Xenazine Information
Xenazine (Tetrabenazine)
Xenazine (Tetrabenazine) Indications And Usage
Xenazine (Tetrabenazine) is indicated for the treatment of chorea associated with Huntington's disease.
Xenazine (Tetrabenazine) Dosage Forms And Strengths
Xenazine (Tetrabenazine) tablets are available in the following strengths and packages:
The 12.5 mg Xenazine (Tetrabenazine) tablets are white, cylindrical biplanar tablets with beveled edges, non-scored, embossed on one side with "CL" and "12.5."
The 25 mg Xenazine (Tetrabenazine) tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, scored, embossed on one side with "CL" and "25."
Xenazine (Tetrabenazine) Warnings And Precautions
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 (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. 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 (Tetrabenazine) 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 (Tetrabenazine) .
Proper dosing of Xenazine (Tetrabenazine) involves titration of therapy to determine an individualized dose for each patient. When first prescribed, Xenazine (Tetrabenazine) therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is tolerated 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 (Tetrabenazine) .
Doses above 50 mg should not be given without CYP2D6 genotyping patients to determine if they are poor metabolizers
Patients with Huntington's disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Xenazine (Tetrabenazine) increases the risk for suicidality in patients with HD. All patients treated with Xenazine (Tetrabenazine) should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with Xenazine (Tetrabenazine) .
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 (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 (Tetrabenazine) for up to 48 weeks; in the second study, 75 patients received Xenazine (Tetrabenazine) for up to 80 weeks), the rate of depression/worsening depression was 35%.
In all of the HD chorea studies of Xenazine (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% 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 (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.
Before prescribing a daily dose of Xenazine (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 Xenazine (Tetrabenazine) .
Patients who are PMs of Xenazine (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
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with Xenazine (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 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 (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.
Recurrence of NMS has been reported. If treatment with Xenazine (Tetrabenazine) is needed after recovery from NMS, patients should be monitored for signs of recurrence.
Sedation is the most common dose-limiting adverse effect of Xenazine (Tetrabenazine) . 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 (Tetrabenazine) -treated patients and in 1 (3%) placebo-treated patient. Sedation was the reason upward titration of Xenazine (Tetrabenazine) was stopped and/or the dose of Xenazine (Tetrabenazine) was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of Xenazine (Tetrabenazine) resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/somnolence was observed in 17% and 57% of Xenazine (Tetrabenazine) -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 (Tetrabenazine) and know how the drug affects them.
Xenazine (Tetrabenazine) 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 The use of Xenazine (Tetrabenazine) 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
Xenazine (Tetrabenazine) 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
Since Xenazine (Tetrabenazine) or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that Xenazine (Tetrabenazine) 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 (Tetrabenazine) '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
Xenazine (Tetrabenazine) Adverse Reactions
The following risks are discussed in greater detail in other sections of the labeling:
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 (Tetrabenazine) was administered to 773 unique subjects and patients. The conditions and duration of exposure to Xenazine (Tetrabenazine) 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 (Tetrabenazine) group than in the placebo group. Forty-nine of 54 (91%) patients who received Xenazine (Tetrabenazine) 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).
Xenazine (Tetrabenazine) Use In Specific Populations
It is not known whether Xenazine (Tetrabenazine) 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 (Tetrabenazine) , a decision should be made whether to discontinue nursing or to discontinue Xenazine (Tetrabenazine) , taking into account the importance of the drug to the mother.
Xenazine (Tetrabenazine) Drug Abuse And Dependence
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 (Tetrabenazine) 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 (Tetrabenazine) misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).
Abrupt discontinuation of Xenazine (Tetrabenazine) from patients did not produce symptoms of withdrawal or a discontinuation syndrome; only symptoms of the original disease were observed to re-emerge
Xenazine (Tetrabenazine) 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 CHNOis 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, magnesium stearate, maize starch, and talc. 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 Xenazine (Tetrabenazine) or as a white non-scored tablet containing 12.5 mg of Xenazine (Tetrabenazine) .
Xenazine (Tetrabenazine) Clinical Studies
Study 1
The efficacy of Xenazine (Tetrabenazine) 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. The dose of Xenazine (Tetrabenazine) was started at 12.5 mg per 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 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 (Tetrabenazine) returned to baseline.
Figure 1. Mean ± s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Subjects Treated with Xenazine (Tetrabenazine) (n=54) or Placebo (n=30)
Figure 2 illustrates the cumulative percentages of patients from the Xenazine (Tetrabenazine) 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 Xenazine (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 Xenazine (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.
A Physician-rated Clinical Global Impression (CGI) favored Xenazine (Tetrabenazine) statistically. In general, measures of functional capacity and cognition showed no difference between Xenazine (Tetrabenazine) 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 (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 (Tetrabenazine) 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 (Tetrabenazine) for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of Xenazine (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).
Xenazine (Tetrabenazine) How Supplied/storage And Handling
Xenazine (Tetrabenazine) tablets are available in the following strengths and packages:
The 12.5 mg Xenazine (Tetrabenazine) tablets are white, cylindrical biplanar tablets with beveled edges, non-scored, embossed on one side with "CL" and "12.5".
Bottles of 112: NDC 67386-421-01
The 25 mg Xenazine (Tetrabenazine) tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, scored, embossed on one side with "CL" and "25".
Bottles of 112: NDC 67386-422-01
Xenazine (Tetrabenazine) Patient Counseling Information
See
Physicians are advised to discuss the following issues with patients and their families:
Xenazine (Tetrabenazine)
Xenazine (Tetrabenazine) Medication Guide
Read the Medication Guide that comes with Xenazine (Tetrabenazine) before you start taking it and each time you refill the prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. You should share this information with your family members and caregivers.
Xenazine (Tetrabenazine) is a medicine that is used to treat the involuntary movements (chorea) of Huntington's disease. Xenazine (Tetrabenazine) does not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntington's disease, such as problems with thinking or emotions.
It is not known whether Xenazine (Tetrabenazine) is safe and effective in children.
Sleepiness (sedation) is a common side effect of Xenazine (Tetrabenazine) . While taking Xenazine (Tetrabenazine) , Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking Xenazine (Tetrabenazine) may increase any sleepiness caused by Xenazine (Tetrabenazine) .
Xenazine (Tetrabenazine) contains the active ingredient tetrabenazine. It also contains these inactive ingredients: lactose, maize starch, talc, and magnesium stearate. The 25 mg tablet, which is pale yellow, also contains yellow iron oxide.
Medicines are sometimes prescribed for conditions that are not listed in a Medication Guide. Do not use Xenazine (Tetrabenazine) for a condition for which it was not prescribed. Do not give Xenazine (Tetrabenazine) to other people, even if they have the same symptoms that you have. It may harm them. Keep Xenazine (Tetrabenazine) out of the reach of children.
This Medication Guide summarizes the most important information about Xenazine (Tetrabenazine) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Xenazine (Tetrabenazine) that is written for healthcare professionals. You can also call the Xenazine (Tetrabenazine) Information Center at
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured by:Recipharm Fontaine SASRue des Prés Potets21121 Fontaine-les-DijonFrance
For: Lundbeck Inc.Deerfield, IL 60015, U.S.A.
Xenazine (Tetrabenazine) is a registered trademark of Biovail Laboratories International (Barbados) SRL
Revised: April 2011606430B
Xenazine (Tetrabenazine)
Xenazine (Tetrabenazine)
