Source: Health Products Regulatory Authority (ZA) Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand, 1685, Customer Care: 0860/ADCOCK (232625)
Pharmacological classification: A1.2 Psychoanaleptics (antidepressants)
Pharmacotherapeutic group and ATC code: Psychoanaleptics; Other antidepressants
ATC code: N06AX26
The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter.
In vitro studies indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems, including predominantly the serotonin but probably also the norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems.
However, the precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear.
Vortioxetine is slowly, but well absorbed after oral administration and the peak plasma concentration is reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean Cmax values of 9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed (see section 4.2).
The mean volume of distribution (Vss) is 2,600 L, indicating extensive extravascular distribution. Vortioxetine is highly bound to plasma proteins (98 to 99%) and the binding appears to be independent of vortioxetine plasma concentrations.
Vortioxetine is extensively metabolised in the liver, primarily through oxidation and subsequent glucuronic acid conjugation.
In vitro, the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C9, CYP2C19, CYP2A6, CYP2B6 and CYP2C8 are involved in the metabolism of vortioxetine.
No inhibitory or inducing effect of vortioxetine was observed in vitro in the drug-drug interaction studies for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 (see section 4.5).
Vortioxetine is a poor P-gp substrate and inhibitor.
The major metabolite of vortioxetine is pharmacologically inactive.
The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. Approximately ⅔ of the inactive vortioxetine metabolites are excreted in the urine and approximately ⅓ in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces. Steady-state plasma concentrations are achieved in approximately 2 weeks.
The pharmacokinetics are linear and time independent in the dose range studied (2,5 to 60 mg/day). In accordance with the half-life, the accumulation index is 5 to 6 based on AUC0-24h following multiple doses of 5 to 20 mg/day.
There is a curve-linear concentration-response relationship between the plasma concentrations of vortioxetine after single and multiple doses of 2,5 to 60 mg/day and the occupancy of the 5-HT transporter in the brain, as measured using PET.
In elderly healthy subjects (aged ≥65 years; n=20), the exposure to vortioxetine increased up to 27% (Cmax and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of 10 mg/day. The lowest effective dose of 5 mg vortioxetine once daily should always be used as the starting dose in patients ≥65 years (see section 4.2).
However, caution should be exercised when prescribing to elderly patients at doses higher than 10 mg vortioxetine once daily (see section 4.2 and 4.4).
Following a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group) caused modest exposure increases (up to 30%), compared to healthy matched controls. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during dialysis (AUC and Cmax were 13% and 27% lower, respectively; n=8) following a single 10 mg dose of vortioxetine. No dose adjustment is needed (see section 4.2 and 4.4).
Following a single dose of 10 mg vortioxetine, no impact of mild or moderate hepatic impairment (Child-Pugh Criteria A or B; n=8 per group) was observed on the pharmacokinetics of vortioxetine (changes in AUC were less than 10%). No dose adjustment is needed (see section 4.2). Vortioxetine has not been studied in patients with severe hepatic impairment and caution should be exercised when treating these patients (see section 4.4).
The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers.
Co-administration of strong CYP3A4/2C9 inhibitors to CYP2D6 poor metabolisers could potentially result in higher exposure (see section 4.5).
In CYP2D6 ultra-rapid metabolisers, the plasma concentration of vortioxetine 10 mg/day were between those obtained in extensive metabolisers at 5 mg/day and 10 mg/day.
Depending on individual patient response, a dose adjustment may be considered (see section 4.2).
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