INSTRUCTION
for medical use of the medicinal product

FLUCONAZOLE

 

Composition:

Active substance: fluconazole;

100 ml of solution contains 200 ml of fluconazole;

Auxiliary substances: Sodium chloride, disodium EDTA, water for injections.

Dosage form. Solution for infusion.

Main physical and chemical properties: transparent colorless solution.

Pharmacotherapeutical group. Antimycotic preparations for systemic use. Triazole derivatives. АТС code J02А C01.

Pharmacological properties.

Pharmacodynamics.

Fluconazole is a representative of a new class of triazole antimycotic agents, potent selective inhibitor of synthesis of sterols in cells of fungi.

Prescribed activity of fluconazole at opportunistic fungal infections, including those caused by Candida spp., including generalized candidiasis in immunosuppressed animals; Cryptococcus neoformans; including intracranial infections; Misrosporum spp. and Tychophyton spp.

Also the activity of fluconazole has been studied on models of endemic mycoses in animals, including infections caused by Blastomyces dermatitides, Sossidioides ittitis (including intracranial infection) and Nistoplasma capsulatum in animals with normal immunity and immunosuppressed animals.

There are some cases of super infection caused by types of Candida, other than C. albicans, which have a natural insensitivity to fluconazole (eg. Саndida krusei). Such cases require alternative antimycotic therapy.

Fluconazole is highly specific for cytochrome P450-dependent fungal enzymes. With a daily dose of 50 mg during 28 days, fluconazole does not influence testosterone concentration in blood plasma in men and steroid hormones concentration in women of childbearing age.

With a daily dose from 200 mg to 400 mg, fluconazole has no significant clinical effect on endogenous steroid level or on ACTH-stimulated response in healthy male volunteers. Cross experiments with antipyrine indicate absence of fluconazole effect on metabolism in 50 mg dose in single or repeated application.

Pharmacokinetics.

In blood plasma, the drug’s concentration is proportional to a dose. The balanced concentration of 90% is achieved on the 4^th -5^th day of drug treatment in repeated intake once a day.

On the first day of administration of the loading dose, that is twice as big as the usual daily dose, it allows to achieve the balanced concentration of 90% on the second day. The actual volume of distribution of the preparation is close to the total volume of water in the body.

The binding of Fluconazole to blood proteins does not exceed 11-12%.

Fluconazole has a high pervasion degree in all tested liquid mediums of the body.

The levels of the preparation in saliva and sputum are the same as its concentration in blood plasma. At patients with fungal meningitis, fluconazole level in cerebrospinal fluid is 80% of its concentration in blood plasma.

High concentrations of fluconazole in skin, higher than the serum indications, are achieved in the stratum corneum, epidermis-dermis layer and sudoriferous glands. Fluconazole is accumulated in the stratum corneum. At the intake of 50 mg of the preparation once a day, concentration of fluconazole after 12 days was 73 mcg/g and in 7 days after treatment cessation, the concentration was 5.8 mcg/g. At the intake of 150 mg of the preparation once a week, concentration of fluconazole in stratum corneum on day 7 was 23.4 mcg/g and in 7 days after the second dose - 7.1 mcg/g.

The concentration of fluconazole in nails after 4 months of the intake of 150 mg once a week was 4.05 mcg/g in healthy nails and 1.8 mcg/g - in unhealthy nails; fluconazole was found in nail samples in 6 months after the cessation of the treatment.

The preparation is excreted mainly by the kidneys, and about 80% of the taken dose is excreted with the urine in unchanged state.

The semiejection period from blood plasma makes 30 hours after oral intake of 150 mg in a single dose. This allows to apply fluconazole in a single dose for vaginal candidiasis, and to apply it once a day or once a week for other diseases.

Pharmacokinetics characteristics of fluconazole in children

Table 2.

The pharmacokinetic characteristics of fluconazole at intravenous use in children.

Age	Dose (mg/kg)	Semiejection period (hours)	Area under a curve concentration−hour (АUС, mcg х h/ml)
11 days − 11 months	Single 3 mg/kg	23	110,1
5−15 years	Repeated 2 mg/kg	17,4*	67,4*
5−15 years	Repeated 4 mg/kg	15,2*	139,1*
5−15 years	Repeated 8 mg/kg	17,6*	196,7*

 

Note:  * − data received on the last day of the intake.

