Complete SPL Sections
WARNING: DEPRESSION AND SUICIDALITY
Boxed Warning Section
Tetrabenazine tablets can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of tetrabenazine tablets must balance the risks of depression and suicidality with the clinical need for control of chorea. 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. Tetrabenazine tablets are contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] .
1 INDICATIONS AND USAGE
Indications & Usage Section
Tetrabenazine tablets are indicated for the treatment of chorea associated with Huntington's disease.
2 DOSAGE AND ADMINISTRATION
Dosage & Administration Section
3 DOSAGE FORMS AND STRENGTHS
Dosage Forms & Strengths Section
Tetrabenazine tablets are available in the following strengths: The 12.5 mg tetrabenazine tablets are white to off white, circular, flat faced beveled edge, non-scored, uncoated tablets debossed with '1' on one side. The 25 mg tetrabenazine tablets are yellow, circular, flat faced beveled edge uncoated tablets debossed with '179' on one side and scored on other side.
4 CONTRAINDICATIONS
Contraindications Section
Tetrabenazine is contraindicated in patients: Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions ( 5.1 )]. With hepatic impairment [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions ( 7.3 )]. Taking reserpine. At least 20 days should elapse after stopping reserpine before starting tetrabenazine [see Drug Interactions ( 7.2 )]. Taking deutetrabenazine or valbenazine [see Drug Interactions ( 7.7 )].
5 WARNINGS AND PRECAUTIONS
Warnings And Precautions Section
6 ADVERSE REACTIONS
Adverse Reactions Section
The following serious adverse reactions are described below and elsewhere in the labeling: Depression and Suicidality [see Warnings and Precautions ( 5.1 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.4 )] Akathisia, Restlessness, and Agitation [see Warnings and Precautions ( 5.5 )] Parkinsonism [see Warnings and Precautions ( 5.6 )] Sedation and Somnolence [see Warnings and Precautions ( 5.7 )] QTc Prolongation [see Warnings and Precautions ( 5.8 )] Hypotension and Orthostatic Hypotension [see Warnings and Precautions ( 5.9 )] Hyperprolactinemia [see Warnings and Precautions ( 5.10 )] Binding to Melanin-Containing Tissues [see Warnings and Precautions ( 5.11 )]
7 DRUG INTERACTIONS
Drug Interactions Section
8 USE IN SPECIFIC POPULATIONS
Use In Specific Populations Section
9 DRUG ABUSE AND DEPENDENCE
Drug Abuse And Dependence Section
10 OVERDOSAGE
Overdosage Section
Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with tetrabenazine have been reported in the literature. The dose of tetrabenazine in these patients ranged from 100 mg to 1 g. Adverse reactions associated with tetrabenazine overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose.
11 DESCRIPTION
Description Section
Tetrabenazine tablets are 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 molecular formula C 19 H 27 NO 3 is represented by the following structural formula: Tetrabenazine is a white to slightly yellow crystalline powder that is insoluble in water and soluble in ethanol. Each tetrabenazine tablet contains either 12.5 mg or 25 mg of tetrabenazine as the active ingredient. Tetrabenazine tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: anhydrous lactose, corn starch, sodium starch glycolate Type A potato, ferric oxide yellow (for 25 mg), colloidal silicon dioxide, magnesium stearate and talc. Tetrabenazine tablets are supplied as a yellow scored tablet containing 25 mg of tetrabenazine or as a white to off white non-scored tablet containing 12.5 mg of tetrabenazine.
12 CLINICAL PHARMACOLOGY
Clinical Pharmacology Section
13 NONCLINICAL TOXICOLOGY
Nonclinical Toxicology Section
14 CLINICAL STUDIES
Clinical Studies Section
Study 1 The efficacy of 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. Tetrabenazine was started at a dose of 12.5 mg per 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 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 patients in the drug group declined by an estimated 5 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 tetrabenazine returned to baseline. Figure 2 illustrates the cumulative percentages of patients from the 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 the tetrabenazine-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 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. A Physician-rated Clinical Global Impression (CGI) favored tetrabenazine statistically. In general, measures of functional capacity and cognition showed no difference between 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 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 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 tetrabenazine 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).
