Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead 2191
Category and Class: A 1.2 Psychoanaleptics (antidepressants)
Pharmacotherapeutic group: Other antidepressants
ATC code: N06AX21
Duloxetine is a combined serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor (SNRI) and is chemically unrelated to tricyclic and tetracyclic antidepressant medicine.
Duloxetine weakly inhibits dopamine uptake with no significant affinity for histaminergic, dopaminergic, cholinergic or adrenergic receptors.
Duloxetine dose-dependently increased extracellular levels of serotonin and norepinephrine in various brain areas of animals.
Neurochemical and behavioural studies in laboratory animals showed an enhancement of both serotonin and norepinephrine neurotransmission in the central nervous system (CNS).
The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the CNS.
The presumed mechanism of action of duloxetine in the treatment of depression is thought to be due to its inhibition of neuronal uptake of serotonin and norepinephrine and a resultant increase in serotonergic and noradrenergic neurotransmission in the CNS.
The effect of duloxetine 60 mg once a day in elderly depressed patients (≥65 years) was specifically examined in a study that showed a statistically significant difference in the reduction of the HAMD-17 score for duloxetine-treated patients compared to placebo. Tolerability of duloxetine 60 mg once daily in elderly patients was comparable to that seen in the younger adults. However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and thus, caution is recommended when treating this population.
Duloxetine is well absorbed after oral administration, with the Cmax occurring 6 hours post-dose. Food delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). Steady-state plasma concentrations are achieved after 3 days of dosing.
Duloxetine is highly bound (>90%) to plasma proteins; primarily to albumin and α1-acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.
Duloxetine is extensively metabolised. Both CYP2D6 and CYP1A2 catalyse the formation of two major metabolites (glucuronide conjugate of 4-hydroxy duloxetine, sulphate conjugate of 5-hydroxy, 6-methoxy duloxetine). Circulating metabolites are not pharmacologically active.
The mean elimination half-life of duloxetine is 12,1 hours. The mean plasma clearance of duloxetine is 101 L/hr. The metabolites are excreted principally in urine.
Pharmacokinetic differences have been identified between males and females. The mean plasma clearance was 9% to 55% lower in females, but the duloxetine half-life was similar between males and females. Some women may need a lower dose.
Duloxetine bioavailability appears to be 34% lower in smokers than in non- smokers.
Pharmacokinetic differences have been identified between middle age and elderly females (AUC is 24% higher and half-life is 4,3 hours longer in the elderly).
End-stage renal disease patients receiving chronic intermittent haemodialysis had 2-fold higher duloxetine Cmax and AUC values compared to healthy patients. Therefore, a lower dose should be used in patients with clinically significant renal impairment (see sections 4.2 and 4.3).
The half-life of duloxetine was 34 hours longer in patients with moderate cirrhosis of the liver, Child Pugh B, and exposure as AUC was approximately increased four-fold. Clearance was approximately 15% of that for age and gender-matched healthy patients. Therefore, a lower dose should be used for patients with mild to moderate liver impairment. However, duloxetine is contraindicated in severe impairment of hepatic function (Child-Pugh C) (see sections 4.2 and 4.3).
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