Fluconazole was being given to premature children (gestation period - about 28 weeks) intravenously in the dose of 6 mg/kg every third day during maximum of 5 days period until the newborns stayed in intensive care. The average semiejection period of the medicine reached 74 (44-185) hours on the 1^st day, with a reduction to 53 (30-131) hours on the 7^th day and up to 47 (27-68) hours - on the 13^th day

АUС made 271 (interval 173-385) on the 1^st day, then increased up to the average indicator in 490 (interval 292-734) on the 7^th day and decreased to the average indicator in 360 (interval 167-566) on the 13^th day.

The volume of distribution (ml/kg) made 1183 (interval 1070-1470) on the 1^st day, then it eventually increased up to the average indicator in 1184 (interval 510-2130) on the 7^th day and in 1328 (interval 1040-1680) - on the 13^th day.

The pharmacokinetic characteristics of fluconazole in old people

Concomitant use of diuretics does not significantly influence the indicators of AUC or C_max; in addition, creatinine clearance (74 ml/min), the percentage of recovered drug in unchanged state in the urine (0 - 24 hours, 22%) and evaluation of renal clearance of fluconazole (0.124 ml/min/kg) for the elderly patients were generally lower than similar indicators in young healthy volunteers. Therefore, at the elderly patients, the distinction of the accumulation of fluconazole is associated with reduced indicators of renal function at this age group.

Clinical characteristics.

Indications.

Treatment of following diseases in adults:

• – cryptococcal meningitis;
• – coccidioidosis;
• – invasive candidiasis;
• – mucosal candidiasis including oropharyngeal and oesophageal candidiasis, candiduria,

chronic candidiasis of the skin and mucous membranes;

• – chronic atrophic candidiasis (candidiasis caused by dentures) after ineffective local therapy.

Prevention of following diseases in adults:

• – relapse of cryptococcal meningitis in patients with a high risk of its development;
• – relapse of oropharyngeal and esophagus candidiasis in HIV patients with a high risk of its development;
• – prevention of candida infections in patients with prolonged neutropenia (e.g. patients with malignant blood diseases treated with chemotherapy or patients with transplanted hematopoietic stem cells).

Fluconazole can be used for newborns to treat mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and to prevent candida infections in immunosuppressed patients. Also it can be used as supporting therapy to prevent relapse of cryptococcal meningitis in children with a high risk of its development.

Therapy can be initiated before obtaining the results of culture and other laboratory tests. After obtaining the results, antibacterial therapy should be adjusted appropriately.

Contraindications.

Hypersensitivity to fluconazole and its excipients or other azole substances similar in chemical structure.

Concomitant use of fluconazole and terfenadine is contraindicated to the patients treated with 400 mg of fluconazole once a day or more.

The patients who receive treatment with medicinal preparations, which are metabolized by the CYP3A4 enzyme (e.g. cisapride, astemizole, pimozide, quinidine and erythromycin) and prolong QT interval, should not be treated with fluconazole.

 

Interaction with other medical preparations and other forms of interaction.

Medicinal preparations that should not be used during treatment with Fluconazole.

Cisapride.

Some cases of adverse reactions in heart, including paroxysmal ventricular tachycardia of the "pirouette" type have been reported after concomitant use of fluconazole and cisapride. Concomitant use of 200 mg of fluconazole once a day and 20 mg of cisapride four times a day resulted in a significant increase of the cisapride concentration in blood plasma and prolongation of QT interval.

The use of cisapride is contraindicated for patients treated with fluconazole (see. Section "Contraindications).

Terfenadine.

Due to reported cases of severe rhythm disorders at the time of the concomitant use of fluconazole and terfenadine, the studies on the interaction of these drugs were carried out.

The study of the use of 200 mg of fluconazole once a day did not show a prolongation of QT interval. The use of 400 mg and 800 mg showed that the intake of 400 and more mg of Fluconazole per day significantly increases the terfenadine concentration in blood plasma.

Concomitant use of 400 or more mg of fluconazole per day with terfenadine is contraindicated (see. Section "Contraindications").

Treatment with less than 400 mg of fluconazole per day in combination with terfenadine should be carefully monitored.

Astemizole.

Concomitant use of fluconazole and astemizole can decrease the clearance of astemizole. The increase of astemizole concentration in blood plasma can lead to prolongation of QT interval, and in rare cases - to paroxysmal ventricular tachycardia of the "pirouette" type. Concomitant use of fluconazole and astemizole is contraindicated.

Pimozide and quinidine.

