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DESCRIPTION

XENAZINE (tetrabenazine) is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43, the pKa is 6.51. Tetrabenazine is a 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 C19H27NO3 is represented by the following structural formula:

Tetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.

Each XENAZINE (tetrabenazine) Tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient. XENAZINE (tetrabenazine) Tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose, maize starch, talc, and magnesium stearate. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient. XENAZINE (tetrabenazine) is supplied as a yellowish-buff scored tablet containing 25 mg of tetrabenazine, or as a white non-scored tablet containing 12.5 mg of tetrabenazine.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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 (Ki = 2100 nM).

QTc Prolongation: The effect of a single 25 or 50 mg dose of tetrabenazine 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 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 does not further increase the effect on the QTc interval. Effects at higher exposures to either tetrabenazine or its metabolites have not been eva luated (see PRECAUTIONS - QTc Prolongation).

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.

Pharmacokinetics

Absorption and Distribution: 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 to α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ and β-HTBZ are subsequently metabolized to another major circulating metabolite, O-dealkylated-HTBZ, for which Cmax is reached approximately 2 hours post-dosing.

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. XENAZINE can therefore be administered without regard to meals.

Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-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 and Excretion: α-HTBZ and β-HTBZ, major circulating metabolites, have half-lives of 4-8 hours and 2-4 hours, respectively. 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. β-HTBZ is O-dealkylated principally by CYP2D6.

After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. O-dealkylated HTBZ, α-HTBZ, and β-HTBZ are the major circulating metabolites, and they are subsequently metabolized to sulfate or glucuronide conjugates. CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP2E1 do not play a major role in metabolism of α-HTBZ or β-HTBZ based on in vitro studies.

The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. Their effect on CYP2B6 has not been eva luated. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.

Neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.

Excretion: After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. 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 7-16% 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.

Special Populations

Pediatrics:

The pharmacokinetics of tetrabenazine and its primary metabolites have not been studied in pediatric subjects.

Geriatrics:

The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.

Gender:

There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.

Race:

Racial differences in the pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied.

Renal Disease:

The effect of renal insufficiency on the pharmacokinetics of tetrabenazine and its primary metabolites has not been studied.

Liver Disease:

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 hepatically impaired subjects 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 30-39% 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 is contraindicated in patients with hepatic impairment (see CONTRAINDICATIONS; PRECAUTIONS - Use in Patients with Concomitant Illness; and DOSAGE AND ADMINISTRATION).

CYP2D6 Poor Metabolizers

Although the pharmacokinetics of tetrabenazine and its metabolites in subjects who do not express the drug metabolizing enzyme CYP2D6 (poor metabolizers, PMs) have not been systematically eva luated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased compared to subjects who express the enzyme (extensive metabolizers, EMs), with an increase similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively) (see PRECAUTIONS - Drug Interactions and DOSAGE AND ADMINISTRATION). Patients should be genotyped for CYP2D6 prior to treatment with daily doses of tetrabenazine over 50 mg (see WARNINGS - Laboratory Tests). Patients who are PMs should not be given daily doses greater than 50 mg (see DOSAGE AND ADMINISTRATION).

Drug Interactions

α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. A strong CYP2D6 inhibitor (paroxetine) markedly increases exposure to these metabolites (see PRECAUTIONS - Drug Interactions).

Digoxin: Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that tetrabenazine (25 mg twice daily for 3 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

Study 1

The efficacy of XENAZINE as a treatment for the chorea of Huntington’s disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of Huntington’s disease (HD). The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5-week maintenance period followed by a 1-week washout. The dose of XENAZINE was started at 12.5 mg/day and titrated upward at weekly intervals in 12.5 mg increments until satisfactory control of chorea was achieved, until intolerable side effects occurred, or until a maximal dose of 100 mg per day was reached.

The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington’s Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.

As shown in Figure 1, Total Chorea Scores for subjects in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 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 highly statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of subjects receiving XENAZINE returned to baseline.

Figure 1. Mean ± s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Subjects Treated with Tetrabenazine (n=54) or Placebo (n=30)

Figure 2 illustrates the cumulative percentages of patients from the XENAZINE and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the X axis. The left-ward shift of the curve (toward greater improvement) for tetrabenazine-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. Thus, for example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of tetrabenazine-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 1 were: Placebo 97%, Tetrabenazine 91%.

A Physician-rated Clinical Global Impression (CGI) favored XENAZINE statistically. In general, measures of functional capacity and cognition showed no difference between XENAZINE and placebo. However, one functional measure (Part 4 of the UHDRS), a 25-item scale assessing the capacity for patients to perform certain activities of daily living, showed a decrement for patients treated with tetrabenazine compared to placebo, a difference that was nominally statistically significant. A 3-item cognitive battery specifically developed to assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed a decrement for patients treated with XENAZINE compared to placebo, but the difference was not statistically significant.

