tetrabenazine
Dosage Form: tablet
FULL PRESCRIBING INFORMATION
Xenazine® (tetrabenazine) Tablets
Xenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of Xenazine must balance the risks of depression and suicidality with the clinical need for control of choreiform movements. 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 behaviors of concern promptly to the treating physician.
Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington's disease. Xenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4) and Warnings and Precautions (5.3)].
Indications and Usage for Xenazine
Xenazine is indicated for the treatment of chorea associated with Huntington's disease.
Xenazine Dosage and Administration
General Dosing Considerations
The chronic daily dose of Xenazine used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, Xenazine therapy should be titrated slowly over several weeks to identify a dose of XENAXINE that reduces chorea and is tolerated. Xenazine can be administered without regard to food [see Clinical Pharmacology (12.3)].
Individualization of Dose
The dose of Xenazine 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. 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 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 events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event 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 per day
Patients who require doses of Xenazine 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 Xenazine should then be individualized accordingly to their status as PMs or EMs [see Warnings and Precautions (5.2, 5.4), Use in Specific Populations (8.8), and 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 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 events such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing Xenazine treatment or initiating other specific treatment (e.g., antidepressants) [see Warnings and Precautions (5.2, 5.4), Use in Specific Populations (8.8), and 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 Warnings and Precautions (5.2), Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].
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 Xenazine 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 (8.9), and Clinical Pharmacology (12.3)].
Patients with Hepatic Impairment
Because the safety and efficacy of the increased exposure to Xenazine and other circulating metabolites are unknown, it is not possible to adjust the dosage of Xenazine in hepatic impairment to ensure safe use. Therefore, Xenazine is contraindicated in patients with hepatic impairment [see Contraindications (4), Warnings and Precautions (5.16), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Discontinuation of Treatment
Treatment with Xenazine can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of Xenazine [see Drug Abuse and Dependence (9.2)].
Resumption of Treatment
Following treatment interruption of greater than five (5) days, Xenazine 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 and Strengths
Xenazine tablets are available in the following strengths and packages:
The 12.5 mg Xenazine tablets are white, cylindrical biplanar tablets with beveled edges, non-scored, embossed on one side with "CL" and "12.5."
The 25 mg Xenazine tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, scored, embossed on one side with "CL" and "25."
Contraindications
- Xenazine is contraindicated in patients who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.3)].
- Xenazine is contraindicated in patients with impaired hepatic function [see Dosage and Administration (2.4), Warnings and Precautions (5.16), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
- Xenazine is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). Xenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Warnings and Precautions (5.12) and Drug Interactions (7.2, 7.3)].
- Xenazine is contraindicated in patients taking reserpine. At least 20 days should elapse after stopping reserpine before starting Xenazine [see Warnings and Precautions (5.12) and Drug Interactions (7.2)].
Warnings and Precautions
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, Xenazine 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-evaluate the need for Xenazine 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 Xenazine.
Dosing of Xenazine
Proper dosing of Xenazine involves 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 tolerated [see Dosage and Administration (2.1)]. 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, consider discontinuing Xenazine.
Doses above 50 mg should not be given without CYP2D6 genotyping patients to determine if they are poor metabolizers [see Dosage and Administration (2.2), Warnings and Precautions (5.4), Use in Specific Populations (8.8), and Clinical Pharmacology (12.3)].
Risk of Depression and Suicidality
Patients with Huntington's disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Xenazine increases the risk for suicidality in patients with HD. All patients treated with Xenazine should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with Xenazine.
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 Xenazine 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 Xenazine (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% 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 Xenazine 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.
Laboratory Tests
Before prescribing a daily dose of Xenazine 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 Xenazine.
Patients who are PMs of Xenazine 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 (8.8), and Clinical Pharmacology (12.3)].
Risk of Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with Xenazine and other drugs that reduce dopaminergic transmission [see Warnings and Precautions (5.12) and Drug Interactions (7.7)]. 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 Xenazine 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 Xenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence.
