Apo-Tetrabenazine Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

The central effects of APO-TETRABENAZINE closely resemble those of reserpine, but it differs from the latter in having less peripheral activity and in being much shorter acting. In laboratory animals, tetrabenazine interferes with vesicular storage of biogenic amines, including dopamine as well as serotonin and noradrenaline; this effect is mainly limited to the brain. Dihydrotetrabenazine (HTBZ) is believed to be the principle active moiety, and it is thought that its clinical activity in movement disorders results from its action on monoamine storage in the brain. The duration of action of tetrabenazine ranges from 16 to 24 hours.

Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α -HTBZ and β -HTBZ. These major circulating tetrabenazine metabolites in humans, exhibit high in-vitro binding affinity to bovine VMAT2.

Tetrabenazine also has dopamine antagonistic effects, such as displacing ³H-spiperone from striatal binding sites in vitro and blocking dopaminergic inhibition of prolactin release in vitro and in vivo.

Pharmacokinetics

Tetrabenazine has low and erratic bioavailability. It is extensively metabolized by first-pass metabolism. Little to no unchanged tetrabenazine can be detected in the urine. The major metabolite, dihydrotetrabenazine (HTBZ, a mixture of α -HTBZ and β -HTBZ), is formed by reduction of the C2 ketone group in tetrabenazine. α -HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2. β -HTBZ is O-dealkylated principally by CYP2D6. Following intravenous administration of radiolabeled tetrabenazine to humans, the radioactivity decreased to minimal levels within 10 hours and could not be detected three days later. Forty percent (40%) of total radioactivity was found in the urine within 24 hours and 2.5% in the feces. Fifty four percent (54%) of the total radioactivity was excreted after 48 hours.

INDICATIONS AND CLINICAL USE

APO-TETRABENAZINE has been found useful in the treatment of hyperkinetic movement disorders such as Huntington’s chorea, hemiballismus, senile chorea, tic and Gille’s de la Tourette’s syndrome and tardive dyskinesia.

Tetrabenazine is not indicated for the treatment of levodopa-induced dyskinetic/choreiform movements (see WARNINGS).

Tetrabenazine should only be used by (or in consultation with) physicians who are experienced in the treatment of hyperkinetic movement disorders.

CONTRAINDICATIONS

APO-TETRABENAZINE is contraindicated:

• in patients with a known hypersensitivity to the drug or to any of the components of the formulation (see PRECAUTIONS, General; PHARMACEUTICAL INFORMATION, Composition).
• in patients who are actively suicidal, or in patients with currently untreated or inadequately treated episodes of clinical depression (see WARNINGS).
• in patients with a history of depression, including those with a current episode of depression being satisfactorily treated, APO-TETRABENAZINE should not be used unless the patient is under the care of a supervising psychiatrist experienced with the patient’s disorder and tetrabenazine’s pharmacology
• in patients taking a monoamine oxidase inhibitor (MAOI). At least 14 days should elapse between the discontinuation of an MAOI and initiation of treatment with APO-TETRABENAZINE, as well as between the discontinuation of APO-TETRABENAZINE and the initiation of treatment with an MAOI (see DRUG INTERACTIONS).
• in patients with impaired hepatic function.
• in patients taking reserpine (see DRUG INTERACTIONS). At least 20 days should elapse after stopping reserpine before starting APO-TETRABENAZINE.

WARNINGS

Depression and Suicidality

APO-TETRABENAZINE (tetrabenazine) can increase the risk of depression and suicidal thoughts and behavior (suicidality). When considering the use of NITOMAN the risks of depression and suicidality must be balanced with the clinical need for treatment. 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. APO-TETRABENAZINE is contraindicated in patients who are actively suicidal, in patients with currently untreated or inadequately treated depression. APO-TETRABENAZINE is also contraindicated in patients with a history of depression, including those with a current episode of depression being satisfactorily treated, unless the patient is under the care of a supervising psychiatrist experienced with the patient’s disorder and tetrabenazine’s pharmacology (see CONTRAINDICATIONS).

