Fluconazole 150mg capsules

Boots Thrush 150mg Capsule (Fluconazole)

Each capsule contains Fluconazole 150mg

For excipients, see 6.1

Capsule for oral administration

White to off white powder filled in Blue/Blue coloured hard gelatin capsules of size '1'.

Fluconazole 150mg is indicated for the treatment of the following conditions:

Vaginal candidiasis, acute or recurrent. Candidal balanitis. associated with vaginal candidiasis.

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.

Fluconazole should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.

Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400mg per day or higher based upon results of a multiple dose interaction study. Fluconazole should not be co-administered with cisapride, astemizole, pimozide or quinidine or terfenadine which are known to both prolong the QT-interval and are metabolized by CYP3A4 (See sections 4.4 Special warnings and Special Precautions for Use and 4.5 Interactions with other medicinal products and other forms of interaction).

Fluconazole should be administered with caution to patients with liver dysfunction (see also 4.2).

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.

Patients who develop abnormal liver function tests during Fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop during treatment with Fluconazole.

Patients have rarely 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. If a rash develops in a patient treated for a superficial fungal infection which is considered attributable to Fluconazole, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and Fluconazole discontinued if bullous lesions or erythema multiforme develop.

The coadministration of fluconazole at dosed lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4,3 Contraindications and 4.5 Interaction with Other Medicaments and Other Forms of Interaction).

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. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. 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 arrhythmias

• Concomitant medication not metabolized by CY34A but 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)

Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored (see section 4.5 Interation with Other Medicaments and Other Forms of Interaction).

Fluconazole capsules contain lactose. 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.

The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose fluconazole has not yet been established. Patients on other medications should consult their doctor or pharmacist before starting fluconazole.

Concomitant use of the following other medicinal product is contraindicated:

Terfenadine: - Because of the occurrence of serious cardiac 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. The combined use of fluconazole at doses of 400mg or greater with terfenadine is contraindicated (see section 4.3 Contraindications).The co-administration of fluconazole at doses lower than 400mg per day with terfenadine should be carefully monitored.

Cisapride: - There have been reports of cardiac events including Torsades de Pointes in patients to whom fluconazole and cisapride were coadministered-. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illnesses, and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is unclear. A controlled study found that concomitant fluconazole 200mg once daily and cisapride 20mg four times a day yielded a significant increase in cisapride levels and prolongation of QT interval. Because of the potential seriousness of such an interaction, co-administration of cisapride is contra-indicated in patients receiving fluconazole. (See section 4.3 Contra-indications.)

Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurances of torsade de pointes. Co-administration of fluconazole and astemizole is contraindicated

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

Concomitant use of the following other medicinal products cannot be recommended:

Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardio toxicity (prolonged QT interval, Torsades de Pointes) and consequently sudden heart death. This combination should be avoided.

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

The effect of other medicinal products on 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 pharmacokinetic 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.

The effect of fluconazole on other medicinal products

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 co-administered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to long half-life of fluconazole (See section 4.3).

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T_1/2 of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitryptiline, nortryptiline: Fluconazole increases the effect of amitryptiline and nortriptyline. 5- nortryptiline and/or S-amitryptiline may be measured at initiation of the combination therapy and after 1 week. Dosage of amitryptiline/nortriptyline should be adjusted, if necessary.

Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

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, hematuria 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. Dose adjustment of warfarin may be necessary.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

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.

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C_max with 20-32% and increases t_1/2 by 25-50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on the ciclosporin concentration.

Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiration depression.

Halofantrine: Fluconazole can increase halofantine plasma concentration due to an inhibitory effect of CYP3A4.

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is co-administered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdymolysis is diagnosed or suspected.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during the treatment with losartan. Patients should have their blood pressure monitored continuously.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when co-administered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Oral contraceptives: Two pharmacokinetic 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. Thus multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. With co-administration, serum phenytoin concentration levels should be monitored to avoid phenytoin toxicity

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. This discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increase metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of Rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration

Saquinavir: Fluconazole increases the AUC of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Sulphonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (e.g., chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Endogenous steroid: Fluconazole 50mg daily does not affect endogenous steroid levels in females: 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.

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.

Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 85% and 75%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

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.

Use during pregnancy

Data from several hundred pregnant women treated with standard dosed (<200 mg/day) of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the foetus.

There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole and these events is unclear.

Animal studies show teratogenic effects (see section 5.3).

Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the foetus.

Use during lactation

Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.

Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results as hepatic abnormalities (see section 4.4 Special Warnings and Special Precautions for Use) have been observed during the treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

The following undesirable effects have been observed and reported during the treatment with fluconazole with the following frequencies: Very common (1/10); common (1/100 to < 1/10); uncommon (1/1000, < 1/100), rare (1/10000, < 1/1000) and very rare (>1/10000), not known (cannot be estimated from the available data).

Paediatric Population

The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

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%.

Pharmacotherapeutic group: Triazole derivatives, ATC codeJ02AC

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 shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbital sleeping times in mice (p.o.), increased mean arterial and left ventricular blood pressure and increased heart rate in anaesthetised cats (i.v.) occurred. Inhibition of rat ovarian aromatase was observed at high concentrations.

Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp. including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp. and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidoides immitis, including intracranial infection and with Histoplasma capsulatum in normal and immunosuppressed animals.

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. . Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50mg do not affect its metabolism. There have been reports of cases of super infection 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.

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%).

Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. 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% of the corresponding plasma levels.

High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidemis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50mg once daily, the concentration of fluconazole after 12 days was 73 microgram/g and 7 days after cessation of treatment the concentration was still 5.8 microgram/g .

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.

A study compared the saliva and plasma concentrations of a single fluconazole 100mg dose administration in a capsule or in an oral suspension by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.

Pharmacokinetics in Children

In children, the following pharmacokinetic data have been reported:

*Denotes final day

In premature new-borns (gestational age around 28 weeks), intravenous administration of fluconazole of 6mg/kg was given every third day for a maximum of five doses while the premature new-borns remained in the intensive care unit. 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.

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).

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

No specific incompatibilities have been noted.

2 years

Blisters : Do not store above 25°C. Store in the original package.

PVC/PVdC/Al blister pack size of 1 capsule

No special requirements

Bristol Laboratories Limited

Unit 3, Canalside

Northbridge Road

Berkhamsted

HP4 1EG

United Kingdom

PL 17907/0055

24^th May 2005

02/03/2012