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 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.
Risk of 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 Xenazine, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.
Risk of 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.
Risk of Sedation and Somnolence
Sedation is the most common dose-limiting adverse effect of Xenazine. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence was observed in 17/54 (31%) Xenazine-treated patients and in 1 (3%) placebo-treated patient. Sedation was the reason upward titration of Xenazine was stopped and/or the dose of Xenazine was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of Xenazine resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/somnolence was observed in 17% and 57% of Xenazine-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 a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of Xenazine and know how the drug affects them.
Interaction with Alcohol
Patients should be advised that the concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions (5.9) and Drug Interactions (7.5)].
Risk of QTc Prolongation
Xenazine causes a small increase (about 8 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 Xenazine 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, 7.6) and Use in Specific Populations (8.10)].
Xenazine should also be avoided in patients with congenital long QT syndrome and in patients with a 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 Use in Specific Populations (8.10)].
Concomitant Use of Neuroleptic Drugs, Reserpine and MAOIs
Neuroleptic Drugs
Patients taking neuroleptic (antipsychotic) drugs (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) were excluded from clinical studies during the Xenazine development program. Adverse reactions associated with Xenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists [see Warnings and Precautions (5.5, 5.11), Drug Interactions (7.5, 7.6) and Use in Specific Populations (8.10)].
Reserpine
Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. The physician should wait for chorea to reemerge before administering Xenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting Xenazine. Xenazine and reserpine should not be used concomitantly [see Contraindications (4) and Drug Interactions (7.2)].
Monoamine Oxidase Inhibitors (MAOIs)
Xenazine is contraindicated in patients taking MAOIs. Xenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4) and Drug Interactions (7.3)].
Risk of Hypotension and Orthostatic Hypotension
Xenazine 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 Xenazine-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.
Risk of Hyperprolactinemia
Xenazine 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, a factor of potential importance if Xenazine is being considered for a 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 Xenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of Xenazine.
Risk of Tardive Dyskinesia (TD)
A 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, a 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 Xenazine, 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 Xenazine 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 a patient treated with Xenazine, drug discontinuation should be considered.
Use in Patients with Concomitant Illnesses
Clinical experience with Xenazine in patients with systemic illnesses is limited.
Depression and Suicidality
Xenazine may increase the risk for depression or suicidality in patients with a history of depression or suicidal behavior or in patients with diseases, conditions, or treatments that cause depression or suicidality. Xenazine is contraindicated in patients with untreated or inadequately treated depression or who are actively suicidal [see Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.7)].
Hepatic Disease
Xenazine is contraindicated in patients with hepatic impairment [see Dosage and Administration (2.4), Contraindications (4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Heart Disease
Xenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials.
Binding to Melanin-Containing Tissues
Since Xenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that Xenazine 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 Xenazine's 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)].
Adverse Reactions
The following risks are discussed in greater detail in other sections of the labeling:
- Depression and suicidality [see Warnings and Precautions (5.3)]
- Akathisia, restlessness and agitation [see Warnings and Precautions (5.6)]
- Parkinsonism [see Warnings and Precautions (5.7)]
- Sedation and somnolence [see Warnings and Precautions (5.9)]
- Dysphagia [see Warnings and Precautions (5.8)]
Commonly Observed Adverse Reactions in Controlled Clinical Trials
The most common adverse reactions from Table 1 occurring in over 10% of Xenazine-treated patients, and at least 5% greater than placebo, were sedation/somnolence (31%), fatigue (22%), insomnia (22%), depression (19%), akathisia (19%), and nausea (13%).
