4.1 ATCvet code:
QNO6ABO3
4.2 Pharmacodynamics
Fluoxetine and its active metabolite nor-fluoxetine have been shown to be highly selective
inhibitors of serotonin uptake both in vitro and in vivo. Fluoxetine does not act as a sedative.
Fluoxetine inhibits catecholamine uptake only at high concentrations in vitro and has no effect on
catecholamine uptake in vivo at doses that are used to inhibit serotonin uptake. As a result of
inhibiting serotonin uptake, fluoxetine enhances serotonergic neurotransmission and produces
functional effects resulting from increased activation of serotonin receptors. Fluoxetine lacks any
significant affinity for neurotransmitter receptors, including the muscarinic cholinergic receptor,
adrenergic receptors, or histaminergic H1 receptors, and does not have direct effects on the heart.
4.3 Pharmacokinetics
Fluoxetine is well absorbed after oral administration (approximately 72%) and the absorption is not
affected by feeding. Fluoxetine is metabolised to norfluoxetine, an equipotent SSRI that
contributes to the efficacy of the veterinary medicinal product.
After a single administration of the veterinary medicinal product in dogs, a mean Cmax of
fluoxetine of approximately 135 ng/mL was reached at 2 hours. The mean half-life of fluoxetine was
6.25 hours.
In a 21 day study, fluoxetine was administered daily at a dose of 0.75, 1.5 and 3.0 mg/kg body
weight to laboratory Beagles. The maximum plasma concentration (Cmax) and area under the plasma
concentration time curve (AUC) for fluoxetine were approximately dose proportional between 0.75 and
1.5 mg/kg, with a greater than dose proportional increase at 3 mg/kg. After administration,
fluoxetine readily appeared in plasma with mean Tmax values ranging from 1.25 to 1.75 hours on day
1 and from 2.5 to 2.75 hours on day 21. Plasma levels readily declined with mean t ½ values ranging
from 4.6 to 5.7 hours on day 1 and from 5.1 to 10.1 hours on day 21. Norfluoxetine plasma levels
slowly appeared in plasma and were slowly eliminated with t½ values ranging from 44.2 to 48.9 hours
on day 21. Norfluoxetine Cmax and AUC were generally dose proportional but these values were 3 to 4
fold higher on day 21 than on day 1.
Accumulation of fluoxetine and norfluoxetine occurred following multiple doses until reaching a
steady-state within approximately 10 days. Following the last dose administration, fluoxetine and
norfluoxetine plasma levels declined steadily in a log- linear fashion. Elimination studies in dogs
have shown that 29.8% and 44% of the dose were excreted in urine and faeces, respectively by 14
days following dosing.