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied Section
17 PATIENT COUNSELING INFORMATION
Information For Patients Section
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Suicidality Inform patients and their families that tetrabenazine may increase the risk of suicidal thinking and behaviors. Counsel patients and their families to remain alert to the emergence of suicidal ideation and to report it immediately to the patient’s physician [see Contraindications (4), Warnings and Precautions ( 5.1 )] . Risk of Depression Inform patients and their families that tetrabenazine may cause depression or may worsen preexisting depression. Encourage patients and their families to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and to report such symptoms promptly to the patient’s physician [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . Dosing of Tetrabenazine Inform patients and their families that the dose of tetrabenazine will be increased slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician, and the tetrabenazine dose may need to be reduced or discontinued [see Dosage and Administration (2.2)] . Risk of Sedation and Somnolence Inform patients that tetrabenazine may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to tetrabenazine, they should be careful doing activities that require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions ( 5.7 )] . Interaction with Alcohol Advise patients and their families that alcohol may potentiate the sedation induced by tetrabenazine [see Drug Interactions ( 7.4 )] . Usage in Pregnancy Advise patients and their families to notify the physician if the patient becomes pregnant or intends to become pregnant during tetrabenazine therapy, or is breastfeeding or intending to breastfeed an infant during therapy [see Use in Specific Populations ( 8.1 )] . Dispense with Medication Guide available at: https://www.sunpharma.com/usa/products
MEDICATION GUIDE
SPL MEDGUIDE SECTION
Tetrabenazine Tablets (TET-ra-BEN-a-zine) Read the Medication Guide that comes with tetrabenazine tablets 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. What is the most important information I should know about tetrabenazine tablets? Tetrabenazine tablets can cause serious side effects, including: depression suicidal thoughts suicidal actions You should not start taking tetrabenazine tablets if you are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts or feelings. This is especially important when tetrabenazine tablets are started and when the dose is changed. Call the doctor right away if you become depressed or have any of the following symptoms, especially if they are new, worse, or worry you: feel sad or have crying spells lose interest in seeing your friends or doing things you used to enjoy sleep a lot more or a lot less than usual feel unimportant feel guilty feel hopeless or helpless more irritable, angry or aggressive than usual more or less hungry than usual or notice a big change in your body weight have trouble paying attention feel tired or sleepy all the time have thoughts about hurting yourself or ending your life What are tetrabenazine tablets? Tetrabenazine tablets are medicines those are used to treat the involuntary movements (chorea) of Huntington’s disease. Tetrabenazine tablets do 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 tetrabenazine tablets are safe and effective in children. Who should not take tetrabenazine tablets? Do not take tetrabenazine tablets if you: are depressed or have thoughts of suicide. See “What is the most important information I should know about tetrabenazine tablets?” have liver problems. are taking a monoamine oxidase inhibitor (MAOI) medicine. Ask your doctor or pharmacist if you are not sure. are taking reserpine. Do not take medicines that contain reserpine (such as Serpalan ® and Renese ® -R) with tetrabenazine tablets . If your doctor plans to switch you from taking reserpine to tetrabenazine tablets , you must wait at least 20 days after your last dose of reserpine before you start taking tetrabenazine tablets . What should I tell my doctor before taking tetrabenazine tablets? Tell your doctor about all your medical conditions, including if you: have emotional or mental problems (for example, depression, nervousness, anxiety, anger, agitation, psychosis, previous suicidal thoughts or suicide attempts). have liver disease. have any allergies. See the end of this Medication Guide for a complete list of the ingredients in tetrabenazine tablets. have breast cancer or a history of breast cancer. have heart disease that is not stable, have heart failure or recently had a heart attack. have an irregular heartbeat (cardiac arrhythmia). are pregnant or plan to become pregnant. It is not known if tetrabenazine tablets can harm your unborn baby. are breastfeeding. It is