- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults (16 to 60):One capsule should be swallowed whole.
Children (under 16):Paediatric use is not recommended.
Elderly:Not recommended in patients over 60.
Renal Impairment:There is no separate dosage schedule in patients with renal impairment for single dose therapy.
Women only:If you are pregnant, suspect you might be pregnant or are breast-feeding.If you have any abnormal or irregular vaginal bleeding or a blood stained dischargeIf you have vulval or vaginal sores, ulcers or blisters.If you are experiencing lower abdominal pain or burning sensation on passing water.
Men only:If your sexual partner does not have thrush.If you have penile sores, ulcers or blisters.If you have an abnormal penile discharge (leakage).If your penis has started to smell.If you have pain on passing urine.The product should never be used again if the patient experiences a rash or anaphylaxis following the use of the drug.Recurrent use (men and women): patients should be advised to consult their physician if the symptoms have not been relieved within one week of taking Canesten Thrush Oral Capsule. Canesten Thrush Oral Capsule can be used if the candidal infection returns after 7 days. However, if the candidal infection recurs more than twice within six months, patients should be advised to consult their physician.Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions.Fluconazole must be taken with particular care in patients with congenital or acquired QT prolongation and torsades de pointes or a history thereof, known cardiomyopathy, sinus bradycardia, cardiac arrhythmia, or are treated with a co-medication potentially leading to QT prolongation (see 4.5).Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Anticoagulants:Fluconazole increased the prothrombin time after warfarin administration in healthy males during an interaction study. The change was small (12%) but bleeding events such as bruising, epistaxis, gastrointestinal bleeding, hematuria and melena have been reported in association with increases in prothrombin time in patients receiving fluconazole and warfarin concomitantly. Careful monitoring of prothrombin time in patients receiving coumarin type anticoagulants is recommended.
Sulphonylureas:In healthy volunteers, fluconazole prolonged the serum half-life of oral sulphonylureas such as chlorpropamide, glibenclamide, glipizide and tolbutamide, when co-administered. Fluconazole and oral sulphonylureas may be concomitantly administered to diabetics but the possibility of an hypoglycaemic episode should be considered.
Hydrochlorothiazide:Co-administration of fluconazole and multiple dose hydrochlorothiazide to healthy volunteers during a kinetic interaction study, increased plasma concentrations of fluconazole by 40%. However, although the prescriber should bear this in mind, the fluconazole dose in patients receiving concomitant diuretics should not need to be altered.
Anti-arrhythmic drugsCases of QTc prolongation and/or torsades de pointes may occur after concomitant use of fluconazole with Class I, Class Ia, and all Class III anti-arrhythmic agents. Even though no formal drug interaction studies have been done, concomitant use of these anti-arrhythmic agents and drugs known to prolong the QT interval is not recommended.
Pharmacodynamic interactionsMedicinal products that prolong QT interval: Case reports indicate that fluconazole might have the potential to induce QT prolongation leading to serious cardiac arrhythmia. Patients treated concomitantly with fluconazole and other drugs that prolong QT interval should be carefully monitored, since an additive effect cannot be excluded.
Benzodiazepines:Substantial increases in midazolam concentrations and psychomotor effects are observed when oral midazolam and fluconazole (oral or intravenous) are co-administered. The effect on midazolam appears to be greater when fluconazole is administered orally than when fluconazole is administered intravenously. If concomitant administration of benzodiazepines and fluconazole is required then the prescriber should consider reducing the benzodiazepine dose and appropriate monitoring of the patient should be undertaken.
Phenytoin:Levels of phenytoin may increase to a clinically significant degree during co-administration with fluconazole. Phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels if co-administration is necessary.
Carbamazepine, Phenobarbital, Phenytoin, RifapentineConcurrent administration of fluconazole and carbamazepine, phenobarbital, phenytoin or rifapentine results in enhanced metabolism of fluconazole, potentially reducing fluconazole effective inhibitory serum concentrations. An increase in the fluconazole dose should be considered in patients receiving concomitant carbamazepine, phenobarbital, phenytoin or rifapentine.
