Xenazine (tetrabenazine)

No dosing information is available for this tab.

Tetrabenazine tablets are administered orally without regard to food. If a dose of tetrabenazine is missed, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.

Store tetrabenazine tablets at 25degreesC; excursions permitted between 15-30degreesC.

Tetrabenazine and its alpha-dihydrotetrabenazine (alpha-HTBZ), beta-dihydrotetrabenazine (beta-HTBZ), and 9-desmethyl-beta-dihydrotetrabenazine (DHTBZ) metabolites do not substantially inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor do they substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. Neither tetrabenazine nor its alpha-HTBZ, beta-HTBZ, or 9-desmethyl-beta-DHTBZ metabolites are likely to be substrates or inhibitors of P-glycoprotein (P-gp) at clinically relevant concentrations in vivo.

Tetrabenazine's active metabolites alpha-HTBZ and beta-HTBZ are substrates of CYP2D6.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Deutetrabenazine; Tetrabenazine/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of deutetrabenazine or tetrabenazine with an MAOI may result in restlessness, disorientation, and confusion.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of deutetrabenazine or tetrabenazine with a MAOI is contraindicated.(1-3) A two-week washout period should elapse between discontinuing a MAOI and the initiation of deutetrabenazine or tetrabenazine.(1-3)

DISCUSSION: Because concurrent use of deutetrabenazine or tetrabenazine with an MAOI may result in restlessness, disorientation, and confusion, tetrabenazine should not be given after a course of any of the MAOI's.(1-3) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4,5) Metaxalone is a weak inhibitor of MAO.(6,7)

Deutetrabenazine; Tetrabenazine/Reserpine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Deutetrabenazine and tetrabenazine reversibly inhibit human vesicular monoamine transporter type 2 (VMAT2). Reserpine irreversibly binds to VMAT2.(1,2)

CLINICAL EFFECTS: Concurrent use of deutetrabenazine or tetrabenazine and reserpine may result in overdosage and major depletion of serotonin and norepinephrine in the central nervous system.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of deutetrabenazine(1) and tetrabenazine(2) states that concurrent use of reserpine is contraindicated. Switching patients from reserpine to deutetrabenazine or tetrabenazine should be done with caution and at least 20 days should elapse after discontinuing reserpine before initiating deutetrabenazine or tetrabenazine. Chorea should re-emerge before initiating deutetrabenazine or tetrabenazine.(1,2) The Australian manufacturer of tetrabenazine states under contraindications that tetrabenazine should not be given closer than one day before or in combination with reserpine.(3)

DISCUSSION: Deutetrabenazine and tetrabenazine reversibly inhibit human vesicular monoamine transporter type 2 (VMAT2). Reserpine irreversibly binds to VMAT2. Concurrent use of deutetrabenazine or tetrabenazine and reserpine may result in overdosage and major depletion of serotonin and norepinephrine in the central nervous system.(1,2)

Selected Cyp2d6 Substrates/Mavorixafor

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Deutetrabenazine; Tetrabenazine/Foslevodopa; Levodopa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Deutetrabenazine and tetrabenazine antagonize the action of levodopa by inhibiting monoamine reuptake in the presynaptic terminals, thereby depleting dopamine in the central nervous system.(1-4) Foslevodopa is a prodrug of levodopa.(5)

CLINICAL EFFECTS: Concurrent administration with deutetrabenazine or tetrabenazine may result in decreased effectiveness of levodopa.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of levodopa with tetrabenazine or deutetrabenazine vary in different regions. The Australian manufacturer of tetrabenazine states that concurrent use of levodopa is contraindicated. Levodopa should not be used concurrently with or within one day of discontinuing tetrabenazine.(1) The Australian and UK manufacturers of tetrabenazine state that tetrabenazine is contraindicated in patients with Parkinson's Disease.(1,2) Patients with levodopa-induced dyskinetic or choreiform movements should have their levodopa dose reduced rather than start concurrent therapy with tetrabenazine or deutetrabenazine.(3) If concurrent use is necessary, monitor patients for symptoms of parkinsonism. A dose reduction or discontinuation of tetrabenazine or deutetrabenazine may be required.(2-4)

