and your doctor find the best dose for you.. If you stop taking Tetrabenazine tablet or miss dose, your involuntary movements may return or worsen in 12 to 18 hours after the last dose.. Before starting Tetrabenazine tablet, you should talk to your health care provider about what to do if you miss dose. If you miss dose and it is time for your next dose, do not double the dose.. Tell your doctor if you stop taking Tetrabenazine tablet for more than days. Do not take another dose until you talk to your doctor. If your doctor thinks you need to take more than 50 mg of TETRABENAZINE each day, you will need to have blood test to see if it is safe for you.. Depression, suicidal thoughts, or actions. See What is the most important information should know about Tetrabenazine Neuroleptic Malignant Syndrome (NMS). Call your doctor right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause: high feverstiff musclesproblems thinkingvery fast or uneven heartbeatincreased sweating. high fever. stiff muscles. problems thinking. very fast or uneven heartbeat. increased sweating. Parkinsonism. Symptoms of Parkinsonism include: slight shaking, body stiffness, trouble moving or keeping your balance. Restlessness. You may get condition where you feel strong urge to move. This is called akathisia. Trouble swallowing. Tetrabenazine tablet may increase the chance that you will have trouble swallowing. Increased coughing may be the first sign that you are having trouble swallowing. Trouble swallowing increases your risk of pneumonia. Irregular heartbeat. Tetrabenazine tablet increases your chance of having certain changes in the electrical activity in your heart which can be seen on an electrocardiogram (EKG). These changes can lead to dangerous abnormal heartbeat. Taking Tetrabenazine tablet with certain medicines may increase this chance. Dizziness due to blood pressure changes when you change position (orthostatic hypotension). Change positions slowly from lying down to sitting up and from sitting up to standing when taking Tetrabenazine tablet. Tell your doctor right away if you get dizzy or faint while taking Tetrabenazine tablet. Your doctor may need to watch your blood pressure closely. Tardive dyskinesia (TD). TD is condition where there is repeated facial grimacing that cannot be controlled, sticking out of the tongue, smacking of the lips, puckering and pursing of the lips, and rapid eye blinking. Tetrabenazine tablet works like other drugs that can cause TD. If you get TD with Tetrabenazine tablet, it is possible that the TD will not go away. sleepiness (sedation). trouble sleeping. depression. tiredness (fatigue). anxiety. restlessness. agitation. nausea.

SPL UNCLASSIFIED SECTION.

2.1 General Dosing Considerations. The chronic daily dose of Tetrabenazine tablet used to treat chorea associated with Huntingtons disease (HD) is determined individually for each patient. When first prescribed, Tetrabenazine tablet therapy should be titrated slowly over several weeks to identify dose of Tetrabenazine tablet that reduces chorea and is tolerated. Tetrabenazine tablet can be administered without regard to food [see Clinical Pharmacology (12.3)].

STORAGE AND HANDLING SECTION.

16.2 Storage. Store at 25C (77 F); excursions permitted to 15-30 (59-86F) [see USP Controlled Room Temperature].

TERATOGENIC EFFECTS SECTION.

Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Tetrabenazine tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Tetrabenazine had no clear effects on embryo-fetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or times the maximum recommended human dose [MRHD] of 100 mg/day on mg/m basis). Tetrabenazine had no effects on embryo-fetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on mg/m basis). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately addressed the potential effects of tetrabenazine on embryo-fetal development in humans. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on mg/m basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, major human metabolite, this study may not have adequately assessed the potential effects of tetrabenazine on the offspring of women exposed in utero and via lactation.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, tetrabenazine may cause fetal harm. 8.1) 8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Tetrabenazine tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Tetrabenazine had no clear effects on embryo-fetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or times the maximum recommended human dose [MRHD] of 100 mg/day on mg/m basis). Tetrabenazine had no effects on embryo-fetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on mg/m basis). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, major human metabolite, these studies may not have adequately addressed the potential effects of tetrabenazine on embryo-fetal development in humans. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on mg/m basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, major human metabolite, this study may not have adequately assessed the potential effects of tetrabenazine on the offspring of women exposed in utero and via lactation. 8.2 Labor and Delivery. The effect of Tetrabenazine tablet on labor and delivery in humans is unknown.. 8.3 Nursing Mothers. It is not known whether TETRABENAZINE or its metabolites are excreted in human milk.Since many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Tetrabenazine tablet, decision should be made whether to discontinue nursing or to discontinue Tetrabenazine tablet, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and efficacy of Tetrabenazine tablet in pediatric patients have not been established.. 8.5 Geriatric Use. The pharmacokinetics of Tetrabenazine tablet and its primary metabolites have not been formally studied in geriatric subjects.. 8.6 Hepatic Impairment. Because the safety and efficacy of the increased exposure to Tetrabenazine tablet and other circulating metabolites are unknown, it is not possible to adjust the dosage of Tetrabenazine tablet in hepatic impairment to ensure safe use. The use of Tetrabenazine tablet in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)]. 8.7 Pooror Extensive CYP2D6 Metabolizers. Patients who require doses of Tetrabenazine tablet greater than 50 mg per day, should be first tested and genotyped to determine if they are poor (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Tetrabenazine tablet should then be individualized accordingly to their status as either poor (PMs) or extensive metabolizers (EMs) [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. Poor MetabolizersPoor CYP2D6 metabolizers (PMs) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for -HTBZ and 9-fold for -HTBZ) compared to EMs. The dosage should, therefore, be adjusted according to patients CYP2D6 metabolizer status by limiting single dose to maximum of 25 mg and the recommended daily dose to not exceed maximum of 50 mg/day in patients who are CYP2D6 PMs [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. Extensive/Intermediate MetabolizersIn extensive (EMs) or intermediate metabolizers (IMs), the dosage of Tetrabenazine tablet can be titrated to maximum single dose of 37.5 mg and recommended maximum daily dose of 100 mg [see Dosage and Administration (2.2), Drug Interactions (7.1), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity 5.1) Do not exceed 50 mg/day and the maximum single dose should not exceed 25 mg if administered in conjunction with strong CYP2D6 inhibitor (e .g, fluoxetine, paroxetine) 5.3, 7.1) Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs 5.4, 7.6) Restlessness, agitation, akathisia and parkinsonism: Reduce dose or discontinue if occurs 5.5, 5.6) Dysphagia and aspiration pneumonia: Monitor for dysphagia 5.7) Sedation/Somnolence: May impair patients ability to drive or operate complex machinery 5.8) QTc prolongation: Not recommended in combination with other drugs that prolong QTc 5.9) Exaggerate extrapyramidal disorders when used with drugs that reduce or antagonize dopamine.Discontinue Tetrabenazine tablet if this occurs 5.12) Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity 5.1) Do not exceed 50 mg/day and the maximum single dose should not exceed 25 mg if administered in conjunction with strong CYP2D6 inhibitor (e .g, fluoxetine, paroxetine) 5.3, 7.1) Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs 5.4, 7.6) Restlessness, agitation, akathisia and parkinsonism: Reduce dose or discontinue if occurs 5.5, 5.6) Dysphagia and aspiration pneumonia: Monitor for dysphagia 5.7) Sedation/Somnolence: May impair patients ability to drive or operate complex machinery 5.8) QTc prolongation: Not recommended in combination with other drugs that prolong QTc 5.9) Exaggerate extrapyramidal disorders when used with drugs that reduce or antagonize dopamine.Discontinue Tetrabenazine tablet if this occurs 5.12) 5.1 Clinical Worsening and Adverse Effects. Huntingtons disease is progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In 12-week controlled trial, Tetrabenazine tablet was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown.Prescribers should periodically re-evaluate the need for Tetrabenazine tablet in their patients by assessing the beneficial effect on chorea and possible adverse effects, including depression, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness and disability. It may be difficult to distinguish between drug-induced side-effects and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for Tetrabenazine tablet.. 5.2 Depression and Suicidality. Patients with Huntingtons disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine tablet increases the risk for suicidality in patients with HD. All patients treated with Tetrabenazine tablet should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with Tetrabenazine tablet.In 12-week, double-blind placebo-controlled study in patients with chorea associated with Huntingtons disease, 10 of 54 patients (19%) treated with Tetrabenazine tablet were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received Tetrabenazine tablet for up to 48 weeks; in the second study, 75 patients received Tetrabenazine tablet for up to 80 weeks), the rate of depression/worsening depression was 35%.In all of the HD chorea studies of Tetrabenazine tablet (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.Clinicians should be alert to the heightened risk of suicide in patients with Huntingtons disease regardless of depression indices. Reported rates of completed suicide among individuals with Huntingtons disease ranged from 3-13% and over 25% of patients attempt suicide at some point in their illness.Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with Tetrabenazine tablet and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately. 5.3 Laboratory Tests. Before prescribing daily dose of Tetrabenazine tablet that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of Tetrabenazine tablet.Patients who are PMs of Tetrabenazine tablet will have substantially higher levels of the primary drug metabolites (about 3-fold for -HTBZ and 9-fold for -HTBZ) than patients who are EMs. The dosage should be adjusted according to patients CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg [see Dosage and Administration (2.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 5.4 Neuroleptic Malignant Syndrome (NMS). potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with Tetrabenazine tablet and other drugs that reduce dopaminergic transmission [see Warnings and Precautions (5.12) and Drug Interactions (7.6)]. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection), and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include (1) immediate discontinuation of Tetrabenazine tablet and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.Recurrence of NMS has been reported. If treatment with Tetrabenazine tablet is needed after recovery from NMS, patients should be monitored for signs of recurrence.. 5.5 Akathisia, Restlessness, and Agitation. In 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of Tetrabenazine tablet-treated patients and 0% of placebo-treated patients. In an 80-week open-label study, akathisia was observed in 20% of Tetrabenazine tablet-treated patients. Akathisia was not observed in 48-week open-label study. Patients receiving Tetrabenazine tablet should be monitored for the presence of akathisia. Patients receiving Tetrabenazine tablet should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If patient develops akathisia, the Tetrabenazine tablet dose should be reduced; however, some patients may require discontinuation of therapy.. 5.6 Parkinsonism. Tetrabenazine tablet can cause parkinsonism. In 12-week double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15% of Tetrabenazine tablet-treated patients compared to 0% of placebo-treated patients. In 48-week and 80-week open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of Tetrabenazine tablet-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntingtons disease, it may be difficult to distinguish between this drug-induced side-effect and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntingtons disease. If patient develops parkinsonism during treatment with Tetrabenazine tablet, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.. 5.7 Dysphagia. Dysphagia is component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pneumonia. In 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of Tetrabenazine tablet-treated patients and 3% of placebo-treated patients. In 48-week and 80-week open-label studies, dysphagia was observed in 10% and 8% of Tetrabenazine tablet-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.. 5.8 Sedation and Somnolence. Sedation is the most common dose-limiting adverse reaction of Tetrabenazine tablet. In 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence occured in 17/54 (31%) Tetrabenazine tablet-treated patients and in (3%) placebo-treated patient. Sedation was the reason upward titration of Tetrabenazine tablet was stopped and/or the dose of Tetrabenazine tablet was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of Tetrabenazine tablet resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/ somnolence occured in 17% and 57% of Tetrabenazine tablet-treated patients, respectively. In some patients, sedation occurred at doses that were lower than recommended doses.Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating motor vehicle or operating hazardous machinery, until they are on maintenance dose of Tetrabenazine tablet and know how the drug affects them.. 5.9 QTc Prolongation. Tetrabenazine tablet causes small increase (about msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases [see Clinical Pharmacology (12.2)]. The use of Tetrabenazine tablet should be avoided in combination with other drugs that are known to prolong QTc, including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval [see Drug Interactions (7.5)]. Tetrabenazine tablet should also be avoided in patients with congenital long QT syndrome and in patients with history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval [see Clinical Pharmacology (12.2)]. 5.10 Hypotension and Orthostatic Hypotension. Tetrabenazine tablet induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of Tetrabenazine tablet-treated patients (vs. none on placebo) in the 12-week controlled trial; however, blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.. 5.11 Hyperprolactinemia. Tetrabenazine tablet elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro, factor of potential importance if Tetrabenazine tablet is being considered for patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the Tetrabenazine tablet development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of Tetrabenazine tablet. 5.12 Tardive Dyskinesia (T D). potentially irreversible syndrome of involuntary, dyskinetic movements may develop in patients treated with neuroleptic drugs. In an animal model of orofacial dyskinesias, acute administration of reserpine, monoamine depletor, has been shown to produce vacuous chewing in rats. Although the pathophysiology of tardive dyskinesia remains incompletely understood, the most commonly accepted hypothesis of the mechanism is that prolonged post-synaptic dopamine receptor blockade leads to supersensitivity to dopamine. Neither reserpine nor Tetrabenazine tablet, which are dopamine depletors, have been reported to cause clear tardive dyskinesia in humans, but as pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine, and Tetrabenazine tablet can cause the extrapyramidal symptoms also known to be associated with neuroleptics (e.g., parkinsonism and akathisia), physicians should be aware of the possible risk of tardive dyskinesia. If signs and symptoms of TD appear in patient treated with Tetrabenazine tablet, drug discontinuation should be considered.. 5.13 Binding to Melanin-Containing Tissues. Since Tetrabenazine tablet or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that Tetrabenazine tablet may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye was conducted in the chronic toxicity study in dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.The clinical relevance of Tetrabenazine tablets binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects [see Clinical Pharmacology (12.2)].