1. Name Of The Medicinal Product
Fluconazole 150mg capsules
Boots Thrush 150mg Capsule (Fluconazole)
2. Qualitative And Quantitative Composition
Each capsule contains Fluconazole 150mg
For excipients, see 6.1
3. Pharmaceutical Form
Capsule for oral administration
White to off white powder filled in Blue/Blue coloured hard gelatin capsules of size '1'.
4. Clinical Particulars
4.1 Therapeutic Indications
Fluconazole 150 is indicated for the treatment of the following conditions:
Vaginal candidiasis, acute or recurrent or candidal balanitis associated with vaginal candidiasis.
4.2 Posology And Method Of Administration
Route of administration
Oral.
Fluconazole 150mg capsules should be swallowed whole
In adults aged 16 - 60 years
Vaginal candidiasis or candidal balanitis - 150mg single oral dose.
In children - Not recommended in children aged under 16 years.
Use in elderly - Not recommended in patients aged over 60 years.
Use in renal impairment Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required.
4.3 Contraindications
Fluconazole 150 should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.
Fluconazole should not be co-administered with cisapride or terfenadine which are known to both prolong the QT-interval and are metabolized by CYP3A4 ( See “Interactions with medicinal products and other forms of interaction”).
4.4 Special Warnings And Precautions For Use
Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patients has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Fluconazole should not be used again if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.
Rarely patients have developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. Fluconazole should not be used again, if a rash develops, which is considered attributable to fluconazole.
In rare cases, as with other azoles, anaphylaxis has been reported.
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Although the association of fluconazole and QT-prolongation has not been fully established, fluconazole should be used with caution in patients with potentially proarrythmic conditions such as:
Congenital or documented acquired QT prolongation
Cardiomyopathy, in particular when heart failure is present
Sinus bradycardia
Existing symptomatic arrythmias
Concomitant medication not metabolized by CY34A but known to prolong QT interval.
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalaemia
(See Section 4.5 Interactions with other medicinal products and other forms of interaction)
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The product intended for pharmacy availability without prescription will carry a leaflet which will advise the patient:
Do not use Fluconazole 150mg without first consulting your doctor:
If you are under 16 or over 60 years of age.
If you have an intolerance to lactose.
If you are taking any medicine other than the Pill.
If you have had thrush more than twice in the last six months.
If you suffer from heart disease including heart rhythm problems.
If you have low potassium, magnesium or calcium in your blood (ask your doctor if you are not sure).
If you have any disease or illness affecting your liver or have had unexplained jaundice.
If you suffer from any other chronic disease or illness.
If you or your partner have had exposure to a sexually transmitted disease.
If you are unsure about the cause of your symptoms.
• 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 discharge.
If you have vulval or vaginal sores, ulcers or blisters.
If you are experiencing lower abdominal pain or burning on passing urine.
• Men Only:
If your sexual partner does not have vaginal 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 follows 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 Fluconaole 150mg. Fluconazole 150mg 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose Fluconazole 150 has not yet been established. Patients on other medications should consult their doctor or pharmacist before starting fluconazole.
Rifampicin Concomitant administration of Fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the Fluconazole dose should be considered.
Hydrochlorothiazide In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving Fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the Fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.
Anticoagulants In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored.
Benzodiazepines (Short Acting) Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients should be appropriately monitored.
Sulphonylureas Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind.
Phenytoin Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
Oral contraceptives Three kinetic studies with combined oral contraceptives have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCs of ethinyloestradiol and levonorgestrel were increased 40% and 24% respectively.
In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively. Thus single dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Ciclosporin A kinetic study in renal transplant patients found fluconazole 200mg daily to slowly increase ciclosporin concentrations. However, in another multiple dose study with 100mg daily, fluconazole did not affect ciclosporin levels in patients with bone marrow transplants. Ciclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
Theophylline In a placebo controlled interaction study, the administration of fluconazole 200mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and the therapy modified appropriately if signs of toxicity develop.