Oral Contraceptives:Studies on the use of combined oral contraceptives with multiple doses of fluconazole have been performed. No relevant effects on hormone levels occurred during a study with fluconazole 50mg, whilst the AUCs of ethinylestradiol and levonorgestrel were increased by 40% and 24% respectively during a study with fluconazole 200mg. It is therefore considered that multiple dose fluconazole is unlikely to affect the efficacy of the combined oral contraceptive.
Rifampicin:A 25% decrease in the AUC and 20% shorter half-life of fluconazole occurred when fluconazole and rifampicin were administered concomitantly. An increase in the fluconazole dose should be considered in patients receiving concomitant rifampicin.
Endogenous Steroid:No effect on endogenous steroid levels was observed in females when treated with fluconazole 50mg daily. No significant effect on endogenous steroid levels or on ACTH stimulated response was observed in healthy male volunteers when treated with fluconazole 200 to 400mg daily.
Ergot derivativesBecause of the potential for serious toxicity including vasospasm that can occur with increased plasma concentrations of ergot derivatives (dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, methylergonovine, methysergide) the concurrent use of fluconazole and ergot derivatives is contraindicated (see Contraindications). Fluconazole and ergot derivatives are both metabolized by cytochrome P450 3A4 enzymes, and the competition for metabolism could result in a rapid onset of increased plasma concentration of the ergot derivative.
LosartanCYP2C9 and CYP3A4 are involved in the metabolism of losartan to its active carboxylic acid metabolite E-3174 that is responsible for most of the angiotensin II receptor antagonism that occurs with losartan therapy. Fluconazole was shown to significantly inhibit the conversion of losartan to this metabolite. Monitoring of patients for continued control of their hypertension is recommended.
Ciclosporin:In a kinetic study it was found that fluconazole 200mg daily slowly increases ciclosporin concentrations in renal transplant patients, but a multiple dose study with fluconazole 100mg daily showed no effect on ciclosporin levels in patients with bone marrow transplants. It is therefore recommended that ciclosporin plasma concentration is monitored in patients receiving fluconazole.
Fentanyl, MethadoneCoadministration of fluconazole may cause decreased clearance of fentanyl or methadone and subsequent increased or prolonged opioid effects (CNS depression, respiratory depression). Dosage adjustment of the opioid may be necessary.
Theophylline:Use of fluconazole 200mg for 14 days showed an 18% decrease in the mean plasma clearance of theophylline. Patients who require high doses of theophylline or who may be at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity when fluconazole is co-administered. The therapy should be modified if signs of toxicity occur.
Terfenadine:Fluconazole 200mg daily did not show a prolongation in the QTc interval. Use of fluconazole (taken in multiple doses of 400mg and 800mg per day) and terfenadine concomitantly, significantly increased plasma levels of terfenadine. Spontaneous reports of palpitations, tachycardia, dizziness and chest pains have occurred in patients taking fluconazole and terfenadine concomitantly where the relationship of the reported adverse events to drug therapy or underlying medical condition is uncertain. It is recommended that terfenadine and fluconazole should not be administered concomitantly due to the potential seriousness of such an interaction. (See 4.3).
Cisapride:Cardiac events including torsades de pointes have been reported in patients receiving fluconazole and cisapride concomitantly. Most of these patients appear to have been predisposed to arrhythmias or had serious underlying medical conditions, and the relationship of the reported events to a possible drug interaction is uncertain. Co-administration of cisapride is contra-indicated in patients receiving fluconazole. (See 4.3).