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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, Xenazine was administered to 773 unique subjects and patients. The conditions and duration of exposure to Xenazine 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 a randomized, 12-week, placebo-controlled clinical trial of HD subjects, adverse reactions (ARs) were more common in the Xenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received Xenazine experienced one or more ARs at any time during the study. The ARs most commonly reported (over 10%, and at least 5% greater than placebo) were sedation/somnolence (31% vs. 3% on placebo), fatigue (22% vs. 13% on placebo), insomnia (22% vs. 0% on placebo), depression (19% vs. 0% on placebo), akathisia (19% vs. 0% on placebo), and nausea (13% vs. 7% on placebo).
Adverse Reactions Occurring in ≥4% Patients
The number and percentage of the most commonly reported AEs that occurred at any time during the study in ≥4% of Xenazine-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1 in decreasing order of frequency within body systems for the Xenazine group.
| Body System | AE Term | Xenazine n = 54 n (%) | Placebo n = 30 n (%) |
|---|---|---|---|
| PSYCHIATRIC DISORDERS | Sedation/somnolence | 17 (31%) | 1 (3%) |
| Insomnia | 12 (22%) | - | |
| Depression | 10 (19%) | - | |
| Anxiety/anxiety aggravated | 8 (15%) | 1 (3%) | |
| Irritability | 5 (9%) | 1 (3%) | |
| Appetite decreased | 2 (4%) | - | |
| Obsessive reaction | 2 (4%) | - | |
| CENTRAL & PERIPHERAL NERVOUS SYSTEM | Akathisia | 10 (19%) | - |
| Balance difficulty | 5 (9%) | - | |
| Parkinsonism/bradykinesia | 5 (9%) | - | |
| Dizziness | 2 (4%) | - | |
| Dysarthria | 2 (4%) | - | |
| Gait unsteady | 2 (4%) | - | |
| Headache | 2 (4%) | 1 (3%) | |
| GASTROINTESTINAL SYSTEM DISORDERS | Nausea | 7 (13%) | 2 (7%) |
| Vomiting | 3 (6%) | 1 (3%) | |
BODY AS A WHOLE – GENERAL | Fatigue | 12 (22%) | 4 (13%) |
| Fall | 8 (15%) | 4 (13%) | |
| Laceration (head) | 3 (6%) | - | |
| Ecchymosis | 3 (6%) | - | |
| RESPIRATORY SYSTEM DISORDERS | Upper respiratory tract infection | 6 (11%) | 2 (7%) |
| Shortness of breath | 2 (4%) | - | |
| Bronchitis | 2 (4%) | - | |
| URINARY SYSTEM DISORDERS | Dysuria | 2 (4%) | - |
Dose escalation was discontinued or dosage of study drug was reduced because of one or more ARs in 28 of 54 (52%) patients randomized to Xenazine. These ARs 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 (EPS)
The following table describes the incidence of events considered to be extrapyramidal adverse reactions.
| Event | Patients (%) reporting event | |
|---|---|---|
| Xenazine n = 54 | Placebo n = 30 | |
| ||
| Akathisia * | 10 (19%) | 0 |
| Extrapyramidal event † | 8 (15%) | 0 |
| Any extrapyramidal event | 18 (33%) | 0 |
Patients may have had events in more than one category.
Laboratory Tests
No clinically significant changes in laboratory parameters were reported in clinical trials with Xenazine. In controlled clinical trials, Xenazine caused a small mean increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), laboratory values as compared to placebo.
Vital Signs
In controlled clinical trials, Xenazine did not affect blood pressure, pulse, and body weight. Orthostatic blood pressure was not consistently measured in the Xenazine clinical trials.
Drug Interactions
Strong CYP2D6 Inhibitors
In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYPD6 inhibitors (e.g., paroxtine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in Xenazine dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of Xenazine. The daily dose of Xenazine should not exceed 50 mg per day and the maximum single dose of Xenazine should not exceed 25 mg in patient staking strong CYP2D6 inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Use in Specific Populations (8.9), and Clinical Pharmacology (12.3)].