not known if tetrabenazine passes into breast milk. Tell your doctor about all the medicines you take, including prescription medicines and nonprescription medicines, vitamins and herbal products. Using tetrabenazine tablets with certain other medicines may cause serious side effects . Do not start any new medicines while taking tetrabenazine tablets without talking to your doctor first. How should I take tetrabenazine tablets? Tetrabenazine tablet is a tablet that you take by mouth. Take tetrabenazine tablets exactly as prescribed by your doctor. You may take tetrabenazine tablets with or without food. Your doctor will increase your dose of tetrabenazine tablets each week for several weeks, until you and your doctor find the best dose for you. If you stop taking tetrabenazine tablets or miss a dose, your involuntary movements may return or worsen in 12 to 18 hours after the last dose. Before starting tetrabenazine tablets, you should talk to your healthcare provider about what to do if you miss a dose. If you miss a dose and it is time for your next dose, do not double the dose. Tell your doctor if you stop taking tetrabenazine tablets for more than 5 days. Do not take another dose until you talk to your doctor. If your doctor thinks you need to take more than 50 mg of tetrabenazine tablets each day, you will need to have a blood test to see if it is safe for you. What should I avoid while taking tetrabenazine tablets? Sleepiness (sedation) is a common side effect of tetrabenazine tablets. While taking tetrabenazine tablets, do not drive a car or operate dangerous machinery until you know how tetrabenazine tablets affect you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking tetrabenazine tablets may increase any sleepiness caused by tetrabenazine tablets. What are the possible side effects of tetrabenazine tablets? Tetrabenazine tablets can cause serious side effects, including: Depression, suicidal thoughts, or actions. See “What is the most important information I should know about tetrabenazine tablets?” Neuroleptic Malignant Syndrome (NMS). Call your doctor right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause: high fever stiff muscles problems thinking very fast or uneven heartbeat increased sweating Parkinsonism. Symptoms of Parkinsonism include: slight shaking, body stiffness, trouble moving or keeping your balance. Restlessness. You may get a condition where you feel a strong urge to move. This is called akathisia. Irregular heartbeat. Tetrabenazine tablets increase your chance of having certain changes in the electrical activity in your heart which can be seen on an electrocardiogram (EKG). These changes can lead to a dangerous abnormal heartbeat. Taking tetrabenazine tablets with certain medicines may increase this chance. Dizziness due to blood pressure changes when you change position (orthostatic hypotension). Change positions slowly from lying down to sitting up and from sitting up to standing when taking tetrabenazine tablets. Tell your doctor right away if you get dizzy or faint while taking tetrabenazine tablets. Your doctor may need to watch your blood pressure closely. Common side effects with tetrabenazine tablets include: sleepiness (sedation) trouble sleeping depression tiredness (fatigue) anxiety restlessness agitation nausea Tell your doctor if you have any side effects. Do not stop taking tetrabenazine tablets without talking to your doctor first. Call your doctor for medical advice about side effects. You may report side effects to the Food and Drug Administration (FDA) at 1–800–FDA-1088. General information about tetrabenazine tablets Tetrabenazine tablets contain the active ingredient tetrabenazine. It also contains these inactive ingredients: anhydrous lactose, corn starch, sodium starch glycolate Type A potato, ferric oxide yellow (for 25 mg), colloidal silicon dioxide, magnesium stearate and talc. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use tetrabenazine tablets for a condition for which it was not prescribed. Do not give tetrabenazine tablets to other people, even if they have the same symptoms that you have. It may harm them. Keep tetrabenazine tablets out of the reach of children. This Medication Guide summarizes the most important information about tetrabenazine tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about tetraben...
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-12.5 mg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-277-23 Tetrabenazine Tablets 12.5 mg PHARMACIST: Dispense with Medication Guide to each patient. Rx only 112 Tablets SUN PHARMA
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 25 mg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-179-23 Tetrabenazine Tablets 25 mg PHARMACIST: Dispense with Medication Guide to each patient. Rx only 112 Tablets SUN PHARMA