VORELLIX Film-coated tablet Ref.[50480] Active ingredients: Vortioxetine

Absorption

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 C_max values may be 9 to 33 ng/mL. The absolute bioavailability is 75%. Food has no effect on the Pharmacokinetics (see section 4.2).

Distribution

The mean volume of distribution (V_ss) 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.

Biotransformation

Vortioxetine is extensively metabolised in the liver, primarily through oxidation and subsequent glucuronic acid conjugation. In vitro, the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2CB and CYP2B6 are involved in the metabolism of vortioxetine.

No inhibitory or inducing effect of vortioxetine was observed in vitro for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Vortioxetine is a poor P-gp substrate and inhibitor.

The major metabolite of vortioxetine is pharmacologically inactive.

Elimination

The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. An estimated ⅔ of inactive vortioxetine metabolites are excreted in the urine and ⅓ in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces unchanged. Steady-state plasma concentrations are achieved in approximately 2 weeks.

Linearity / non-linearity

The pharmacokinetics were shown to be linear and time independent in the dose range studied (2,5 to 60 mg/day). ln accordance with the half-life, the accumulation index is 5 to 6 based on AUC_0-24h following multiple doses of 5 to 20 mg/day.

Special patient populations

Elderly

In elderly healthy subjects (aged ≥65 years), the exposure to vortioxetine increased up to 27% (C_max and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of 10 mg/day. Caution should therefore be exercised when treating the elderly (see section 4.2).

Renal impairment

After a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gault formula caused modest exposure increases (up to 30%), compared to health match controls. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during dialysis (AUC and C_max were 13% and 27% lower) following a single 10 mg dose of vortioxetine. No dose adjustment is needed (see section 4.2).

Hepatic impairment

After a single dose of 10 mg vortioxetine, no impact of mild or moderate hepatic impairment (Child-Pugh Criteria A or B) was observed on the pharmacokinetics of vortioxetine (changes in AUC were less than 10%). No dose adjustment is needed. Vortioxetine has not been studied in patients with severe hepatic impairment and caution should be exercised when prescribing to these patients (see section 4.2).

CYP2D6 poor metabolisers

The plasma concentrations of vortioxetine were approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers. Depending on the individual patient response, a dose adjustment may be required.

Pharmacokinetic / pharmacodynamic relationship

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.