Depression, suicidal ideation and suicidal behaviors (suicidality) are known to occur in patients with Huntington’s disease. 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 tetrabenazine were reported to have an adverse event of depression or worsening depression compared to none of the 30 patients that received placebo. In two open-label studies patients were treated with tetrabenazine for up to 48 weeks or up to 80 weeks (n=45 treated up to 80 weeks), the rate of depression/worsening depression was 35%. In all of the patients with chorea associated with Huntington’s disease (n=187), one patient died by suicide, one patient attempted suicide, and six patients had suicidal ideation.

When considering the use of APO-TETRABENAZINE, the potential for an increase in risk of depression, worsening depression and suicidality should be balanced against the need for treatment. All patients treated with APO-TETRABENAZINE for hyperkinetic movement disorders should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with APO-TETRABENAZINE. There is no information on the safety or efficacy of antidepressant drug treatment in tetrabenazine-induced depression.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with APO-TETRABENAZINE, and should be instructed to report behaviors of concern promptly to the treating physician. Patients who express suicidal ideation should be evaluated immediately.

CYP2D6 Metabolizer Status

In vitro and in vivo studies indicate that the major active metabolites of tetrabenazine, α-HTBZ and β-HTBZ, are substrates for CYP2D6. The pharmacokinetics of tetrabenazine and its metabolites in subjects who do not express the drug metabolizing enzyme CYP2D6 (poor metabolizers) have not been systematically evaluated, but exposure to α-HTBZ and β-HTBZ is expected to be increased compared to subjects who express the enzyme (extensive metabolizers). Exposure (AUC) in CYP2D6 poor metabolizers is expected to be similar to exposure in patients taking strong CYP2D6 inhibitors, with increases of approximately 3.4-fold for α-HTBZ and 9.6-fold for β-HTBZ, respectively (see DRUG INTERACTIONS). Therefore, dosing requirements may be influenced by a patient’s CYP2D6 metabolizer status and use of concomitant medications which are strong CYP2D6 inhibitors.

For all patients the initial dose should be low, and dosage should be titrated slowly according to the tolerance and responsiveness of the individual patient. Treatment should be reassessed periodically in the context of the patient’s underlying condition and their concomitant medications. (see DOSAGE AND ADMINISTRATION).

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, 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 not known.

Prescribers should periodically re-evaluate the need for APO-TETRABENAZINE by assessing the effect on chorea and possible adverse effects, including depression and suicidality, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness, and disability.

Parkinsonism

APO-TETRABENAZINE can induce symptoms of parkinsonism, which are seen more frequently in the elderly and at relatively low doses. If a patient develops parkinsonism during treatment with APO-TETRABENAZINE, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary. Levodopa-induced dyskinetic/choreiform movements should be treated by reducing the dose of levodopa, and not by giving APO-TETRABENAZINE, since the latter exacerbates parkinsonian symptoms.

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS) is a rare and potentially fatal symptom complex that has been reported in association with drugs that reduce dopaminergic transmission, including tetrabenazine. 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 diagnostic evaluation of patients with this syndrome is complicated. In arriving at the diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). 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 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.

If the patient requires treatment with tetrabenazine after recovery from NMS, reintroduction of therapy should be carefully considered, and slow titration initiated if required. The patient should be carefully monitored, since recurrences of NMS have been reported with reintroduction of treatment.

Akathisia, Restlessness, and Agitation

APO-TETRABENAZINE may increase the risk of akathisia, restlessness an agitation.

In a 12-week, double blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine-treated patients and 0% of placebo-treated patients. In an 80-week open label study, akathisia was observed in 20% of tetrabenazine-treated patients. Akathisia was not observed in a 48-week open-label study. Patients receiving APO-TETRABENAZINE should be monitored for the presence of akathisia.

Patients receiving APO-TETRABENAZINE 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 APO-TETRABENAZINE dose should be reduced; however, some patients may require discontinuation of therapy.

