Triazole antifungals.

Fluconazole - vaginal candidiasis

Diflucan One contains as its active ingredient fluconazole, 150 mg.

Diflucan One capsules are available for oral administration, as follows: 150 mg: No 1 hard gelatin capsules, blue opaque cap and body: marked with Pfizer logo and code FLU-150.

Diflucan One is indicated for the treatment of the following conditions: Vaginal candidiasis, acute or recurrent; or candidal balanitis associated with vaginal candidiasis.

In adults aged 16 - 60 years

Vaginal candidiasis or candidal balanitis – 150 mg single oral dose

Not recommended in children aged under 16 years.

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.

Diflucan One should not be used in patients with known hypersensitivity to the drug 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 both to prolong the QT interval and be metabolised by CYP3A4 (See section 4.5 Interactions with other medicinal products and other forms of interaction.)

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 administered with caution to patients with potential proarrhythmic conditions such as:

• Congenital or documented acquired QT prolongation

• Cardiomyopathy, in particular when heart failure is present

• Sinus bradycardia

• Existing symptomatic arrhythmias

• Concomitant medication known to prolong QT interval

• Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia

(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 Diflucan One without first consulting your doctor:

If you are under 16 or over 60 years of age.

If you are allergic to any of the ingredients in Diflucan One or other antifungals and other thrush treatments, or have previously had a rash after taking fluconazole .

If you have an intolerance to lactose.

If you are taking any medicine other than the Pill.

If you are taking

the antihistamines terfenadine or astemizole

Cisapride (for indigestion)

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 Diflucan One. Diflucan One 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.

The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose Diflucan One 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 times 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. 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.

Sulfonylureas: Fluconazole has been shown to prolong the serum half life of concomitantly administered oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas 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 50 mg fluconazole study, while at 200 mg daily the AUCs of ethinylestradiol 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 200 mg daily to slowly increase ciclosporin concentrations. However, in another multiple dose study with 100 mg 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 200 mg 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: Interaction studies have been performed because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals and terfenadine concomitantly. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole, taken in doses of 400 mg 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 should not be taken in combination with fluconazole. 

Cisapride: There have been reports of cardiac events including torsade 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 contraindicated in patients receiving fluconazole. 

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 that are also 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.

Diflucan One 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

Skin and Subcutaneous Tissue Disorders: Rash, alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Blood and Lymphatic System Disorders: Leukopenia including neutropenia and agranulocytosis, thrombocytopenia.

Immune System Disorders: Anaphylaxis (including angio-oedema, face oedema, pruritus, urticaria).

Metabolism and Nutritional Disorders: Hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

Cardiac Disorders: QT prolongation, torsade de pointes

McNeil Ltd

P

07 May 2009