DEPVEN XL Extended release tablet Ref.[50494] Active ingredients:

Absorption

Desvenlafaxine is well absorbed. The absolute oral bioavailability of desvenlafaxine is 80%. The mean time to peak plasma concentrations (t~max~) is about 7,5 hours after oral administration. Following a 100 mg single dose, the predicted AUC and C_max are 6,747 ng.hr/ mL and 376 ng/ mL, respectively. There is a linear increase in AUC and C_max after administration of 50 mg to 600 mg doses.

Food effect

There is an increase in C_max of desvenlafaxine under fed conditions (high-fat meal) while desvenlafaxine exposure was not significantly affected by food. This difference is not clinically significant; therefore, desvenlafaxine can be taken without regard to meals.

Distribution

With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4-5 days.

The plasma protein binding of desvenlafaxine is low (30%) and is not dependent on medicine concentration. Desvenlafaxine’s volume of distribution at steady state following intravenous administration is 3,4 L/Kg, indicating distribution into nonvascular compartments.

Biotransformation

Desvenlafaxine is primarily metabolised by conjugation (mediated UGT isoforms, including UGT1A1, UGT 1A3, UGT2B4, UGT2B15, and UGT2B17) and to a minor extent through oxidative metabolism. CYP3A4 is the predominant cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine.

Elimination

The terminal elimination half-life of desvenlafaxine is approximately 11 hours.

Approximately 45% of desvenlafaxine is excreted unchanged in the urine. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite in urine.

Special populations

Renal impairment

The total body clearance of desvenlafaxine is reduced by 29% in patients with mild renal impairment, 39% in patients with moderate renal impairment, and by 51% in patients with severe renal impairment. Patients with end stage renal disease (ESRD) have a 58% reduction in total body clearance of desvenlafaxine. This reduced clearance results in increases in AUC’s of 42% in mild renal impairment, 56% in moderate renal impairment, 108% in severe renal impairment and 116% is ESRD patients. The mean terminal half-life is prolonged to 13,5, 15,5, 17,6, and 22,8 hours in mild, moderate, severe renal impairment and ESRD respectively as compared to 11,1 hours in healthy patients.

Less than 5% of the medicine in the body is cleared during a standard 4-hour haemodialysis procedure. Supplemental doses of DEPVEN should therefore not be given to patients after dialysis. Dosage adjustment is recommended in patients with significant renal function impairment (see section 4.2).

Hepatic impairment

The AUC of desvenlafaxine is increased by approximately 31% and 35% in patients with moderate and severe hepatic impairment respectively. Patients with mild hepatic impairment however, have comparable AUC values to healthy patients.

The mean half-life is increased to approximately 13 and 14 hours in moderate and severe hepatic impairment respectively.

Paediatric population

Safety and efficacy in patients less than 18 years of age has not been established.

Elderly

In a trial of healthy subjects administered doses of up to 300 mg, there was an age-dependent decrease in desvenlafaxine clearance, resulting in a 32% increase in C_max and 55% increase in AUC values in subjects greater than 75 years of age, as compared with subjects 18 to 45 years of age. No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see section 4.2).