Sedation and Somnolence

Sedation is the most common dose-limiting adverse event of APO-TETRABENAZINE. Patients should not perform activities that require them to be alert such as driving a car or operating hazardous machinery, until they are on a maintenance dose of APO-TETRABENAZINE and know how the drug affects them.

Special Populations

Hepatic Impairment

In patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ, and Cmax for tetrabenazine increased 7- to 190-fold compared with detectable peak concentrations in subjects with normal liver function. An increase in Tmax and elimination half-lives for α-HTBZ and β-HTBZ was observed in patients with hepatic impairment. The exposure to α -HTBZ and β -HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. Because the safety and efficacy of the increased exposure to tetrabenazine and other circulating metabolites are unknown, it is not possible to adjust the dosage of NITOMAN in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment (see CONTRAINDICATIONS).

CYP2D6 Poor Metabolizers

See WARNINGS, CYP2D6 Metabolizer Status; DOSAGE AND ADMINISTRATION, Special Populations.

Pregnant Women

There are no adequate and well-controlled studies of the use of tetrabenazine in pregnant women to inform the drug-associated risk of adverse developmental outcomes. Studies in animals have shown reproductive toxicity of tetrabenazine and a major human metabolite of tetrabenazine at clinically relevant doses. The potential risk for humans is unknown. Therefore, APO-TETRABENAZINE is not recommended during pregnancy and in women of childbearing potential not using contraception.

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). Oral administration of a major human metabolite of tetrabenazine, 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day), to pregnant rats throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. 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).

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. With oral administration of 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) to female rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. The no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (AUC) of 9-desmethyl-β-DHTBZ in pregnant rats lower than that in humans at the MRHD.

Breastfeeding

Limited information indicates that APO-TETRABENAZINE is excreted in milk. Therefore, the use of APO-TETRABENAZINE in breast-feeding mothers should be avoided.

Pediatrics (< 18 years of age)

See DOSAGE AND ADMINISTRATION.

Geriatrics (> 65 years of age)

The pharmacokinetics of tetrabenazine and its primary metabolites have not been systematically evaluated in geriatric subjects (see DOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

APO-TETRABENAZINE contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine (see CONTRAINDICATIONS; PHARMACEUTICAL INFORMATION, Composition).

QT Prolongation

In a randomized, placebo-controlled cross-over trial in healthy adult volunteers (n=51), the maximum time-matched, placebo-corrected increase in individually corrected QT (QTcI) following a single 50 mg oral tetrabenazine dose was 7.7 msec (90% CI 5.0-10.4), and 12.5 msec (90% CI 9.7-15.3) following a 400 mg moxifloxacin dose. The effect of tetrabenazine on the QTc interval under conditions of maximum exposure, e.g. in the presence of strong CYP2D6 inhibitors (see DRUG INTERACTIONS), has not been evaluated in a thorough QT study.

Many drugs that cause QT/QTc prolongation have led to an increased risk of ventricular arrhythmias including torsade de pointes. Generally, the risk of torsade de pointes increases with the magnitude of QT/QTc prolongation produced by the drug.

APO-TETRABENAZINE should be avoided in patients at increased risk of experiencing arrhythmic events, such as patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome, in patients with electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) or conditions leading to electrolyte disturbances (e.g., persistent vomiting, eating disorders), and in patients with bradycardia. Concomitant use with drugs known to prolong the QT interval, including but not restricted to antipsychotic medications (e.g., chlorpromazine, thioridazine, haloperidol, ziprasidone), antibiotics (e.g., moxifloxacin), Class IA (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications should be avoided (see DRUG INTERACTIONS).

Orthostatic Hypotension

Treatment emergent postural dizziness and syncope have been reported with tetrabenazine at therapeutic doses and can be symptoms of orthostatic hypotension. In healthy subjects that received single doses of 25 mg or 50 mg tetrabenazine, postural dizziness adverse events were very common and were reported within 1.5 to 4 hours after dosing. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease treatment emergent dizziness was reported in 4% of patients treated with tetrabenazine compared to none on placebo, but blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered for patients who may be at risk of hypotension.