Concomitant use of fluconazole and pimozide or quinidine can lead to inhibition of metabolism of pimozide or quinidine, although there are no relevant in vitro and in vivo studies. The increase of concentration of pimozide or quinidine in blood plasma can lead to prolongation of QT interval, and in rare cases – can lead to the development of paroxysmal ventricular tachycardia of the "pirouette" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.

Erythromycin.

Concomitant use of fluconazole and erythromycin can potentially increase the risk of cardiotoxicity (prolongation of QT interval, paroxysmal ventricular tachycardia of the "pirouette" type) and, as a result, to sudden cardiac death. The combination of these medical preparations is contraindicated.

Concomitant use of fluconazole and the following medical preparations is not recommended

Halofantrine.

Fluconazole can increase the halofantrine concentration in blood plasma by inhibition of CYP3A4. Concomitant use of these medical preparations can potentially increase the risk of cardiotoxicity (prolongation QT, paroxysmal ventricular tachycardia of the "pirouette" type) and, as a result, to sudden cardiac death. The combination of these medical preparations is contraindicated.

Concomitant use of fluconazole and the following medical preparations must be carefully monitored and the dose might have to be adjusted.

Influence of other medicinal preparations on fluconazole

Studies of the interaction have demonstrated that simultaneous food intake, cimetidine, antacids, or further irradiation of the whole body for bone marrow transplantation have no clinically significant effect on the absorption of fluconazole during its oral intake.

Rifampicin.

Concomitant use of fluconazole and rifampicin has resulted in the decrease of AUC by 25% and the duration of the semiejection period of fluconazole by 20%.

Patients, treated with rifampicin and fluconazole, should consider the expediency of the increase in the dose of fluconazole.

Influence of fluconazole on other medicinal preparations

Fluconazole is a vigorous inhibitor of 2C9 isozyme P450 cytochrome (CYP) and a temperate CYP3A4 inhibitor. Fluconazole is also a CYP2S19 inhibitor. In addition to the observed / documented interactions described below, there is a risk of increase of concentration of other compounds in blood plasma which are metabolized by CYP2C9 and CYP3A4 at the concomitant use of fluconazole. So these combinations of drugs must be used with caution; and it is necessary to closely monitor the patients’ state. Fluconazole inhibitory effect on enzymes persists for 4-5 days after the intake due to its prolonged semiejection period.

Alfentanil.

During concomitant use of 20 mg/kg of alfentanil and 400 mg of fluconazole in healthy volunteers, a twofold increase of AUC₁₀ was observed, possibly due to the inhibition of CYP3A4. Adjustment of the alfentanil dose might be necessary.

Amitriptyline, nortriptyline.

Fluconazole increases the effect of amitriptyline and nortriptyline. It is recommended to measure the concentration of 5-nortriptyline and/or S-amitriptyline in the beginning of combination therapy and in one week. If necessary, the dose of amitriptyline / nortriptyline should be adjusted.

Amphotericin B.

Concomitant use of fluconazole and amphotericin B in infected mice with normal immunity and infected mice with immunosuppression has led to the following results: a small additive antifungal effect at systemic C. albicans infection, lack of interaction at intracranial Cryptococcus neoformans infection, and antagonism of the two medical preparations at systemic A. fumigatus infection. The clinical significance of results obtained in the course of these studies, is unknown.

Anticoagulants.

Fluconazole increased the prothrombin time by 12% in healthy male volunteers treated with warfarin.

The post-registration studies had the reports of bleeding (hematoma formation, epistaxis, gastrointestinal bleeding, hematuria and melena) associated with an increase of prothrombin time in patients treated with fluconazole and warfarin concurrently. At the time of the concomitant use of fluconazole and warfarin, there was a twofold increase in prothrombin time, apparently due to the inhibition of metabolism of warfarin because of CYP2C9. It could be necessary to adjust the dose of warfarin. The close control of prothrombin time is needed in patients treated with coumarin anticoagulants.

Short-acting benzodiazepines, such as midazolam, triazolam.

At ingestion of midazolam the intake of fluconazole leads to a significant increase in the concentration of midazolam and the occurrence of adverse psychomotor reactions.

This midazolam’s effect is more expressed when the patient intakes fluconazole in capsules than when the patient is treated intravenously.

