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Pharmacotherapeutic group: Antidepressants - Tricyclic antidepressant (melitracen) and neuroleptic of the thioxanthene group (flupentixol). ATC-code: N 06 CA 02.
Pharmacology: Pharmacodynamics: Deanxit consists of two well known and well proven compounds: Flupentixol is a neuroleptic of the thioxanthene group with anxiolytic and antidepressant properties when given in small doses.
Melitracen is a tricyclic antidepressant with activating properties in low doses. It has similar pharmacological properties as amitriptyline but is less sedative.
In combination the compounds render a preparation with antidepressant, anxiolytic and activating properties.
Pharmacokinetics: Flupentixol: Flupentixol is a mixture of two geometric isomers, the active cis(Z)-flupentixol and trans(E)-flupentixol, approximately in the ratio of 1:1.
Absorption: Oral administration results in maximum serum levels in about 12 hours. Oral bioavailability is about 40%.
Distribution: The apparent volume of distribution (Vd)β is about 14.1 l/kg.
The plasma protein binding is about 99%.
Biotransformation: The metabolism of flupentixol proceeds along three main routes - sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. Flupentixol dominates over metabolites in brain and other tissues.
Elimination: The elimination half-life (T1/2 β) is about 61 hours and the mean systemic clearance (Cls) is about 0.29 l/min.
Flupentixol is excreted mainly with faeces, but also to some degree with the urine. When tritium labelled flupentixol was administered to man the excretion pattern shows the excretion via faeces to be about 4 times the urinary excretion.
In nursing mothers flupentixol is excreted in small amounts with the breast milk. The ratio milk conc./serum conc. in women is on average 1.3.
Linearity: The kinetics is linear. Steady state plasma levels are achieved in about 7 days. The mean minimum steady state level corresponding to 5 mg flupentixol orally once-a-day was about 1.7 ng/ml (3.9 nmol/l).
Older people: Pharmacokinetic investigations have not been done in elderly patients. However, for the related thioxanthene drug, zuclopenthixol, the pharmacokinetic parameters are widely independent of the age of the patient.
Reduced hepatic function: No data available.
Reduced renal function: Based on the previously mentioned characteristics for elimination it is reasonable to assume that reduced kidney function is likely not to have much influence on the serum levels of parent drug.
Melitracen: Absorption: Oral administration results in maximum serum levels in about 5 hours. Oral bioavailability is not known.
Distribution: The apparent volume of distribution (Vd)β is not known. The plasma protein binding in rats is about 89%.
Biotransformation: The metabolism of melitracen proceeds mainly by demethylation and hydroxylation. The main active metabolite is the secondary amine, litracen.
Elimination: The elimination half-life (T1/2 β) is about 62 hours in man. The systemic clearance (CLs) is not known.
In rats melitracen is excreted mainly with faeces, but also to some degree with the urine. The excretion pattern showed the excretion via faeces to be about 2½ times the urinary excretion.
It is not known whether melitracen is excreted with breast milk.
Older people: No data available.
Reduced hepatic function: No data available.
Reduced renal function: No data available.
Toxicology: Preclinical safety data: Acute toxicity: Flupentixol has low acute toxicity, but the acute toxicity of tricyclic antidepressants including melitracen is high.
Chronic toxicity: In chronic toxicity studies there were no findings of concern for the therapeutic use of flupentixol or melitracen.
Reproduction toxicity: In preclinical fertility studies in rats, where flupentixol and melitracen were administered separately slight effects on fertility were noted. Flupentixol slightly affected the pregnancy rate of female rats, whereas melitracen slightly repressed fertility and fecundity of male rats. Effects were seen at doses well in excess of those applied during clinical use.
Combination of flupentixol and melitracen did not induce major malformations or affect pregnancy and embryofoetal development in rats or rabbits. In mice melitracen was associated with lower foetal body weight, but no major malformations were noted.
No effect on parturition or postnatal development of melitracen was noted in mice or rats.
