tetrabenazine 25 MG Oral Tablet [Xenazine]

INDICATIONS AND USAGE Tetrabenazine tablets are indicated for the treatment of chorea associated with Huntington's disease. Tetrabenazine tablets are a vesicular monoamine transporter 2 (VMAT) inhibitor indicated for the treatment of chorea associated with Huntington's disease. ( 1 )

DOSAGE AND ADMINISTRATION Individualization of dose with careful weekly titration is required. The 1 st week’s starting dose is 12.5 mg daily; 2 nd week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to a 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 a 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 a poor metabolizer (PM) or an extensive metabolizer (EM). ( 2.2 , 5.3 ) Maximum daily dose in PMs: 50 mg with a maximum single dose of 25 mg ( 2.2 ) Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with a maximum single dose of 37.5 mg ( 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 tablets. ( 2.2 ) 2.1 General Dosing Considerations The chronic daily dose of tetrabenazine tablets used to treat chorea associated with Huntington’s disease (HD) is determined individually for each patient. When first prescribed, tetrabenazine tablets therapy should be titrated slowly over several weeks to identify a dose of tetrabenazine tablets that reduces chorea and is tolerated. Tetrabenazine tablets can be administered without regard to food [see Clinical Pharmacology ( 12.3 )] . 2.2 Individualization of Dose The dose of tetrabenazine tablets should be individualized. Dosing Recommendations Up to 50 mg per day The 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 a day. Tetrabenazine tablets should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a 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 tablets treatment or initiating other specific treatment (e.g., antidepressants) [see Adverse Reactions ( 6.1 )] . Dosing Recommendations Above 50 mg per day Patients who require doses of tetrabenazine tablets 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 tablets 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 Metabolizers Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of tetrabenazine tablets above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a 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 tablets 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 Metabolizers In 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 a maximum of 50 mg [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 ) ] . 2.3 Dosage Adjustment with CYP2D6 Inhibitors Strong CYP2D6 Inhibitors Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ, therefore, the total dose of tetrabenazine tablets should not exceed a 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 tablets can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of tetrabenazine tablets [see Drug Abuse and Dependence ( 9.2 ) ] . 2.5 Resumption of Treatment Following treatment interruption of greater than five (5) days, tetrabenazine tablets 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.

WARNINGS AND PRECAUTIONS Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity. ( 5.2 ) Do not exceed 50 mg/day and the maximum single dose should not exceed 25 mg if administered in conjunction with a 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 ) Sedation/Somnolence: May impair patient’s ability to drive or operate complex machinery. ( 5.7 ) QTc prolongation: Not recommended in combination with other drugs that prolong QTc. ( 5.8 ) 5.1 Depression and Suicidality Patients with Huntington’s disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine increases the risk for suicidality in patients with HD. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease, 10 of 54 patients (19%) treated with tetrabenazine 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 for up to 48 weeks; in the second study, 75 patients received tetrabenazine for up to 80 weeks), the rate of depression/worsening depression was 35%. In all of the HD chorea studies of tetrabenazine (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation. When considering the use of tetrabenazine, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with tetrabenazine should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with tetrabenazine, 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. 5.2 Clinical Worsening and Adverse Effects Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, tetrabenazine 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 in their patients by assessing the effect on chorea and possible adverse effects, including depression and suicidality, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness, and disability. It may be difficult to distinguish between adverse reactions 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. 5.3 Laboratory Tests Before prescribing a daily dose of tetrabenazine 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. Patients who are PMs of tetrabenazine will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient's 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 ), Clinical Pharmacology ( 12.3 )] . 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine and other drugs that reduce dopaminergic transmission [see 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; (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 with resumption of drug therapy. If treatment with tetrabenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5 Akathisia, Restlessness, and Agitation Tetrabenazine may increase the risk of akathisia, restlessness, and agitation. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine-treated patients and 0% of placebo-treated patients. In an 80-week open-label study, akathisia was observed in 20% of tetrabenazine-treated patients. Patients receiving tetrabenazine should be monitored for the presence of akathisia. Patients receiving tetrabenazine should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine dose should be reduced; however, some patients may require discontinuation of therapy. 5.6 Parkinsonism Tetrabenazine can cause parkinsonism. In a 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-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-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between this drug-induced adverse reaction 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 Huntington's disease. If a patient develops parkinsonism during treatment with tetrabenazine, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary. 5.7 Sedation and Somnolence Sedation is the most common dose-limiting adverse reaction of tetrabenazine. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence occurred in 17/54 (31%) of tetrabenazine-treated patients and in 1 (3%) of placebo-treated patient. Sedation was the reason upward titration of tetrabenazine was stopped and/or the dose of tetrabenazine was decre

CONTRAINDICATIONS Tetrabenazine tablets are contraindicated in patients: • Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.1) ]. • With hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. • Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablets should not be used in combination with an MAOI, or within a 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 tablets [see Drug Interactions (7.2) ] . • Taking deutetrabenazine or valbenazine [see Drug Interactions ( 7.7 )] . • Actively suicidal, or who have depression which is untreated or undertreated ( 4 , 5.1 ) • Hepatic impairment ( 4 , 8.6 , 12.3 ) • Taking monoamine oxidase inhibitors (MAOIs) or reserpine ( 4 , 7.2 , 7.3 ) • Taking deutetrabenazine or valbenazine ( 4 , 7.7 )

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 a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α- and β-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 i = 2100 nM). 12.2 Pharmacodynamics QTc Prolongation The effect of a single 25 or 50 mg dose of tetrabenazine tablets on the QT interval was studied in a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, tetrabenazine tablets caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of tetrabenazine tablets does not further increase the effect on the QTc interval. Effects at higher exposures to either tetrabenazine tablets or its metabolites have not been evaluated [see Warnings and Precautions (5.8), Drug Interactions (7.5)] . Melanin Binding Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing [see Warnings and Precautions (5.11)] . 12.3 Pharmacokinetics Absorption Following 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 α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (C max ) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmeth-yl-α-DHTBZ. β-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which C max is reached approximately 2 hours post-dosing. Food Effects The effects of food on the bioavailability of tetrabenazine were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ [see Dosage and Administration (2.1)] . Distribution Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11 C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Metabolism After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ are the major circulating metabolites and are subsequently metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-α-DHTBZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ. The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, β-HTBZ or 9 desmethyl-β-DHTBZ 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 α- or β-HTBZ or 9-desmethyl-β-DHTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-β-DHTBZ metabolites are likely to be substrates or inhibitors of P-glycoprotein at clinically relevant concentrations in vivo . Elimination After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine, and fecal recovery accounted for approximately 7 to 16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-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 Gender There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ. Hepatic Impairment The 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 a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmax 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 (tmax) of α-HTBZ and β-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 α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30 to 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 tablets is contraindicated in patients with hepatic impairment [see Contraindications (4), Use in Specific Populations (8.6)] . Poor CYP2D6 Metabolizers Although the pharmacokinetics of tetrabenazine tablets 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 α-HTBZ and β-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 Inhibitors In vitro studies indicate that α-HTBZ and β-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 a single 50 mg dose of tetrabenazine given after 10 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg dai