Not applicable.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use.
Carcinogenesis
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.
Mutagenesis
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of Salmonella typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/ml) showed no evidence of chromosomal mutations.
Reproductive toxicity
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg.
There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification.
The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. These effects on parturition are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
Reconstitution instructions:
The reconstituted suspension will provide a white to off-white orange-flavoured suspension after reconstitution.
Powder for oral suspension 10 mg/ml in 60 ml capacity bottle: 35 ml suspension after reconstitution:
1. Tap the bottle to release the powder.
2. Add a small quantity of still water and shake it vigorously. Add water up to the level marked () on the bottle (this corresponds in total to adding the required 24 ml of water).
3. Shake well for 1 to 2 minutes to obtain a homogenous suspension.
4. After reconstitution there will be a usable volume of 35 ml.
5. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days).
Powder for oral suspension 10 mg/ml in 175 ml capacity bottle: 100 ml suspension after reconstitution:
1. Tap the bottle to release the powder.
2. Add a small quantity of still water and shake it vigorously. Add water up to the level marked () on the bottle (this corresponds in total to adding the required 66 ml of water).
3. Shake well for 1 to 2 minutes to obtain a homogenous suspension.
4. After reconstitution there will be a usable volume of 100 ml.
5. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days).
Instructions for use:
Shake the closed bottle of the reconstituted suspension before each use.
Instructions to use the oral syringe: Shake the prepared suspension well.
1. Open the bottle (safety cap).
2. Insert the adapter fitted onto the oral syringe into the bottle neck (Figure 1).
3. Turn the bottle with the oral syringe upside down and withdraw the quantity of suspension prescribed by the doctor (Figure 2). The graduations on the oral syringe are shown in ml. A maximum dose of 400 mg daily should not be exceeded in paediatric population.
4. Remove the oral syringe from the bottle.
5. The medicinal product may be given directly into the mouth from the oral syringe. The patient should remain upright during administration. Point the oral syringe at the inside of the cheek; release the suspension slowly into the patient's mouth (Figure 3).
6. Rinse the oral syringe.
7. Close the bottle with the safety cap; the adapter will remain on the bottle neck.
Dose conversion of the powder for oral suspension from mg/ml to ml/kg body weight (BW) for paediatric patients:
Forcan 10 mg/ml powder for oral suspension:
In children Forcan powder for oral suspension should be measured as closely as possible according to the following equation:
The graduations of the oral syringe are in increments of 0.2 ml. Therefore for intermediate weights and dosages, the dose to be given in ml should be calculated then rounded up or down to the nearest graduation of the oral syringe.
For example, a child weighing 11 kg prescribed Forcan 3 mg/kg/day should receive 33 mg/day, equivalent to 3.3 ml of the 10 mg/ml oral suspension. The dose may be rounded up to 3.4 ml, the nearest graduation on the oral syringe to provide the full dose.
A maximum dose of 400 mg daily should not be exceeded in the paediatric population (see table *).
The use of Forcan 10mg/ml powder for oral suspension is not recommended for doses > 15.0 ml (see table for doses highlighted in grey). When doses exceed 15.0 ml, it is recommended to use Forcan 40mg/ml powder for oral suspension.
Table Dosage examples:
| Posology (Corresponding dose in ml/day) | |||
| Weight Kg | 3 mg/kg/day | 6 mg/kg/day | 12 mg/kg/day |
| 3 kg | 1.0 ml | 1.8 ml | 3.6 ml |
| 5 kg | 1.6 ml | 3.0 ml | 6.0 ml |
| 7.5 kg | 2.2 ml | 4.6 ml | 9.0 ml |
| 10 kg | 3.0 ml | 6.0 ml | 12.0 ml |
| 12.5 kg | 3.8 ml | 7.6 ml | 15.0 ml |
| 15 kg | 4.6 ml | 9.0 ml | 18.0 ml |
| 20 kg | 6.0 ml | 12.0 ml | 24.0 ml |
| 25 kg | 7.6 ml | 15.0 ml | 30.0 ml |
| 30 kg | 9.0 ml | 18.0 ml | 36.0 ml |
| 35 kg | 10.6 ml | 21.0 ml | 40.0 ml* |
| 40 kg | 12.0 ml | 24.0 ml | 40.0 ml* |
| 45 kg | 13.6 ml | 27.0 ml | 40.0 ml* |
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Any remaining suspension should be discarded 28 days after reconstitution.
