Deutetrabenazine use may increase the risk for depression and suicidal ideation; do not use in patients who are suicidal or have untreated or inadequately treated depression. Patients with Huntington's disease are at increased risk for depression and suicidal ideation or behaviors (suicidality). In a placebo-controlled trial of patients with Huntington's disease, suicidal ideation was reported by 2% of deutetrabenazine-treated patients compared to 0% of placebo-treated patients. No suicide attempts or completed suicides were reported. Depression was reported by 4% of patients treated with deutetrabenazine. During placebo-controlled trials of adults with tardive dyskinesia (TD), depression or dysthymic disorder was reported in 2% of deutetrabenazine-treated patients compared to 1% of placebo-treated patients. Use deutetrabenazine with caution in patients with a history of depression or suicidal thoughts or behavior; weigh the risk of suicidality against the need for treatment. Patients or caregivers should report unusual changes in mood, behaviors, or actions promptly to the treating health care professional. If depression or suicidality does not resolve, consider discontinuing treatment with deutetrabenazine. Periodically reevaluate the clinical need for deutetrabenazine.[61845]

Deutetrabenazine may cause pseudoparkinsonism. Reduce the deutetrabenazine dose if a patient develops parkinsonism during treatment; discontinuation may be necessary for some patients. Rigidity may develop as part of the underlying disease process in Huntington's disease; it may be difficult to distinguish between a potential drug-induced adverse reaction and progression of the underlying disease process. Drug-induced parkinsonism may cause more functional disability than untreated chorea in some patients with Huntington's disease. Signs and symptoms of parkinsonism in patients being treated for tardive dyskinesia have included bradykinesia, gait disturbance, and the emergence or worsening of tremor. In most cases, parkinsonism occurred within the first 2 weeks after treatment initiation or dose escalation. In reported cases, parkinsonism resolved after treatment discontinuation.[61845]

Neuroleptic malignant syndrome (NMS) has not been reported with the use of deutetrabenazine; however, NMS has been reported with tetrabenazine (a closely related VMAT2 inhibitor). Be alert for the signs and symptoms of NMS, which include high fever, muscle rigidity, altered mental status, irregular blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia, elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. If NMS occurs, discontinue deutetrabenazine, and implement intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with reinitiation of drug therapy; if treatment with deutetrabenazine is needed after recovery from NMS, monitor for signs of recurrence.[61845]

Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. An exposure-response analysis on QTc prolongation from a study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that a clinically relevant effect can be excluded at exposures after single doses of 24 and 48 mg of deutetrabenazine.[61845]

Deutetrabenazine may increase the risk of akathisia, agitation, and restlessness in patients with Huntington's disease or tardive dyskinesia. In a randomized, placebo-controlled trial in Huntington's disease patients, akathisia, agitation, or restlessness was reported by 4% of patients who received deutetrabenazine compared to 2% of patients who received placebo. Akathisia, agitation, or restlessness was reported by 2% of patients with tardive dyskinesia who received deutetrabenazine compared to 1% of patients who received placebo during randomized, placebo-controlled trials. Agitation led to deutetrabenazine discontinuation in 2% of patients with Huntington's disease. Monitor patients for signs or symptoms of restlessness or agitation, as these symptoms may be indicators of developing akathisia. If akathisia develops, reduce the deutetrabenazine dose; treatment discontinuation may be necessary.[61845]

Drowsiness (somnolence) is a common dose-limiting adverse reaction of deutetrabenazine. Drowsiness was reported in 11% of deutetrabenazine-treated patients compared to 4% of placebo-treated patients in a double-blind, placebo-controlled trial of patients with Huntington's disease. Fatigue occurred in 9% of deutetrabenazine-treated patients compared to 4% of placebo-treated patients. Dizziness (4%) was the most common reaction resulting in dose reduction. Other neurologic adverse reactions observed during the trial include insomnia (7% deutetrabenazine vs. 4% placebo) and anxiety (4% vs. 2%). Contusion occurred in 4% of patients who received deutetrabenazine compared to 2% of patients who received placebo. In tardive dyskinesia studies, insomnia was reported in 4% of deutetrabenazine-treated patients compared to 1% of placebo-treated patients.[61845]

In a 12-week, double-blind, placebo-controlled trial of patients with Huntington's disease, diarrhea occurred in 9% of deutetrabenazine-treated patients compared to 0% of placebo-treated patients. Other gastrointestinal adverse reactions observed during the trial include xerostomia (9% deutetrabenazine vs. 7% placebo) and constipation (4% vs. 2%).[61845]

Urinary tract infection (cystitis) was reported in 7% of deutetrabenazine-treated patients vs. 2% of placebo-treated patients in a double-blind, placebo-controlled study of patients with Huntington's disease. In tardive dyskinesia studies, naso-pharyngitis was reported in 4% of deutetrabenazine-treated patients vs. 2% of placebo-treated patients.[61845]