Concomitant use of 200 mg of fluconazole and 7.5 mg of midazolam in oral intake led to an increase of AUC and semiejection period in 3.7 and 2.2 times correspondingly. The use of 200 mg of fluconazole per day and 0.25 mg of triazolam in oral intake led to an increase of AUC and semiejection period in 4.4 and 2.3 times correspondingly. There are observed potentiation and prolongation effects of triazolam in concomitant use of fluconazole and triazolam.

If prescription of benzodiazepine is necessary for the patient treated with fluconazole, the dose of fluconazole should be reduced, and the patient’s state should be carefully monitored.

Carbamazepine.

Fluconazole inhibits metabolism of carbamazepine and generates an increase of carbamazepine level in blood serum by 30%. There is a risk of carbamazepine’s toxicity manifestations. It could be necessary to adjust the dose of carbamazepine depending on its concentration and the drug activity.

Calcium channel blockers.

Some calcium antagonists (nifedipine, isradypin, amlodipine and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole can potentially increase the systemic exposure of calcium channel blockers. Close monitoring is recommended to prevent the development of adverse reactions.

Celecoxib.

During concomitant use of fluconazole (200 mg per day) and celecoxib (200 mg), C_max and AUC of celecoxib increased by 68% and 134% correspondingly. Double reduction of celecoxib dose could be necessary in case of concomitant use of fluconazole and celecoxib.

Cyclophosphamide.

Concomitant use of cyclophosphamide and fluconazole increases the levels of bilirubin and creatinine in blood serum. These drugs can be used concurrently, considering the risk of increase of bilirubin and creatinine concentration in blood serum.

Fentanyl.

One lethal case of fentanyl intoxication due to possible interaction between fentanyl and fluconazole was reported. In addition, a study involving 12 healthy volunteers has demonstrated that fluconazole significantly delayed the elimination of fentanyl. The increase of concentration of fentanyl can lead to respiratory depression, so the patients’ state should be closely monitored. It could be necessary to adjust the dose of fentanyl.

Inhibitors of HMG-CoA reductase.

Concomitant use of fluconazole and inhibitors of HMG-CoA reductase metabolized by CYP3A4 (atorvastatin and simvastatin) or inhibitors of HMG-CoA reductase metabolized by CYP2C9 (fluvastatin), increases the risk of myopathy and rhabdomyolysis. If the concomitant use of these drugs is necessary, the patients should be closely monitored for the occurrence of symptoms of myopathy and rhabdomyolysis, and monitoring of creatine kinase should also be carried out. The use of inhibitors of HMG-CoA reductase should be stopped in case of significant increase of creatine kinase’s level or if there is a diagnosis or a concern over myopathy / rhabdomyolysis.

Immunosuppressive agents (e.g. cyclosporine, everolimus, tacrolimus and syrolimus).

Cyclosporine.

Fluconazole significantly increases the concentration and AUC of cyclosporine. The 1.8-fold increase of AUC of cyclosporine was observed during the concomitant use of 200 mg of fluconazole per day and 2.7 mg/kg of cyclosporine per day. The concomitant use of these medical preparations can be carried out, if the dose of cyclosporine is decreased depending on its concentration. 

Everolimus.

Although in vitro and in vivo studies were not carried out, fluconazole can increase the concentration of everolimus in blood serum because of the inhibition of CYP3A4.

Syrolimus.

Fluconazole increases the concentration of syrolimus in blood plasma apparently by the inhibition of syrolimus metabolism with CYP3A4 enzyme and P-glycoprotein. The concomitant use of these medical preparations is possible, if a dose of syrolimus is adjusted depending on its concentration and effects.

Tacrolimus.

It was reported that interaction between fluconazole and tacrolimus resulted in the 5-fold increase of tacrolimus concentration in blood serum during its oral intake because of the inhibition of tacrolimus metabolism with CYP3A4 enzyme in the intestine. During tacrolimus intravenous administration, significant changes in pharmacokinetics were not observed. Cases of increased nephrotoxicity during concomitant use of fluconazole and tacrolimus were reported. The dose of tacrolimus for oral intake should be decreased depending on the concentration of tacrolimus.

It is necessary to closely monitor the state of the patients who intake tacrolimus and fluconazole concurrently.

Losartan.

Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which causes most of antagonism to the angiotensin II receptors during the administration of losartan. It is recommended to regularly monitor the patients’ blood pressure.

Methadone.

Fluconazole can increase the concentration of methadone in blood serum. It could be necessary to adjust the dose of methadone in concomitant use of fluconazole and methadone.

