Dosing Recommendations Up to 50 mg/day
The starting dose should be 12.5 mg/day given once in the morning. After 1 week, the dose should be increased to 25 mg/day given as 12.5 mg twice a day. XENAZINE 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/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 XENAZINE treatment or initiating other specific treatment (e.g., antidepressants) [see Adverse Reactions (6.1)].
Dosing Recommendations Above 50 mg/day
Patients who require doses of XENAZINE greater than 50 mg/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 XENAZINE 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 XENAZINE above 50 mg/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/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 XENAZINE 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)].
Adverse Reactions Occurring in Greater Than or Equal to 4% of Patients
The number and percentage of the most common adverse reactions that occurred at any time during the study in greater than or equal to 4% of XENAZINE-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1.
Table 1: Adverse Reactions in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease| Adverse Reaction | XENAZINE
n=54
% | Placebo
n=30
% |
|---|
Sedation/somnolence | 31 | 3 |
Insomnia | 22 | 0 |
Fatigue | 22 | 13 |
Depression | 19 | 0 |
Akathisia | 19 | 0 |
Anxiety/anxiety aggravated | 15 | 3 |
Fall | 15 | 13 |
Nausea | 13 | 7 |
Upper respiratory tract infection | 11 | 7 |
Irritability | 9 | 3 |
Balance difficulty | 9 | 0 |
Parkinsonism/bradykinesia | 9 | 0 |
Vomiting | 6 | 3 |
Laceration (head) | 6 | 0 |
Ecchymosis | 6 | 0 |
Decreased appetite | 4 | 0 |
Obsessive reaction | 4 | 0 |
Dizziness | 4 | 0 |
Dysarthria | 4 | 0 |
Unsteady gait | 4 | 0 |
Headache | 4 | 3 |
Shortness of breath | 4 | 0 |
Bronchitis | 4 | 0 |
Dysuria | 4 | 0 |
Dose 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 XENAZINE. 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 AR and are, therefore, counted more than once.
Adverse Reactions Due to Extrapyramidal Symptoms
Table 2 describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at a greater frequency in XENAZINE-treated patients compared to placebo-treated patients.
Table 2: Adverse Reactions Due to Extrapyramidal Symptoms in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease | XENAZINE
n=54
% | Placebo
n=30
% |
|---|
Akathisia Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. | 19 | 0 |
Extrapyramidal event Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia. | 15 | 0 |
Any extrapyramidal event | 33 | 0 |
Patients may have had events in more than one category.
Dysphagia
Dysphagia is a 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 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, dysphagia was observed in 10% and 8% of XENAZINE-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.
Poor Metabolizers
Poor CYP2D6 metabolizers (PMs) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) compared to EMs. The dosage should, therefore, be adjusted according to a patient’s CYP2D6 metabolizer status by limiting a single dose to a maximum of 25 mg and the recommended daily dose to not exceed a 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 Metabolizers
In extensive (EMs) or intermediate metabolizers (IMs), the dosage of XENAZINE can be titrated to a maximum single dose of 37.5 mg and a recommended maximum daily dose of 100 mg [see Dosage and Administration (2.2), Drug Interactions (7.1), Clinical Pharmacology (12.3)].
QTc Prolongation
The effect of a single 25 or 50 mg dose of XENAZINE 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, XENAZINE 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 XENAZINE does not further increase the effect on the QTc interval. Effects at higher exposures to either XENAZINE 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)].
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 (Cmax) 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-desmethyl-α-DHTBZ. β-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
Food Effects
The effects of food on the bioavailability of XENAZINE 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 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
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, XENAZINE is contraindicated in patients with hepatic impairment [see Contraindications (4), Use in Specific Populations (8.6)].
Poor CYP2D6 Metabolizers
Although the pharmacokinetics of XENAZINE 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 daily. There was an approximately 30% increase in Cmax and an approximately 3-fold increase in AUC for α-HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For β-HTBZ, the Cmax and AUC were increased 2.4- and 9-fold, respectively, in subjects given paroxetine prior to tetrabenazine given alone. The elimination half-life of α-HTBZ and β-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 XENAZINE 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)].
Digoxin
Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that XENAZINE (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, XENAZINE does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that XENAZINE or its metabolites are P-glycoprotein inhibitors.
Carcinogenesis
No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine (5, 15, and 30 mg/kg/day) for 26 weeks.
No increase in tumors was observed in Tg.rasH2 transgenic mice treated orally with a major human metabolite, 9-desmethyl-β-DHTBZ (20, 100, and 200 mg/kg/day), for 26 weeks.
Mutagenesis
Tetrabenazine and metabolites α-HTBZ, β-HTBZ, and 9-desmethyl-β-DHTBZ were negative in an in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in an in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. 9-desmethyl-β-DHTBZ was not clastogenic in an in vitro chromosomal aberration assay in human peripheral blood mononuclear cells in the presence or absence of metabolic activation. In vivo micronucleus assays 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.
Impairment of Fertility
Oral administration of tetrabenazine (5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis).
No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (5, 15, or 30 mg/kg/day; up to 3 times the MRHD on a mg/m2 basis) prior to and throughout mating with untreated females.
Because rats dosed with tetrabenazine do not produce 9-desmethyl-β-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of XENAZINE to impair fertility in humans.
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 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. XENAZINE was started at a dose of 12.5 mg/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 a maximal dose of 100 mg/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 patients 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 statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of patients receiving XENAZINE returned to baseline.
Figure 1: Mean ± s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Patients Treated with XENAZINE (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 the XENAZINE-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 a 6-point or greater improvement compared to 50% of XENAZINE-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 XENAZINE 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 XENAZINE 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).