DISCUSSION: Deutetrabenazine and tetrabenazine can antagonize the effect of levodopa.(1-4) Most manufacturers either recommend against concurrent use(2,3) or state that concurrent use is contraindicated.(4) The combination has been used in the treatment of levodopa-induced peak dose dyskinesias.(6)

Selected Cyp1a2 Or Cyp2d6 Substrates/Givosiran

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Givosiran interferes with the first and rate-limiting step in hepatic heme biosynthesis, which may lower hepatic heme levels and decrease production and/or activity of cytochrome P450 enzymes.(1,2)

CLINICAL EFFECTS: Concurrent use of givosiran may result in elevated levels of and toxicity from agents metabolized by CYP1A2 or CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Avoid the concurrent use of givosiran with agents that are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is unavoidable, decrease the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for toxicity.

DISCUSSION: A study of 9 patients with acute intermittent porphyria found that givosiran decreased the maximum concentration (Cmax) and area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and 3.1-fold, respectively, compared to caffeine alone. Givosiran also decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2- and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine. Selected CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine, and yohimbine.

Selected Cyp2d6 Substrates/Panobinostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Panobinostat is a moderate inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of panobinostat may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: Avoid the concurrent use of panobinostat with agents that are sensitive CYP2D6 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is warranted, monitor patients for toxicity.(1)

DISCUSSION: In a study in 14 subjects with advanced cancer, panobinostat (20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by 20-200% and 20-130%, respectively. Dextromethorphan exposures were extremely variable.(1) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Deutetrabenazine;Tetrabenazine/Quinidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: After ingestion, tetrabenazine is rapidly converted to the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and beta-HTBZ). Both alpha and beta-HTBZ are metabolized by CYP2D6. Strong inhibitors of CYP2D6, such as quinidine, may inhibit the metabolism of tetrabenazine active metabolites.(1) Deutetrabenazine is a deuterated form of tetrabenazine.(2)

CLINICAL EFFECTS: Concurrent use of a strong CYP2D6 inhibitor, such as quinidine, may result in increased levels of and adverse effects from deutetrabenazine(2) or tetrabenazine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of deutetrabenazine when administered with quinidine is 36 mg daily (given as 18 mg twice daily).(2) The maximum recommended dose of tetrabenazine when administered with quinidine is 50 mg daily (given as 25 mg twice daily).(1) Monitor patients receiving concurrent therapy for adverse effects, including depression, suicidal thoughts, stiff muscles, trouble swallowing, irritability or agitation, shaking, and restlessness. If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or tetrabenazine may need adjustment.

DISCUSSION: In a study in 24 healthy subjects, following the administration of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively. The area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and 6.5-fold, respectively.(2) In a study in 25 healthy subjects, following the administration of a single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold, respectively. The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and 9-fold, respectively.(1)

Deutetrabenazine;Tetrabenazine/Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: After ingestion, tetrabenazine is rapidly to converted the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and beta-HTBZ). Both alpha and beta-HTBZ are metabolized by CYP2D6. Strong inhibitors of CYP2D6 may inhibit the metabolism of tetrabenazine active metabolites.(1) Deutetrabenazine is a deuterated form of tetrabenazine.(2)

CLINICAL EFFECTS: Concurrent use of a strong CYP2D6 inhibitor may result in increased levels of and adverse effects from deutetrabenazine(2) or tetrabenazine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of deutetrabenazine when administered with a strong inhibitor of CYP2D6 is 36 mg daily (tablets: given as 18 mg twice daily; or extended-release tablets: given as 36 mg daily).(2,3) The maximum recommended dose of tetrabenazine when administered with a strong inhibitor of CYP2D6 is 50 mg daily (given as 25 mg twice daily).(1) Monitor patients receiving concurrent deutetrabenazine or tetrabenazine and a strong CYP2D6 inhibitor for adverse effects, including depression, suicidal thoughts, stiff muscles, trouble swallowing, irritability or agitation, shaking, and restlessness. If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or tetrabenazine may need adjustment.