Terfenadine Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other azole antifungals in conjunction with terfenadine, interactions studies have been performed. One study at a 200mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400mg and 800mg daily dose of fluconazole demonstrated that fluconazole taken in multiple doses of 400mg per day or greater significantly increased plasma levels of terfenadine when taken concomitantly. There have been spontaneously reported cases of palpitations, tachycardia, dizziness, and chest pain in patients taking concomitant fluconazole and terfenadine where the relationship of the reported adverse events to drug therapy or underlying medical conditions was not clear. Because of the potential seriousness of such an interaction, it is recommended that terfenadine not be taken in combination with fluconazole. (See “Contra-indications”).
Cisapride There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were co-administered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval.
Co-administration of cisapride is contra-indicated in patients receiving fluconazole. (See “Contra-indications”).
Zidovudine The AUC of zidovudine can be significantly increased during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
Rifabutin There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.
Tacrolimus There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.
The use of fluconazole in patients concurrently taking astemizole or other drugs metabolised by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when co-administering fluconazole. This is particularly important for drugs known to prolong QT interval. Patients should be carefully monitored.
Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.
Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.
4.6 Pregnancy And Lactation
Use during pregnancy There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole and these events is unclear (see section 5.3 Preclinical safety data). Accordingly, Fluconazole 150 should not be used in pregnancy, or in women of childbearing potential unless adequate contraception is employed.
Use during lactation Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
4.7 Effects On Ability To Drive And Use Machines
Experience with Fluconazole indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.
4.8 Undesirable Effects
Fluconazole 150mg is generally well tolerated.
Nervous System Disorders: Headache, dizziness, seizures, taste perversion.
Gastrointestinal disorders: Abdominal pain, diarrhoea, flatulence, nausea, dyspepsia, vomiting.
Hepatobiliary Disorders Hepatic failure, hepatitis, hepatocellular necrosis, jaundice (see section 4.4 Special warnings and precautions for use).
Skin and Subcutaneous Tissue Disorders :Rash, Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrosis.
Blood and Lymphatic System Disorders: Leukopenia including neutropenia and agranulocytosis, thrombocytopenia.
Immune System Disorders:
Anaphylaxis(including angioedema, face oedema, pruritus, urticaria).
Metabolic/Nutritional Disorders:
Hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.
Cardiac Disorders: QT prolongation, torsade de pointes ( see section 4.4 Special Warnings and Special Precautions for Use).
4.9 Overdose
There have been reports of overdosage with fluconazole and in one case, a 42 year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg of fluconazole,. The patient was admitted to the hospital and his condition resolved within 48 hours.
In the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.
As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Triazole derivatives, ATC code J02AC
Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.
Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.
There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.
5.2 Pharmacokinetic Properties
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 with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. 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.
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. 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 genital candidiasis.
5.3 Preclinical Safety Data
Reproductive toxicity
Adverse foetal effects have been seen in animals only at high dose levels associated with maternal toxicity. 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 50mg/kg and higher doses. At doses ranging from 80mg/kg (approximately 20-60 times the recommended human dose) to 320mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of oestrogen synthesis in rats and may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition.
Carcinogenesis
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10mg/ 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 S.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 1000μg/ml) showed no evidence of chromosomal mutations.
Impairment of fertility
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, although the onset of parturition was slightly delayed at 20mg/kg orally. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. 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. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1 Pharmacodynamic properties).
6. Pharmaceutical Particulars
6.1 List Of Excipients
Colloidal anhydrous silica
Anhydrous lactose
Magnesium Stearate
Maize Starch
Sodium Lauryl Sulphate
Capsule shell contains
Patent blue ( E 131)
Titanium dioxide (E171)
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Gelatin
6.2 Incompatibilities
No specific incompatibilities have been noted.
6.3 Shelf Life
2 years
6.4 Special Precautions For Storage
Blisters : Do not store above 25°C. Store in the original package.
6.5 Nature And Contents Of Container
PVC/PVdC/Al blister pack size of 1 capsule
6.6 Special Precautions For Disposal And Other Handling
No special requirements
7. Marketing Authorisation Holder
Bristol Laboratories Limited
Unit 3, Canalside
Northbridge Road
Berkhamsted
HP4 1EG
United Kingdom
8. Marketing Authorisation Number(S)
PL 17907/0055
9. Date Of First Authorisation/Renewal Of The Authorisation
24th May 2005
10. Date Of Revision Of The Text
24/06/2010
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