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.
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.
Absorption
After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2.
Distribution
The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).
Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels.
High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g.
Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy.
Biotransformation
Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a moderate inhibitor of the isozymes CYP2C9 and CYP3A4. Fluconazole is also a strong inhibitor of the isozyme CYP2C19.
Elimination
Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.
Pharmacokinetics in renal impairment
In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood.
Pharmacokinetics during lactation
A pharmacokinetic study in ten lactating women, who had temporarily or permanently stopped breast-feeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours following a single 150 mg dose of Mycosyst. Fluconazole was detected in breast milk at an average concentration of approximately 98% of those in maternal plasma. The mean peak breast milk concentration was 2.61 mg/L at 5.2 hours post-dose. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 ml/kg/day) based on the mean peak milk concentration is 0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose (<2 weeks of age) or 13% of the recommended infant dose for mucosal candidiasis.
Pharmacokinetics in children
Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study.
After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µg·h/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13.
Pharmacokinetics in elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µg·h/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group.
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:
Mycosyst 10 mg/ml powder for oral suspension:
In children Mycosyst 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 Mycosyst 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 Mycosyst 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 Mycosyst 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.
