AUSTEDO Prolonged-release tablet Ref.[116189] Active ingredients: Deutetrabenazine

Depression

Deutetrabenazine may cause depression or worsen pre-existing depression (see section 4.8). Patients should be closely monitored for the emergence of such adverse reactions. Patients and their caregivers should be informed of the risks and instructed to report any concerns to their doctor immediately. If depression does not resolve, discontinuing treatment with deutetrabenazine should be considered.

QTc prolongation

Deutetrabenazine may prolong the QTc interval, but the degree of QTc prolongation is not clinically significant when deutetrabenazine is administered within the recommended dose range (see section 5.1). Deutetrabenazine should be used with caution in combination with other medicinal products that prolong the QTc interval (see section 4.5) and in patients with congenital long QT syndrome, bradycardia, hypokalaemia, hypomagnesaemia or a history of cardiac arrhythmias.

Neuroleptic malignant syndrome (NMS)

There is a potential risk of NMS associated with medicinal products that reduce dopaminergic transmission (see section 4.5). Main symptoms of NMS are mental changes, rigidity, hyperthermia, autonomic dysfunction and elevated creatinine phosphokinase levels. If NMS is suspected, deutetrabenazine should be discontinued immediately and appropriate symptomatic treatment should be initiated.

Akathisia, agitation and restlessness

Deutetrabenazine may increase the risk of akathisia, agitation, and restlessness in patients with tardive dyskinesia (see section 4.8). Patients receiving deutetrabenazine should be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia during treatment with deutetrabenazine, the dose should be reduced; some patients may require discontinuation of therapy.

Somnolence

Somnolence is a very common dose-limiting adverse reaction of deutetrabenazine (see section 4.8) and, therefore, patients should be advised to exercise caution when driving or operating machines (see section 4.7). Due to possible additive effects, caution should also be advised when patients are taking other sedating products or alcohol in combination with deutetrabenazine (see section 4.5).

Parkinsonism

Deutetrabenazine may cause parkinsonism in patients with tardive dyskinesia (see section 4.8). If a patient develops parkinsonism, the deutetrabenazine dose should be reduced and discontinuation of treatment should be considered if the event does not resolve.

Binding to melanin-containing tissues

Since deutetrabenazine or its metabolites bind to melanin-containing tissues (e.g. skin and eye), it could accumulate in these tissues over time. This raises the possibility that deutetrabenazine may cause toxicity in these tissues after extended use. The clinical relevance of deutetrabenazine's binding to melanin-containing tissues is unknown.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per prolonged-release tablet, i.e. is essentially 'sodium-free'.

This medicinal product contains sunset yellow FCF and/or allura red AC which may cause allergic reactions (see section 2).

Reserpine

Deutetrabenazine and reserpine must not be used concomitantly (see section 4.3). Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. At least 20 days must elapse after stopping reserpine before starting deutetrabenazine. Prescribers should wait for dyskinesia to re-emerge before administering deutetrabenazine to help reduce the risk of overdose and major depletion of serotonin and noradrenaline in the central nervous system.

Monoamine Oxidase Inhibitors (MAOIs)

Deutetrabenazine must not be used in combination with an MAOI (e.g. moclobemide, tranylcypromine, isocarboxazid, selegiline, rasagiline, safinamide, linezolid) (see section 4.3). At least 14 days must elapse after stopping an MAOI before starting deutetrabenazine.

Other VMAT2 inhibitors

Deutetrabenazine must not be used in patients currently taking other VMAT2 inhibitors (e.g. tetrabenazine) (see section 4.3). Deutetrabenazine can be started the day after the discontinuation of tetrabenazine at a dose which is approximately half the tetrabenazine daily dose.

Medicinal products known to reduce dopaminergic transmission

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 (see section 4.4).

Medicinal products known to prolong the QTc interval

Deutetrabenazine may prolong the QTc interval. Deutetrabenazine should be used with caution in combination with other medicinal products that prolong the QTc interval (see section 4.4). 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).

Alcohol or other sedating products

Concomitant use of alcohol or other sedating products is not recommended, as these may have additive effects and worsen sedation and somnolence (see section 4.4). 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).

Strong CYP2D6 inhibitors

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 (see section 5.2). A reduction in the dose of deutetrabenazine may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of deutetrabenazine. The daily dose of deutetrabenazine should not exceed 36 mg in patients taking strong CYP2D6 inhibitors (see section 4.2).

Levodopa and other dopaminergic medicinal products

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.

Pregnancy

There is a limited amount of data from the use of deutetrabenazine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Austedo is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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 Austedo 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 (see section 5.3). 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 (see section 4.4).

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 (see Table 1).

Table 1. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.