Study 2

A second controlled study was performed in patients who had been treated with open-label XENAZINE for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of tetrabenazine 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 1 (about 3.5 units).

INDICATIONS AND USAGE

XENAZINE is indicated for the treatment of chorea associated with Huntington’s disease.

CONTRAINDICATIONS

XENAZINE is contraindicated in patients who are actively suicidal, or in patients with untreated or inadequately treated depression. XENAZINE is contraindicated in patients with impaired hepatic function. XENAZINE is contraindicated in patients taking monoamine oxidase inhibitors. XENAZINE is contraindicated in patients taking reserpine. At least 20 days should elapse after stopping reserpine before starting XENAZINE (see PRECAUTIONS - Drug Interactions).

WARNINGS

Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. Although XENAZINE has been shown to decrease the chorea of HD in a 12-week controlled trial, it 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. Therefore, proper use of the drug requires attention to all facets of the underlying disease process over time. Prescribers should periodically re-eva luate the need for XENAZINE in their patients by assessing the beneficial effect on choreiform movements 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 XENAZINE.

Need for Careful Dosing of XENAZINE

Proper dosing of XENAZINE involves careful titration of therapy to determine an individualized dose for each patient. When first prescribed, XENAZINE therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is well tolerated (see DOSAGE AND ADMINISTRATION). Some adverse effects such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism and akathisia may be dose-dependent and may resolve or lessen with dosage adjustment or specific treatment. If the adverse effect does not resolve or decrease, consideration should be given to discontinuing tetrabenazine.

Doses above 50 mg should not be given without CYP2D6 genotyping (see WARNINGS – Laboratory Tests and PRECAUTIONS – Drug Interactions).

Risk of Depression and Suicidality

Patients with Huntington’s disease are at increased risk for depression and suicidal ideation and behavior (suicidality). Tetrabenazine increases these risks. All patients treated with tetrabenazine should be observed closely for new or worsening depression or suicidality.

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 XENAZINE for up to 48 weeks; in the second study, 75 patients received XENAZINE 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.

Clinicians should be alert to the heightened risk of suicide in patients with Huntington’s disease regardless of depression indices. Reported rates of completed suicide among individuals with Huntington’s disease range from 3-13%; over 25% of patients attempt suicide at some point in the illness.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with XENAZINE and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be eva luated immediately (see PRECAUTIONS - Information for Patients).

If depression or suicidality occurs, the dose of XENAZINE should be reduced. Initiating treatment with, or increasing the dose of, a concomitant antidepressant may also be useful. In patients with new onset depression who require antidepressants that are strong CYP2D6 inhibitors (such as paroxetine and fluoxetine), the total dose of XENAZINE should be halved (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). If depression or suicidality does not resolve, consideration should be given to discontinuing treatment with tetrabenazine.

Caution should be exercised in treating patients with XENAZINE who have a history of depression or prior suicide attempts or ideation, as these patients may be at increased risk for suicidal behavior (see PRECAUTIONS - Information for Patients). Patients who are actively suicidal or with untreated or inadequately treated depression should not be treated with tetrabenazine (see CONTRAINDICATIONS).

Antidepressants that are strong CYP2D6 inhibitors significantly increase exposure to α- and β-HTBZ (see PRECAUTIONS - Drug Interactions).

Laboratory Tests

Before patients are given a daily dose of greater than 50 mg, they should be tested for the CYP2D6 gene to determine whether they are poor metabolizers (PMs) or extensive or intermediate metabolizers (EMs or IMs). When a dose of tetrabenazine is given to PMs, exposure will be substantially higher (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than it would be in EMs. The dosage should therefore be adjusted according to a patient’s CYP2D6 metabolizer status by limiting the dose to 50 mg in patients who are CYP2D6 poor metabolizers (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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. 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 diagnostic eva luation of patients with this syndrome is complicated. In arriving at the diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). 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 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.

If the patient requires treatment with tetrabenazine after recovery from NMS, the potential reintroduction of therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

PRECAUTIONS

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 XENAZINE-treated patients and 0% of placebo-treated patients. In an 80-week open-label study, akathisia was observed in 20% of XENAZINE-treated patients. Akathisia was not observed in a 48-week open-label study. Patients receiving XENAZINE should be monitored for the presence of akathisia. Patients receiving XENAZINE 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 XENAZINE dose should be reduced; however, some patients may require discontinuation of therapy.

Parkinsonism

XENAZINE 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 XENAZINE-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 XENAZINE-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 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 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.

Dysphagia

Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. The latter symptom may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of XENAZINE-treated patients and 3% of placebo-treated patients. In 48-week and 80-week open-label studies