Nonsteroid anti-inflammatory drugs.

In concomitant use of fluconazole, the indicators of C_max and AUC of flurbiprofen were increased by 23% and 81% compared with indicators when flurbiprofen was used solely. Similarly, during the concomitant use of fluconazole and racemic ibuprofen (400 mg), Cmax and AUC of pharmacologically active isomer, S–(+)– of ibuprofen were increased by 15% and 82% compared with indicators when racemic ibuprofen was used solely.

Although specific studies weren’t carried out, fluconazole can potentially increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). It is recommended to conduct monitoring of adverse reactions and toxic manifestations associated with NSAIDs. It could be necessary to adjust the dose of NSAIDs.

Phenytoin.

Fluconazole inhibits the metabolism of phenytoin in the liver.

Concomitant use of fluconazole and phenytoin can increase the concentration of phenytoin up to a clinically significant degree.

If the concomitant use of drugs is necessary, then phenytoin’s level should be monitored and its dose should be adjusted for therapeutic concentration in blood serum.

Prednisolone.

A case was reported where the patient received treatment with prednisone after liver transplantation, and has developed acute insufficiency of the adrenal cortex that occurred three months later after a course of fluconazole therapy. Probably, discontinuation of fluconazole administration was a cause of increasing activity of CYP3A4, which resulted in acceleration of metabolism of prednisone. It is necessary to closely monitor the state of the patients, who intake fluconazole and prednisone concurrently for a long time, in order to prevent insufficiency of the adrenal cortex after discontinuation of fluconazole intake.

Rifabutin.

It was reported that interaction between fluconazole and rifabutin results in the increase of the rifabutin serum levels.

Some cases of uveitis during the concomitant use of fluconazole and rifabutin were reported. When using this combination of drugs, it is necessary to consider the symptoms of toxic effects of rifabutin. The state of the patients who intake rifabutin and fluconazole concurrently should be closely monitored.

Saquinavir.

Fluconazole increases C_max and AUC of saquinavir by 50% and 55% approximately, by inhibition of saquinavir metabolism in the liver with CYP3A4 enzyme and by inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir / ritonavir were not studied, so they could be more expressed. It could be necessary to adjust the dose of saquinavir.

Sulfonylureas.

Fluconazole prolonged semiejection period of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers during concomitant administration.

Fluconazole and oral sulfonylurea drugs can be used concurrently for patients with diabetes, but it is necessary to consider the possible development of hypoglycemia. It is recommended to provide  periodical control of blood sugar and decrease the dose of sulfonylurea accordingly in case of concomitant use of fluconazole.

Theophylline.

The intake of 200 mg of fluconazole for 14 days has resulted in a decrease of the average rate of theophylline clearance from blood plasma by 18%.

It is necessary to watch for the symptoms of theophylline overdose in the patients, treated with fluconazole and theophylline in high doses or in the patients with increased risk of theophylline toxic effects. The therapy should be adjusted properly if there are any symptoms of the overdose.

Vinca alkaloid.

Although relevant studies were not carried out, fluconazole can possibly cause the increase of concentration of vinca alkaloid in blood plasma (e.g. vincristine and vinblastine) by means of inhibition of CYP3A4, and it results in a development of neurotoxic effects.

Vitamin A

It was reported that the patient, treated with trans-retinoic acid (an acid form of vitamin A) and fluconazole concurrently, had adverse reactions in the central nervous system (CNS) in the form of pseudotumor of the brain, which disappeared after discontinuation of fluconazole. These drugs can be used concurrently, but it is necessary to consider the risk of adverse reactions in the central nervous system.

Voriconazole (CYP2C9 and CYP3A4 inhibitor).

Concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole  (400 mg on the first day, then 200 mg every 24 hours for 4 days) in 8 healthy male volunteers has resulted in the increase of Cmax and AUC_τ of voriconazole on the average up to 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether a decrease of the dose and/or frequency of fluconazole or voriconazole administration result in elimination of this effect. In case of administration of voriconazole after fluconazole, it is necessary to observe for the development of side effects associated with voriconazole.

Zidovudine.

Kinetic studies have shown increased levels of zidovudine which were associated with a decrease of its transformation into its main metabolite. It is necessary to closely monitor the state of the patients who used such combination, in order to detect side effects of zidovudine. A decrease of the dose of zidovudine can be considered.

Azithromycin.