Dysphagia

Dysphagia is a characteristic of Huntington’s Chorea. 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 and a 48-week follow-on open-label extension in patients with chorea associated with Huntington’s disease, dysphagia was observed in ≤ 3% of tetrabenazine-treated patients. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown. APO-TETRABENAZINE and other drugs that reduce dopaminergic transmission should be used with caution in patients at risk for aspiration pneumonia.

Hyperprolactinemia

Administration of a single 12.5 mg dose of tetrabenazine in healthy volunteers resulted in a statistically significant increase of 4- to 5-fold in serum prolactin concentrations. 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 (not evaluated in the tetrabenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If symptomatic hyperprolactinemia is suspected, appropriate laboratory testing should be done, and consideration should be given to discontinuation of tetrabenazine.

Since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in-vitro, tetrabenazine should be administered to patients with previously detected breast cancer only if the benefit outweighs the risk. Caution should be exercised when considering tetrabenazine treatment in patients with pituitary tumors.

Binding to Melanin-Containing Tissues

Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. Chronic toxicity studies in a pigmented species, such as dogs, did not include ophthalmologic or microscopic examination of the eye. There are insufficient data from monitoring in humans to exclude ophthalmic toxicity during long-term exposure.

The clinical relevance of tetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmic monitoring, prescribers should be aware of the possibility of ophthalmologic effects after long-term exposure.

DRUG INTERACTIONS

CYP2D6 Inhibitors

In vitro and in vivo studies indicate that the major active metabolites of tetrabenazine 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 the day prior to, and following, 8 days of administration of 20 mg daily of the strong CYP2D6 inhibitor paroxetine. There was an approximately 45% increase in C_max and an approximately 3.4-fold increase in AUC_0-∞ for α-HTBZ in subjects given paroxetine and tetrabenazine, compared to tetrabenazine alone. For β-HTBZ, the C_max and AUC_0-∞ were increased 2.7 and 9.6-fold respectively, in subjects given paroxetine and tetrabenazine, compared to tetrabenazine alone. The elimination half-life of α-HTBZ and β-HTBZ was approximately a mean of 14 hours when tetrabenazine was given with paroxetine, compared to means of 7 hours and 5 hours for α-HTBZ and β-HTBZ with tetrabenazine alone.

Caution should be used when adding a CYP2D6 inhibitor (such as fluoxetine, paroxetine, quinidine, duloxetine, terbinafine, amiodarone, or sertraline) to a patient already receiving a stable dose of tetrabenazine and a reduction in the dose of tetrabenazine may be needed (see DOSAGE AND ADMINISTRATION, Special Populations)

The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the pharmacokinetics of tetrabenazine has not been evaluated.

Levodopa

Tetrabenazine exacerbates Parkinsonian symptoms, and thereby attenuates the effect of levodopa (see WARNINGS, Parkinsonism).

Monoamine Oxidase Inhibitors (MAOIs) and Antidepressants

APO-TETRABENAZINE is contraindicated in patients taking MAOIs. APO-TETRABENAZINE should not be used in combination with an MAOI due to the risk of hypertensive crisis. At least 14 days should elapse between discontinuing therapy with an MAOI and initiation of treatment with APO-TETRABENAZINE, as well as between the discontinuation of APO-TETRABENAZINE and the initiation of treatment with an MAOI (see CONTRAINDICATIONS).

Central excitation and possibly hypertension have occurred when tetrabenazine was added to existing therapy with desipramine or MAOIs.

There is no information on the safety and efficacy of antidepressant drugs, including MAOIs, in the treatment of tetrabenazine-induced depression (see CONTRAINDICATIONS).

Neuroleptic Agents

The risk of neuroleptic malignant syndrome and extrapyramidal disorders (e.g., parkinsonism, akathisia) may be increased, when administering APO-TETRABENZINE concomitantly with dopamine antagonists or antipsychotics (e.g. haloperidol, chlorpromazine, metoclopramide, olanzapine, risperidone, etc.). Neuroleptic malignant syndrome has been observed in isolated cases in patients treated with APO-TETRABENAZINE (see WARNINGS: Parkinsonism; Neuroleptic Malignant Syndrome, Akathisia, Restless and Agitation).

