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The following risks are discussed in greater detail in other sections of the labeling:
- Depression and suicidality [see WARNINGS AND PRECAUTIONS]
- Akathisia, restlessness and agitation [see WARNINGS AND PRECAUTIONS]
- Parkinsonism [see WARNINGS AND PRECAUTIONS]
- Dysphagia [see WARNINGS AND PRECAUTIONS]
- Sedation and somnolence [see WARNINGS AND PRECAUTIONS]
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.
Table 1: Treatment Emergent Adverse Reactions in Patients
Treated with XENAZINE and with a Greater Frequency than Placebo in the 12-Week,
Double-Blind, Placebo- Controlled Trial of XENAZINE
|Body System||AE Term||XENAZINE
n = 54
n = 30
|PSYCHIATRIC DISORDERS||Sedation/ somnolence||17 (31%)||1 (3%)|
|Anxiety/anxiety aggravated||8 (15%)||1 (3%)|
|Irritability||5 (9%)||1 (3%)|
|Appetite decreased||2 (4%)||-|
|Obsessive reaction||2 (4%)||-|
|Balance difficulty||5 (9%)||-|
|CENTRAL & PERIPHERAL||Parkinsonism/ bradykinesia||5 (9%)||-|
|NERVOUS SYSTEM||Dizziness||2 (4%)||-|
|Gait unsteady||2 (4%)||-|
|Headache||2 (4%)||1 (3%)|
|GASTROINTESTINAL||Nausea||7 (13%)||2 (7%)|
|SYSTEM DISORDERS||Vomiting||3 (6%)||1 (3%)|
|Fatigue||12 (22%)||4 (13%)|
|BODY AS A WHOLE -||Fall||8 (15%)||4 (13%)|
|GENERAL||Laceration (head)||3 (6%)||-|
|RESPIRATORY SYSTEM||Upper respiratory tract infection||6 (11%)||2 (7%)|
|DISORDERS||Shortness of breath||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.
Table 2: Treatment Emergent EPS in Patients Treated with
XENAZINE Occurring with a Greater Frequency than Placebo in the 12-Week,
Double-Blind, Placebo-Controlled Trial of XENAZINE
|Event||Patients (%) reporting event|
n = 54
n = 30
|Extrapyramidal event2||8 (15%)||0|
|Any extrapyramidal event||18 (33%)||0|
|1Patients with the following adverse event
preferred terms were counted in this category: akathisia, hyperkinesia,
2Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia.
Patients may have had events in more than one category.
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 Patients (%) reporting event aminotransferase (ALT) and aspartate aminotransferase (AST), laboratory values as compared to placebo.
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.
Read the Xenazine (tetrabenazine tablets) Side Effects Center for a complete guide to possible side effects
Strong CYP2D6 Inhibitors
In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYP2D6 inhibitors (e.g., paroxetine, 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 patients taking strong CYP2D6 inhibitors [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Use in Specific Populations, and CLINICAL PHARMACOLOGY].
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, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
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, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see WARNINGS AND PRECAUTIONS].
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 and CLINICAL PHARMACOLOGY].
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].
Drug Abuse And Dependence
Controlled Substance Class
XENAZINE is not a controlled substance.
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].
Read the Xenazine Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/29/2012
This monograph has been modified to include the generic and brand name in many instances.
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