Zidovudine:Zidovudine levels in AIDS or ARC patients were determined before and after daily treatment with fluconazole 200mg for 15 days. A significant increase in zidovudine AUC was observed (20%). A second study in HIV infected patients also showed a significant increase in zidovudine AUC (74%) when fluconazole was administered concomitantly. Patients received zidovudine 200mg every eight hours either with or without fluconazole 400mg for seven days on two occasions, 21 days apart. The increased zidovudine levels are most likely caused by a decrease in the conversion of zidovudine to its major metabolite. It is recommended that patients receiving fluconazole and zidovudine be monitored for zidovudine related adverse reactions.
Rifabutin:Increased serum levels of rifabutin have been reported in patients receiving fluconazole and rifabutin concomitantly, suggesting a possible interaction. Uveitis has also been reported in patients receiving this combination. It is therefore recommended that patients are carefully monitored.
Tacrolimus, Sirolimus:Increased serum levels of tacrolimus have been reported in patients receiving fluconazole and tacrolimus concomitantly, suggesting a possible interaction. There have also been reports of nephrotoxicity in patients receiving this combination. Patients receiving tacrolimus or sirolimus and fluconazole concomitantly should be carefully monitored.Astemizole or other drugs metabolised by the cytochrome P450 system taken concomitantly with fluconazole may be associated with elevations in serum levels of these drugs in patients. Fluconazole should be co-administered with caution in these circumstances and careful monitoring of patients should be undertaken.Studies show that when fluconazole is taken orally with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, the absorption of fluconazole is not significantly impaired. Drug drug interaction studies with other medications have not been conducted but prescribers should be aware that such interactions may occur.
An observational study has suggested an increased risk of spontaneous abortion in women treated with fluconazole during the first trimester.Fluconazole should not be used during pregnancy or in women of childbearing potential unless adequate contraception is being used. Fluconazole is found in breast milk so it should not be used whilst breast-feeding.
Blood and lymphatic system disordersLeukopenia, neutropenia, agranulocytosis, thrombocytopenia.
Cardiac disordersTorsades de pointes/QT prolongation.
Gastrointestinal disordersNausea, diarrhea, vomiting, gastrointestinal and abdominal pains, abdominal distension, flatulence.
Hepatobiliary disordersMost events were observed when a multiple treatment was used: mild transient elevations in transaminases, hepatitis (non infective), jaundice, cholestasis and acute hepatic failure, including fatalities.
Immune System DisordersAllergic reaction, anaphylactic reaction, anaphylactic shock. Hypersensitivity reactions including symptoms such as rash, urticaria, oedema, pruritus, cardio-respiratory distress.
InvestigationsElectrocardiogram QT prolonged, electrocardiogram QT corrected interval prolonged, hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Nervous system disordersSeizures, dizziness, headache, dysgeusia.
Skin and subcutaneous tissue disordersRash, pruritus, alopecia, exfoliative skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Reproductive Toxicity:At 25 and 50mg/kg and higher doses, increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed. At doses ranging from 80mg/kg to 320mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. This may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition as it is consistent with the inhibition of oestrogen synthesis in rats.
Carcinogenesis:No evidence of carcinogenic potential was observed in mice and rats treated orally with fluconazole for 24 months at doses of 2.5, 5 or 10mg/kg/day. The incidence of hepatocellular adenomas was increased in male rats treated with 5 and 10mg/kg/day.
Mutagenesis:Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium and in the mouse lymphoma L5178Y system. No evidence of chromosomal mutations was observed in cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole). Data derived from in vitro studies (human lymphocytes exposed to fluconazole) are not consistent.
Impairment of Fertility:The fertility of male or female rats treated orally with daily doses of fluconazole at doses of 5, 10 or 20mg/kg or with parenteral doses of 5, 25 or 75mg/kg was not affected, although the onset of parturition was slightly delayed at 20mg/kg p.o. In an intravenous perinatal study in rats at 5, 20 and 40mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20mg/kg and 40mg/kg, but not at 5mg/kg. The disturbances in parturition were reflected by a slight increase in the number of stillborn pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats 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.
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