Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective serotonin reuptake inhibitors. ATC code: N06A B03.
Mechanism of action
Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α1-, α2-, and β-adrenergic; serotonergic; dopaminergic; histaminergic1; muscarinic; and GABA receptors.

Clinical efficacy and safety
Major depressive episodes: Clinical trials in patients with major depressive episodes have been conducted versus placebo and active controls. Fluoxetine has been shown to be significantly more effective than placebo, as measured by the Hamilton Depression Rating Scale (HAM-D). In these studies, Fluoxetine produced a significantly higher rate of response (defined by a 50% decrease in the HAM-D score) and remission compared to placebo.

Dose response: In the fixed-dose studies of patients with major depression there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, it is clinical experience that uptitrating might be beneficial for some patients.

Obsessive-compulsive disorder: In short-term trials (under 24 weeks), fluoxetine was shown to be significantly more effective than placebo. There was a therapeutic effect at 20mg/day, but higher doses (40 or 60mg/day) showed a higher response rate. In long-term studies (three short-term studies extension phase and a relapse prevention study), efficacy has not been shown.

Bulimia nervosa: In short-term trials (under 16 weeks), in out-patients fulfilling DSM-III-R-criteria for bulimia nervosa, fluoxetine 60mg/day was shown to be significantly more effective than placebo for the reduction of bingeing, vomiting and purging activities. However, for long-term efficacy no conclusion can be drawn.

Pre-Menstrual Dysphoric Disorder: Two placebo-controlled studies were conducted in patients meeting Pre-Menstrual Dysphoric Disorder (PMDD) diagnostic criteria according to DSM-IV. Patients were included if they had symptoms of sufficient severity to impair social and occupational function and relationships with others. Patients using oral contraceptives were excluded. In the first study of continuous 20mg daily dosing for 6 cycles, improvement was observed in the primary efficacy parameter (irritability, anxiety and dysphoria). In the second study, with intermittent luteal phase dosing (20mg daily for 14 days) for 3 cycles, improvement was observed in the primary efficacy parameter (Daily Record of Severity of Problems score). However, definitive conclusions on efficacy and duration of treatment cannot be drawn from these studies.

Major depressive episodes (children and adolescents): Clinical trials in children and adolescents aged 8 years and above have been conducted versus placebo. Fluoxetine, at a dose of 20 mg, has been shown to be significantly more effective than placebo in two short-term pivotal studies, as measured by the reduction of Childhood Depression Rating Scale-Revised (CDRS-R) total scores and Clinical Global Impression of Improvement (CGI-I) scores. In both studies, patients met criteria for moderate to severe MDD (DSM-III or DSM-IV) at three different evaluations by practicing child psychiatrists.
Efficacy in the fluoxetine trials may depend on the inclusion of a selective patient population (one that has not spontaneously recovered within a period of 3-5 weeks and whose depression persisted in the face of considerable attention).
There is only limited data on safety and efficacy beyond 9 weeks. In general, efficacy of fluoxetine was modest. Response rates (the primary endpoint, defined as a 30% decrease in the CDRS-R score) demonstrated a statistically significant difference in one of the two pivotal studies (58% for fluoxetine versus 32% for placebo, P=0.013; and 65% for fluoxetine versus 54% for placebo, P=0.093). In these two studies, the mean absolute changes in CDRS-R from baseline to endpoint were 20 for fluoxetine versus 11 for placebo, P=0.002; and 22 for fluoxetine versus 15 for placebo, P<0.001.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Fluoxetine is well absorbed from the gastro-intestinal tract after oral administration. The bioavailability is not affected by food intake.

Distribution
Fluoxetine is extensively bound to plasma proteins (about 95%) and it is widely distributed (volume of distribution: 20-40 L/kg). Steady-state plasma concentrations are achieved after dosing for several weeks. Steady-state concentrations after prolonged dosing are similar to concentrations seen at 4 to 5 weeks.

Metabolism
Fluoxetine has a non-linear pharmacokinetic profile with first-pass liver effect. Maximum plasma concentration is generally achieved 6 to 8 hours after administration. Fluoxetine is extensively metabolized by the polymorphic enzyme CYP2D6. Fluoxetine is primarily metabolized by the liver to the active metabolite norfluoxetine (desmethylfluoxetine), by desmethylation.

Elimination
The elimination half-life of fluoxetine is 4 to 6 days and for norfluoxetine 4 to 16 days. These long half- lives are responsible for persistence of the drug for 5-6 weeks after discontinuation. Excretion is mainly (about 60%) via the kidney. Fluoxetine is secreted into breast milk.

At-risk populations

Elderly: Kinetic parameters are not altered in healthy elderly when compared to younger subjects.
Children and adolescents: The mean fluoxetine concentration in children is approximately 2-fold higher than that observed in adolescents and the mean norfluoxetine concentration 1.5-fold higher.
Steady-state plasma concentrations are dependent on body weight and are higher in lower weight children (see section 4.2).
As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady state concentrations were achieved within 3 to 4 weeks of daily dosing.

Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), fluoxetine and norfluoxetine half-lives are increased to 7 and 12 days, respectively. A lower or less frequent dose should be considered.

Renal insufficiency: After single-dose administration of fluoxetine in patients with mild, moderate, or complete (anuria) renal insufficiency, kinetic parameters have not been altered when compared to healthy volunteers. However, after repeated administration, an increase in steady-state plateau of plasma concentrations may be observed.