Deutetrabenazine

Concomitant use of alcohol or other sedating products is not recommended, as these may have additive effects and worsen sedation and somnolence. Examples of sedating products include benzodiazepines (e.g. midazolam, diazepam, lorazepam), antidepressants (e.g. mirtazapine, amitriptyline, trazodone), antipsychotics (e.g. promethazine, chlorprothixene), opioids (e.g. oxycodone, buprenorphine), antihistamines (e.g. diphenhydramine, dimenhydrinate), and centrally acting antihypertensives (e.g. clonidine, moxonidine).

Deutetrabenazine may prolong the QTc interval. Deutetrabenazine should be used with caution in combination with other medicinal products that prolong the QTc interval and in patients with congenital long QT syndrome, bradycardia, hypokalaemia, hypomagnesaemia or a history of cardiac arrhythmias.

Examples of medicinal products that prolong the QTc interval include: antiarrhythmics class IA (e.g. quinidine, disopyramide) and class III (e.g. amiodarone, sotalol), antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol, droperidol, ziprasidone), tricyclic antidepressants (e.g. amitriptyline), selective serotonin reuptake inhibitors (e.g. citalopram, escitalopram), antimicrobials (e.g. fluoroquinolones, triazole derivative (e.g. voriconazole), erythromycin IV, pentamidine, antimalarial medicinal products), and antihistamines (e.g. hydroxyzine, mizolastine).

In patients receiving strong CYP2D6 inhibitors or who are poor CYP2D6 metabolisers, the daily dose of deutetrabenazine should not exceed 36 mg.

Concomitant use of strong CYP2D6 inhibitors, such as quinidine (antiarrhythmic and antimalarial medicinal product), and paroxetine, fluoxetine, and bupropion (antidepressants), has been shown to increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine. In the presence of a strong CYP2D6 inhibitor (paroxetine), systemic exposure of the individual active metabolites increased 1.9-fold for deuterated α-dihydrotetrabenazine [HTBZ] and 6.5-fold for deuterated β-HTBZ resulting in an overall 3-fold increase in the active metabolites, deuterated total (α + β)-HTBZ.

Levodopa and other dopaminergic medicinal products (e.g. pramipexole, ropinirole) may reduce the effect of deutetrabenazine. Caution should be applied if deutetrabenazine is used with levodopa and other dopaminergic medicinal products.

The effect of deutetrabenazine on fertility in humans and animals has not been evaluated. Oral administration of deutetrabenazine to female rats resulted in oestrous cycle disruption. In animal studies with tetrabenazine, female cycle lengths were increased and a delay in fertility was observed.

The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of medicinal products that reduce dopaminergic transmission (e.g. haloperidol, chlorpromazine, metoclopramide, ziprasidone, promazine), therefore caution is recommended.

There is a limited amount of data from the use of deutetrabenazine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Deutetrabenazine is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether deutetrabenazine or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from deutetrabenazine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of deutetrabenazine on fertility in humans and animals has not been evaluated. Oral administration of deutetrabenazine to female rats resulted in oestrous cycle disruption. In animal studies with tetrabenazine, female cycle lengths were increased and a delay in fertility was observed.

Deutetrabenazine has moderate influence on the ability to drive and use machines. Deutetrabenazine may cause somnolence, therefore patients being treated with deutetrabenazine should be advised to refrain from driving or operating hazardous machinery, until they are on a maintenance dose and know how the medicinal product affects them.

Summary of the safety profile

Most commonly reported adverse reactions associated with deutetrabenazine were somnolence (11%), diarrhoea, dry mouth, and fatigue (each 9%). Somnolence may occur more frequently at the beginning of treatment and decrease with treatment continuation.

The most serious adverse reactions were depression and dysthymic disorder (2%).

Tabulated list of adverse reactions

Adverse reactions from clinical studies and post-marketing reports are presented according to MedDRA system organ classification. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequency categories are based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000) and not known (cannot be estimated from the available data).

The following adverse reactions have been identified for deutetrabenazine.

List of adverse reactions:

^* Preferred terms depression and dysthymic disorder were grouped for frequency calculation.
^** Preferred terms agitation, restlessness and akathisia were grouped for frequency calculation.