Source: Medicines Authority (MT) Revision Year: 2022 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France
Pharmacotherapeutic group: Other antidepressant
ATC code: N06AX14
Tianeptine is an antidepressant.
In animals, Tianeptine has the following properties:
The precise contribution of each effect to the antidepressant activity is unknown.
Four double-blind placebo controlled trials have been performed to investigate the short term efficacy of tianeptine in major depressive disorder in adults, one with fixed doses (37.5 mg, 75 mg) and two with possible dose up-or-down titration (initial dose 37.5 mg then 25, 37.5 or 50 mg) and one in elderly patients (311 patients aged 65 years and above; ~100 patients by treatment arm, including ~20 patients above 75 years in each arm) with a potential dose increase according to patient improvement after 2 weeks of treatment (25 mg then 25mg or 50 mg). In the adult studies, primary endpoint was change in MADRS total score from baseline for the fixed and flexible dose trials.
At the end of treatment (6 weeks), significant efficacy of tianeptine was demonstrated in the 2 flexible dose trials, but not in the fixed dose study. In one study an active control was used, imipramine and showed assay sensitivity.
In the elderly study (potential dose increase trial), after 8 weeks of treatment, significant efficacy of tianeptine was demonstrated on the primary endpoint (HAMD total score change from baseline). The active control, escitalopram, used in this trial showed assay sensitivity.
The maintenance of antidepressant efficacy was evaluated a relapse and recurrence prevention trial. Patients responding to 6-weeks of acute treatment with open-label tianeptine at flexible daily dosage from 2 to 4 tablets (25 to 50 mg/d) according to the investigator’s judgement were randomized to either tianeptine or to placebo to 16.5 further months. Tianeptine demonstrated a statistically significant superiority compared to placebo (p<0.001) on the primary outcome measure, the prevention of depressive relapse or recurrence, as measured by time to relapse or recurrence. The incidence of relapse during the 6 months double-blind follow-up was 6% and 22% for tianeptine and placebo, respectively. The incidence of relapse or recurrence during the 18 months double-blind follow-up was 16% and 36%, respectively.
Gastrointestinal absorption is rapid and complete with negligible influence of food.
Distribution is rapid, and is associated with a high level of protein binding (approximately 94%), primarily to albumin.
The molecule is extensively metabolised in the liver by the processes of beta-oxidation not through the CYP450 pathway. Its major metabolite is the active pentanoic acid (MC5) less potent than tianeptine.
Elimination of tianeptine is characterized by a short terminal half-life of 3 hours with most metabolites recovered in urine.
In elderly patients, the concentrations of tianeptine were increased by 30% and that of MC5 were approximately doubled after single and repeated administrations compared to younger ones (see section 4.2).
In very old (87 ± 5 years) and frail (45 ± 9 kg) patients, a significant increase in Cmax and AUC of tianeptine and MC5 after single administration was observed (see section 4.2).
Tianeptine pharmacokinetics is unchanged but the MC5 AUC is approximately doubled following single and repeated administrations (see section 4.2).
AUC of both tianeptine and MC5, following a 12.5mg dose intake, increase as compared to the adult depressed patients (see section 4.2).
In milder conditions of cirrhosis, such as for chronic alcoholics, effects on pharmacokinetic parameters are negligible (see section 4.2).
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenicity. In a conventional fertility study, an increase in pre-implantation losses was observed at the maternotoxic dose of 45 mg/kg/day (about 12 times the human dose based on BSA). Tianeptine was not teratogenic in rats and rabbits.
In a peri- and postnatal study, dysgalactia in the dams and increased post-implantation and post-natal losses were observed in rats at a maternotoxic dose of 45 mg/kg/day (about 12 times the human dose based on BSA).
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