Alcohol or Other CNS Sedating Drugs

Patients should be advised that the concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Reserpine

Concomitant use of tetrabenazine and reserpine is contraindicated. Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Caution should therefore be used when switching a patient from reserpine to APO-TETRABENAZINE. At least 20 days should elapse after stopping reserpine before starting APO-TETRABENAZINE(see CONTRAINDICATIONS).

Anti-arrhythmic Drugs and Other QTc-Prolonging Drugs

APO-TETRABENAZINE prolongs the QTc interval by approximately 8 msec (see PRECAUTIONS, QT interval). Because of the potential for additive effects on QTc interval prolongation, the concomitant use of APO-TETRABENAZINE with Class Ia (e.g., disopyramide, procainamide, quinidine) or Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs and other drugs that are associated with QTc interval prolongation should be avoided.

Chemical/pharmacological classes in which some, although not necessarily all, class members have been implicated in QTc prolongation and/or torsade de pointes include: Class 1c antiarrhythmics (e.g., flecainide, propafenone); antipsychotics (e.g., chlorpromazine, haloperidol); antidepressants (e.g., fluoxetine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline); opioids (e.g., methadone); macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, tacrolimus); quinolone antibiotics (e.g., moxifloxacin, ciprofloxacin); antimalarials (e.g., quinine, chloroquine); azole antifungals (e.g., ketoconazole); domperidone; 5-HT3 receptor antagonists (e.g., ondansetron); kinase inhibitors (e.g., sunitinib); histone deacetylase inhibitors (e.g., vorinostat); beta-2 adrenoceptor agonists (e.g., salmeterol).

Antihypertensive Drugs and Beta-Blockers

The concomitant use of APO-TETRABENAZINE with antihypertensive drugs and beta-blockers may increase the risk of orthostatic hypotension (see PRECAUTIONS, Orthostatic Hypotension).

ADVERSE REACTIONS

Although tetrabenazine has been in clinical use for a number of years, controlled clinical trials with the drug are limited. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease dose escalation was discontinued or dosage of study drug was reduced in 28 of 54 patients randomized to tetrabenazine because of one or more of the following adverse events (listed in decreasing order of frequency): sedation, akathisia, parkinsonism, depression, anxiety, fatigue and diarrhea.

Clinical Trial Adverse Reactions

The most commonly observed adverse reactions with tetrabenazine during clinical use of the drug include (in decreasing order of frequency):

• Drowsiness, weakness (sedation /somnolence)
• Fatigue
• Insomnia
• Irritability
• Dizziness
• Depression
• Restlessness, akathisia
• Anxiety/anxiety aggravated
• Nausea, vomiting, epigastric pain
• Signs and symptoms of parkinsonism

Post-Market Adverse Reactions

• Tremor
• Worsening aggression
• Pneumonia
• Hyperhidrosis
• Skin rash
• Drooling
• Agitation
• Confusion, disorientation
• Hypotension
• Weight increased
• Increased appetite

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms

Signs and symptoms of overdosage may include sweating and hypotension. Also reported were: acute dystonia, oculogyric crisis, nausea and vomiting, sedation, confusion, diarrhea, hallucinations, rubor and tremor. Overdose of APO-TETRABENAZINE may cause an increase in incidence and/or severity of the adverse reactions reported at therapeutic doses.

Management and Treatment

Treatment should consist of 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

DOSAGE AND ADMINISTRATION

General

The initial dose should be low, and dosage should be titrated slowly according to the tolerance and responsiveness of the individual patient. Once a stable dose has been achieved, treatment should be reassessed periodically in the context of the patient’s underlying condition and their concomitant medications.

