Austedo (deutetrabenazine)

Dosage of deutetrabenazine should be individualized based on efficacy (i.e., reduction of chorea or tardive dyskinesia) and tolerability.

Deutetrabenazine immediate-release tablets should be administered orally with food. Extended-release deutetrabenazine tablets are administered orally with or without food. Both immediate- and extended-release tablets should be swallowed whole and not chewed, crushed, or broken.

Total daily dosages of the immediate-release tablets less than 12 mg are administered once daily; total daily dosages of 12 mg or higher should be administered in 2 divided doses.

Store deutetrabenazine immediate- and extended-release tablets at 25degreesC; excursions permitted between 15-30degreesC. Protect from light and moisture.

No dosing information is available for this tab.

Drug interaction studies evaluating the effect of deutetrabenazine or its active metabolites (deuterated alpha-dihydrotetrabenazine (deuterated alpha-HTBZ) and deuterated beta-dihydrotetrabenazine (deuterated beta-HTBZ)) on cytochrome P-450 (CYP) isoenzymes or P-glycoprotein (P-gp) have not been conducted to date. In vitro studies indicate that other metabolites of deutetrabenazine (M1 and M4) are not expected to cause clinically important drug interactions.

Tetrabenazine, a closely related VMAT2 inhibitor, and its active metabolites (alpha-HTBZ and beta-HTBZ) do not substantially inhibit 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 active metabolites are likely to be substrates or inhibitors of P-gp at clinically relevant concentrations.

Deutetrabenazine's active metabolites (deuterated alpha-HTBZ and deuterated 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/Desvenlafaxine (>100 Mg)

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

MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

PREDISPOSING FACTORS: With perphenazine and tolterodine, 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: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) The manufacturer of desvenlafaxine does not provide recommendations for use of desvenlafaxine at dosages between 100-400 mg concurrently with CYP2D6 substrates. Monitor for toxicity of the CYP2D6 substrate and consider reducing its dosage.

DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, 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)

Selected Cyp2d6 Substrates/Desvenlafaxine

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

MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

PREDISPOSING FACTORS: With perphenazine and tolterodine, 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: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) The manufacturer of desvenlafaxine does not provide recommendations for use of desvenlafaxine at dosages between 100-400 mg concurrently with CYP2D6 substrates. Monitor for toxicity of the CYP2D6 substrate and consider reducing its dosage.

DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

*Patients with Huntington's disease who are suicidal or have untreated or inadequately treated depression.

*Hepatic impairment.

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

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

*Concomitant therapy with tetrabenazine or valbenazine.

• Neuroleptic malignant syndrome
• Parkinsonism
• Suicidal ideation

• Akathisia
• CYp2d6 poor metabolizer
• Depression

There are no moderate contraindications for this drug.

Adverse effects occurring in patients with Huntington's disease with an incidence >8% and more than placebo include: somnolence, diarrhea, dry mouth, and fatigue.

Adverse effects occurring in patients with tardive dyskinesia with an incidence of 4% and more than placebo include: nasopharyngitis and insomnia.

Less Frequent

• Akathisia
• Suicidal ideation

Rare or Very Rare

• Parkinsonism
• Suicidal

More Frequent

• Diarrhea
• Drowsy
• Fatigue
• Pharyngitis
• Xerostomia

Less Frequent

• Acute cognitive impairment
• Agitation
• Bruising
• Constipation
• Depression
• Dizziness
• Insomnia
• Nervousness
• Symptoms of anxiety
• Urinary tract infection

No enhanced messaging available.

The manufacturer states that the safety and efficacy of deutetrabenazine in pediatric patients have not been established for the treatment of chorea associated with Huntington's disease or for the treatment of tardive dyskinesia.

Safety and efficacy of deutetrabenazine have not been established in pediatric patients for the treatment of Tourette syndrome+. Efficacy was not demonstrated in 2 randomized controlled trials in patients 6-16 years of age with Tourette syndrome+. One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the other study evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included 274 patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (TGTSS-TSS). Deutetrabenazine was not substantially different from placebo in reducing tics based on changes from baseline to week 8 on the YGTSS-TTS in either study. Adverse effects were mild to moderate and no new safety signals were identified.

The manufacturer states that there are no adequate data regarding the developmental risk associated with the use of deutetrabenazine in pregnant women. Reproduction studies revealed no clear adverse effect on embryofetal development when deutetrabenazine was administered orally during the period of organogenesis to rats at dosages up to 6 times the maximum recommended human dosage. However, when tetrabenazine (a closely related VMAT2 inhibitor) was administered to rats throughout pregnancy and lactation, increased stillbirths, reduced pup survival, and delayed pup maturation were observed.

It is not known whether deutetrabenazine or its metabolites are distributed into milk in humans. The effects of deutetrabenazine or its metabolites on breast-fed infants or on milk production also are unknown. The developmental and health benefits of breast-feeding to the infant should be considered along with the mother's clinical need for deutetrabenazine and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The manufacturer states that dosage of deutetrabenazine should be selected with caution in geriatric patients, usually beginning with the lower end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in such patients.

Clinical studies of deutetrabenazine did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. Other clinical experience with deutetrabenazine has not identified differences in responses between geriatric and younger adult patients.

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer recommends that dosage selection of deutetrabenazine in geriatric patients should be cautious, usually beginning with the lower end of the dosage range.