Shelf life
Capsules: 3 years.
Oral solution: 2 years.
Incompatibilities
Not applicable.
List of excipients
The oral solution contains:
Benzoic acid
Sucrose
Glycerine
Mint flavour (containing 0.23 % ethanol (alcohol))
Purified water
The capsules contain:
Maize starch flowable
Dimeticone
Capsule components:
Patent blue V (E131)
Yellow iron oxide (E172)
Titanium dioxide (E171)
Gelatin
Pharmaceutical grade edible printing ink, containing shellac, hydrated ferric oxide (black) E172, propylene glycol and may contain ammonium hydroxide and potassium hydroxide.
Preclinical safety data
There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies.
Adult animal studies
In a 2-generation rat reproduction study, fluoxetine did not produce adverse effects on the mating or fertility of rats, was not teratogenic, and did not affect growth, development, or reproductive parameters of the offspring.
The concentrations in the diet provided doses approximately equivalent to 1.5, 3.9, and 9.7 mg fluoxetine/kg body weight.
Male mice treated daily for 3 months with fluoxetine in the diet at a dose approximately equivalent to 31 mg/kg showed a decrease in testis weight and hypospermatogenesis. However, this dose level exceeded the maximum-tolerated dose (MTD) as significant signs of toxicity were seen.
Juvenile animal studies
In a juvenile toxicology study in CD rats, administration of 30 mg/kg/day of fluoxetine hydrochloride on postnatal days 21 to 90 resulted in irreversible testicular degeneration and necrosis, epididymal epithelial vacuolation, immaturity and inactivity of the female reproductive tract and decreased fertility. Delays in sexual maturation occurred in males (10 and 30 mg/kg/day) and females (30 mg/kg/day). The significance of these findings in humans is unknown. Rats administered 30 mg/kg also had decreased femur lengths compared with controls and skeletal muscle degeneration, necrosis and regeneration. At 10 mg/kg/day, plasma levels achieved in animals were approximately 0.8 to 8.8 fold (fluoxetine) and 3.6 to 23.2 fold (norfluoxetine) those usually observed in paediatric patients. At 3 mg/kg/day, plasma levels achieved in animals were approximately 0.04 to 0.5 fold (fluoxetine) and 0.3 to 2.1 fold (norfluoxetine) those usually achieved in paediatric patients.
A study in juvenile mice has indicated that inhibition of the serotonin transporter prevents the accrual of bone formation. This finding would appear to be supported by clinical findings. The reversibility of this effect has not been established.
Another study in juvenile mice (treated on postnatal days 4 to 21) has demonstrated that inhibition of the serotonin transporter had long-lasting effects on the behaviour of the mice. There is no information on whether the effect was reversible. The clinical relevance of this finding has not been established.
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.
Biotransformation
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 metabolised by the polymorphic enzyme CYP2D6. Fluoxetine is primarily metabolised 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.
Special populations
Elderly: Kinetic parameters are not altered in healthy elderly when compared to younger subjects.
Paediatric population: 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. 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.
Date of revision of the text
08 March 2018
Marketing authorisation holder
Eli Lilly and Company Limited
Lilly House
Priestley Road
Basingstoke
Hampshire
RG24 9NL
United Kingdom
Special precautions for storage
Do not store above 30°C.
Oral solution: Store in the original bottle to protect from light.
Nature and contents of container
Capsules: PVC/aluminium blister packs of 2, 7, 12, 14, 20, 28, 30, 50, 56, 70, 98, 100 and 500 capsules.
Oral solution: Brown glass bottles containing 60 ml, 70 ml or 140 ml oral solution. The pack may include one of the following measuring and dosing devices:
- a measuring cup, with a 5 ml graduation,
- a 5 ml capacity syringe with graduations to measure 1.25, 2.5, 3.75 and 5 ml,
- a 5 ml capacity syringe with graduations to measure 5, 10, 15 and 20 mg,
- a double-ended spoon with the smaller spoon marked with a fill level equivalent to 2.5 ml and the larger spoon marked with a fill level equivalent to 5 ml.
Not all pack/bottle sizes may be marketed.
Marketing authorisation number(s)
| Capsules:
Oral solution:
| PL 00006/0195 PL 00006/0272
|
Special precautions for disposal and other handling
No special requirements.
Date of first authorisation/renewal of the authorisation
Capsules:
| Date of first authorisation:
Date of latest renewal:
| 25 November 1988
01 April 2013
|
Oral solution:
| Date of first authorisation:
Date of latest renewal:
| 28 October 1992
01 April 2013
|