Adults

For most patients, an initial starting dose of 12.5 mg (half a tablet) two to three times a day is recommended. This can be increased slowly by 12.5 mg a day at weekly intervals, until the maximal tolerated and effective dose is reached for the individual and may have to be up/down titrated depending on individual tolerance (see ADVERSE REACTIONS). For some patients, a slower titration may be more appropriate (see Special Populations, CYP2D6 Poor Metabolizers, and Geriatrics below). In most cases the maximal tolerated dose will be 25 mg t.i.d. In very rare cases, a 200 mg dose has been reached (the maximum recommended dose in some publications).

If there is no improvement at the maximal tolerated dose in seven days, it is unlikely that APO-TETRABENAZINE will be of benefit to the patient, either by increasing the dose or by extending the duration of treatment.

Re-initiation of APO-TETRABENAZINE After Treatment Interruption

Following treatment interruption of greater than five days, APO-TETRABENAZINE should be re-titrated when resumed. For short-term treatment interruption of less than five days, NITOMAN can be resumed at the previous maintenance dose without titration.

Special Populations

Hepatic Impairment

The use of APO-TETRABENAZINE in patients with liver disease is contraindicated (see CONTRAINDICATIONS and WARNINGS, Special Populations).

CYP2D6 Poor Metabolizer

Although the pharmacokinetics of tetrabenazine and its metabolites in subjects who do not express the drug metabolizing enzyme CYP2D6 (poor metabolizers) have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased compared to subjects who express the enzyme (extensive metabolizers), with AUC_0-∞ increases similar to those observed in patients taking strong CYP2D6 inhibitors (approximately 3.4-and 9.6-fold, respectively; see DRUG INTERACTIONS). Caution in dosing should be exercised (see WARNINGS, CYP2D6 Metabolizer Status).

Geriatrics (> 65 years of age)

The pharmacokinetics of tetrabenazine and its primary metabolites have not been systematically evaluated in geriatric subjects. Clinical experience suggests that a reduced initial and maintenance dose should be used. Parkinsonian-like adverse reactions are relatively common in geriatric and debilitated patients and may be dose-limiting.

Pediatrics (< 18 years of age)

No adequately controlled clinical studies have been performed in children. Limited clinical experience suggests that treatment should be started at approximately half the adult dose and titrated slowly and carefully according to tolerance and individual response.

PART II: PHARMACEUTICAL INFORMATION

I. Drug Substance

Proper Name: tetrabenazine

Chemical Name: (3RS,11bRS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a] isoquinolin-2-one

Structural Formula:

N

O

O

O

CH₃

CH₃

CH₃

CH₃

H

H

and enantiomer

Molecular Formula: C₁₉H₂₇NO₃

Molecular Weight: 317.42 g/mol

Description: White to almost white crystalline powder

II. Composition: Each APO-TETRABENAZINE tablet contains 25 mg tetrabenazine, anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and yellow ferric oxide.

III. Stability and Storage

Recommendations: APO-TETRABENAZINE tablets should be stored at controlled room temperature, 15-30°C (59-86°F) in a tightly closed container. AVAILABILITY OF DOSAGE FORMS

Yellow, round, flat-faced, beveled edge tablet. Engraved “APO” over “25” on one side, single scored on the other side, containing 25 mg tetrabenazine. Bottles of 100 tablets.

PLEASE NOTE : THIS PRODUCT MONOGRAPH DOES NOT CONTAIN TOXICOLOGY INFORMATION.

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, single dose, double-blinded, 2-way crossover comparative bioavailability study was conducted under fasting conditions in 39 healthy male volunteers. The rate and extent of absorption of tetrabenazine following a single oral dose (1 x 25 mg tablet) of Apo- Tetrabenazine was compared with Nitoman^® Tablets (tetrabenazine). The results from measured data are summarized in the following table:

Table 1

REFERENCES

1. 1)

   Asher, SW, Aminoff, MJ. Tetrabenazine and movement disorders. Neurology 1981;

   31:1051-4.

2. 2) Jankovic, J. Treatment of hyperkinetic movement disorders with tetrabenazine: A double-blind crossover study. Ann Neurol 1982; 11(1):41-7.
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