Reserpine
Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering Xenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting Xenazine. Xenazine and reserpine should not be used concomitantly [see Contraindications (4), Warnings and Precautions (5.12), and Clinical Pharmacology (12.3)].
Monoamine Oxidize Inhibitors (MAOIs)
Xenazine is contraindicated in patients taking MAOIs. Xenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4), Warnings and Precautions (5.12), and Clinical Pharmacology (12.3)].
Alcohol
Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions (5.10)].
Drugs that Cause QTc Prolongation
Since Xenazine causes a small increase in QTc prolongation (about 8 msec), the concomitant use with other drugs that are known to cause QTc prolongation should be avoided 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. Xenazine should also be avoided in patients with congenital long QT syndrome and in patients with a 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 Warnings and Precautions (5.11, 5.12), Drug Interactions (7.7), and Clinical Pharmacology (12.2)].
Neuroleptic Drugs
Adverse reactions associated with Xenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists, including antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) [see Warnings and Precautions (5.5, 5.10, 5.11, 5.12) and Drug Interactions (7.6)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Xenazine 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 3 times the maximum recommended human dose [MRHD] of 100 mg/day on a mg/m2 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 a mg/m2 basis). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, a 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 a mg/m2 basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a 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.
Labor and Delivery
The effect of Xenazine on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether Xenazine 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 Xenazine, a decision should be made whether to discontinue nursing or to discontinue Xenazine, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of Xenazine in children have not been established.
Geriatric Use
The pharmacokinetics of Xenazine and its primary metabolites have not been formally studied in geriatric subjects.
Use in Patients with Hepatic Disease
The use of Xenazine in patients with liver disease is contraindicated [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.16), and Clinical Pharmacology (12.3)].
Use in Patients with Depression and Suicidality
Patients with HD are at increased risk for depression, suicidal ideation and behavior (suicidality), and Xenazine increases these risks. Xenazine is contraindicated in patients with untreated or inadequately treated depression or who are actively suicidal. Xenazine may increase the risk for depression or suicidality in patients with a history of depression or suicidal behavior or in patients with diseases, conditions, or treatments that cause depression or suicidality [see Contraindications (4) and Warnings and Precautions (5.3)].
Depression
Symptoms of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks may increase with Xenazine. Depression/worsening depression was noted in 35% of Xenazine-treated patients during studies with Xenazine.
Suicidality
The rate of completed suicide among individuals with Huntington's disease ranges from 3-13% and over 25% of patients with HD attempt suicide at some point in their illness.
Use in Poor or Extensive CYP2D6 Metabolizers
Patients who require doses of Xenazine 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 Xenazine 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 (5.2, 5.4) and Clinical Pharmacology (12.3)].
Poor Metabolizers
Poor CYP2D6 metabolizers (PM) 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 (5.2, 5.4), and 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 Interaction (7.1), and Clinical Pharmacology (12.3)].
Use in Patients at Risk from QTc Prolongation
Xenazine causes a small increase in QTc interval (8 msec). It should be avoided in patients with congenital long QT syndrome, or a history of hypokalemia or hypomagnesemia, or cardiac arrhythmias (e.g., bradycardia), or 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 Warnings and Precautions (5.5, 5.11, 5.12), Drug Interactions (7.5, 7.6), and Clinical Pharmacology (12.2)].
Use in Patients with Renal Disease
The effects of renal insufficiency in the pharmacokinetics of Xenazine and its primary metabolites have not been formally studied.
Drug Abuse and Dependence
Controlled Substance Class
Xenazine is not a controlled substance.
Abuse
Clinical trials did not reveal any tendency for drug seeking behavior, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where Xenazine has been marketed.
As with any CNS-active drug, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of Xenazine misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).
Abrupt discontinuation of Xenazine from patients did not produce symptoms of withdrawal or a discontinuation syndrome; only symptoms of the original disease were observed to re-emerge [see Dosage and Administration (2.5)].
Overdosage
Human Experience
Three episod
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