Serum prolactin concentrations have not been evaluated during deutetrabenazine therapy; however, tetrabenazine, a closely related VMAT2 inhibitor, elevates serum prolactin concentrations in humans. In healthy volunteers, administration of tetrabenazine 25 mg increased peak plasma prolactin concentrations 4- to 5-fold. It is unknown if chronic elevations of prolactin occur with treatment. Patient conditions that may be prolactin-dependent (e.g., breast cancer, amenorrhea, galactorrhea, gynecomastia, and impotence) may develop or worsen. If hyperprolactinemia is suspected, obtain appropriate laboratory testing; consider deutetrabenazine discontinuation.[61845]

Deutetrabenazine is contraindicated for use in patients with hepatic impairment or hepatic disease because of the possibility for increased drug exposure and a greater risk of serious adverse reactions. The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied. In a clinical study of tetrabenazine, a closely related VMAT2 inhibitor, there was a large increase in exposure to tetrabenazine and its active metabolites in patients with hepatic impairment.[61845]

Deutetrabenazine use is contraindicated in patients who are receiving or have received MAOI therapy within the past 14 days. Deutetrabenazine is a reversible, monoamine-depleting drug that works by inhibiting the vesicular monoamine transporter 2 (VMAT2). Deutetrabenazine is contraindicated in patients who are receiving or have received reserpine within the past 20 days. Reserpine irreversibly binds to VMAT2, and the effect of reserpine lasts several days. Allow at least 20 days for chorea to reemerge before initiating deutetrabenazine to help reduce the risk of major depletion of serotonin and norepinephrine within the CNS. Deutetrabenazine is also contraindicated in patients taking tetrabenazine.[61845]

Deutetrabenazine is contraindicated in patients with Huntington's disease with active suicidal ideation or who have untreated or inadequately treated depression. Use deutetrabenazine with caution in patients with a history of depression or suicidal thoughts or behavior; weigh the risk of suicidality against the need for chorea treatment. Patients with Huntington's disease are at increased risk for depression and suicidal ideation or behaviors (suicidality). Deutetrabenazine use may increase the risk for suicidality in patients with Huntington's disease. Report unusual changes in mood, behaviors, or actions promptly to the treating health care professional. If depression or suicidality does not resolve, consider discontinuing treatment with deutetrabenazine. Periodically reevaluate the clinical need for deutetrabenazine.[61845]

Avoid using deutetrabenazine in patients with congenital long QT syndrome or a history of cardiac arrhythmias. Use deutetrabenazine with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.[28432] [28457] [56592] [65180] [61845]

Deutetrabenazine has the potential to impair cognitive and motor skills. Sedation is a common dose-limiting side effect of deutetrabenazine. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness, until they know how deutetrabenazine affects them. Alcohol consumption may exacerbate sedation associated with the drug.[61845]

The effect of deutetrabenazine on serum prolactin concentrations has not been evaluated, but it is possible the drug may induce hyperprolactinemia. Tetrabenazine, a closely related VMAT2 inhibitor, can cause hyperprolactinemia. Some human breast cancers may be prolactin-dependent. Therefore, use deutetrabenazine cautiously in those who have a history of breast cancer.[61845]

There are no adequate data on the developmental risk associated with deutetrabenazine use during pregnancy. Deutetrabenazine (5, 10, or 30 mg/kg/day) produced no clear adverse effects on embryofetal development when given to rats during the period of organogenesis. However, administration of tetrabenazine, a closely related VMAT2 inhibitor, to rats from organogenesis through lactation resulted in an increase in stillbirths and postnatal mortality.[61845]

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for deutetrabenazine and any potential adverse effects on the breast-feeding infant from the drug or the mother's underlying condition. There are no data on the presence of deutetrabenazine or its metabolites in human breast milk, the effects on the breast-fed infant, or the effects of the drug on milk production.[61845]

The safety and efficacy of deutetrabenazine have not been established in infants, children, or adolescents for any indication. Efficacy was not demonstrated in 2 randomized, double-blind, placebo-controlled clinical studies of pediatric patients 6 to 16 years of age with Tourette syndrome. The estimated treatment effect of deutetrabenazine on the Yale Global Tic Severity Scale Total Tic Score (primary outcome) was not statistically different from placebo in either study. Adverse reactions reported with deutetrabenazine in at least 5% of pediatric patients and with a greater incidence than in patients receiving placebo included headache (13%), somnolence (11%), fatigue (8%), increased appetite (5%), and increased weight (5%). Animal toxicity data have also shown that oral deutetrabenazine administered to juvenile rats from postnatal days 21 through 70 (at 5 mg/kg/day or more per day) resulted in an increased incidence of adverse effects (e.g., tremor, hyperactivity, adverse increases in motor activity,and reduced body weight and food consumption) compared to adult rats. All drug-related findings were reversible after a drug-free period. The no observed adverse effect level (NOAEL) in juvenile rats was 2.5 mg/kg/day.[61845]