DISCUSSION: In a study in 24 healthy subjects, following the administration of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively. The area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and 6.5-fold, respectively.(2) In a study in 25 healthy subjects, following the administration of a single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold, respectively. The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and 9-fold, respectively.(1) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(1-4)

Patients who are actively suicidal or patients with untreated or inadequately treated depression.

Hepatic impairment.

Concomitant therapy with a monoamine oxidase (MAO) inhibitor. At least 14 days should elapse between discontinuance of an MAO inhibitor and initiation of tetrabenazine.

Concomitant therapy with reserpine. At least 20 days should elapse between discontinuance of reserpine and initiation of tetrabenazine therapy.

Concomitant therapy with deutetrabenazine or valbenazine.

• Disease of liver
• Neuroleptic malignant syndrome
• Parkinsonism

• Akathisia
• CYp2d6 poor metabolizer
• Depression
• Suicidal ideation
• Torsades de pointes

• Dysphagia
• Hyperprolactinemia
• Hypotension
• Orthostatic hypotension

Adverse effects reported in >=5%of patients with Huntington's chorea receiving tetrabenazine and at an incidence greater than that reported with placebo include sedation or somnolence, insomnia, fatigue, depression, anxiety, irritability, balance difficulties, extrapyramidal adverse effects (e.g., akathisia, bradykinesia, parkinsonism, hypertonia), nausea, vomiting, ecchymosis, falls, laceration of the head, and upper respiratory tract infection.

More Frequent

• Akathisia
• Extrapyramidal disease
• Parkinsonism

Less Frequent

• Agitation
• Dyspnea

Rare or Very Rare

• Neuroleptic malignant syndrome
• Pneumonia
• Suicidal ideation

More Frequent

• Depression
• Drowsy
• Fatigue
• Insomnia
• Nausea
• Sedation
• Symptoms of anxiety

Less Frequent

• Anorexia
• Bronchitis
• Dizziness
• Dysarthria
• Dysphagia
• Dysuria
• Ecchymosis
• Headache disorder
• Irritability
• Nervousness
• Orthostatic hypotension
• Unsteady gait
• Upper respiratory infection
• Vomiting

Rare or Very Rare

• Acute cognitive impairment
• Aggressive behavior
• Hyperhidrosis
• Hyperprolactinemia
• Skin rash
• Tremor

No enhanced messaging available.

The manufacturer states that safety and efficacy of tetrabenazine have not been established in pediatric patients.

Although controlled clinical trials have not been conducted to date, tetrabenazine has been effective in a limited number of pediatric patients with hyperkinetic movement disorders, including Tourette syndrome+ and severe chorea+. Limited experience suggests that the drug may have a similar adverse effect profile in pediatric patients as in adults, possibly with fewer parkinsonian adverse effects.

May cause fetal harm based on animal studies. There are no adequate and well-controlled studies of tetrabenazine in pregnant women. Reproduction studies in animals revealed no clear effects on embryofetal development when tetrabenazine was administered orally during the period of organogenesis at dosages up to 3 and 12 times the maximum recommended human dosage in rats and rabbits, respectively. However, when the drug was administered to rats during pregnancy and lactation, increased stillbirths, reduced pup survival, and delayed pup maturation were observed. Rats dosed orally with tetrabenazine do not produce 9-desmethyl-beta-dihydrotetrabenazine (DHTBZ), a major human metabolite of the drug. Oral administration of 9-desmethyl-beta-DHTBZ to rats at clinically relevant doses during the period of organogenesis or throughout pregnancy and lactation increased embryofetal and offspring postnatal mortality, decreased growth, and produced neurobehavioral and reproductive impairment in offspring. Maternal toxicity was also observed.

It is not known whether tetrabenazine or its metabolites distribute into milk; one study suggests that the drug does distribute into human milk. The effects of tetrabenazine on breastfed infants or on the production of milk are unknown. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for tetrabenazine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

The manufacturer provides no specific dosage recommendations for tetrabenazine in geriatric patients.

Pharmacokinetics of tetrabenazine and its principal metabolites have not been evaluated in geriatric individuals.