Concomitant oral single intake of 1200 mg of azithromycin and 800 mg of fluconazole hasn’t resulted in any significant pharmacokinetic interactions between fluconazole and azithromycin. There is no significant effect on the pharmacokinetics between interactions of fluconazole and azithromycin.

Oral contraceptives.

No significant effect on hormone levels during the intake of 50 mg of fluconazole was observed. However, there there was an extension of the area under the curve “concentration-time” of (AUC) ethinylestradiol by 40% and levonorgestrel by 24% during the intake of 200 mg per day.

The studies showed that during the intake of 300 mg of fluconazole once a week, AUC of ethinylestradiol and norethindrone was higher respectively by 24% and 13. It is unlikely that repeated intake of fluconazole at these doses had a negative impact on the effectiveness of combined oral contraceptives.

Hydrochlorothiazide.

In the study of the interaction of kinetics in healthy volunteers treated with fluconazole, the repeated use of hydrochlorothiazide resulted in the increase of concentration of fluconazole in blood plasma by 40%. The impact on this rate doesn’t require any change of the fluconazole dose in patients treated with diuretics, but doctors should consider possible interaction.

The studies of interaction with other drugs haven’t been carried out, so the interaction is potentially possible.

Peculiarities of use.

Dermatophytosis.

According to the results of the study of fluconazole for the treatment of dermatophytosis in children, fluconazole doesn’t exceed griseofulvin in efficiency and the overall rate of its effectiveness is less than 20%. Therefore, fluconazole shouldn’t be used for treatment of dermatophytosis.

Cryptococcosis.

There is not enough evidence of efficacy of fluconazole for the treatment of cryptococcosis in different localizations (e.g. pulmonary cryptococcosis and cryptococcosis of skin), so there are no recommendations regarding the dosage regimen for the treatment of such diseases.

Deep endemic mycoses.

There is not enough evidence of efficacy of fluconazole for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis and cutaneous lymphatic sporotrichosis, so there are no recommendations regarding the dosage regimen for treatment of such diseases.

Renal system.

The medical preparation should be used with caution for the patients with kidney dysfunction (see section "Dosage and method of application").

Hepatobiliary system.

The medical preparation should be used carefully for the patients with liver dysfunction. In rare cases, the use of fluconazole was followed by toxic liver damages, including death.

In cases when the development of hepatotoxicity was associated with the use of fluconazole, there was no observed dependence of the total daily dose, duration of therapy, sex or age.

Hepatotoxic action of fluconazole was generally reversible, and its signs disappeared after discontinuance of therapy. It is necessary to monitor the patients with violated indicators of liver function caused by fluconazole treatment, for revealing the signs of a serious liver damage. The medical preparation should be discontinued when the clinical signs of liver damage, which can be associated with the use of fluconazole, occur.

Patients should be informed about the symptoms that could indicate a serious impact on the liver (expressed asthenia, anorexia, constant nausea, vomiting and jaundice). In this case, it is necessary to consult a doctor, and to discontinue the use of fluconazole immediately.

Dermatological reactions.

Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis occur rarely. AIDS patients are more prone to serious skin reactions.

The intake of the medical preparation should be discontinued if a patient with superficial fungal infection has a rash which can be associated with fluconazole.

It is necessary to monitor the patients with invasive / systemic fungal infections for a rash and fluconazole intake should be cancelled if the bullous lesions or erythema multiforme occur.

Cardiovascular system.

The cases of QT-interval prolongation and paroxysmal ventricular tachycardia of the "pirouette" type were rarely detected in patients treated with fluconazole. These cases concerned the patients with serious diseases and a combination of many risk factors, such as structural heart disease, electrolyte abuse and concomitant use of other drugs affecting the QT interval.

Fluconazole should be prescribed with caution for the patients with  the history of potentially pro-arrhythmic conditions. Concomitant use of fluconazole with the drugs that prolonged a QTs interval and the drugs, metabolized by CYP3A4 enzyme of P450 cytochrome, is contraindicated.

Halofantrine.

Halofantrine is a substrate of CYP3A4 enzyme and it prolongs QTs interval at application in the recommended therapeutic dosages. Concomitant use of fluconazole and halofantrine is not recommended.

Hypersensitivity.

In rare cases, the development of anaphylactic reactions was reported.

Cytochrome Р450.

Fluconazole is a potent inhibitor of CYP2C9 enzyme and a moderate inhibitor of CYP3A4 enzyme. Fluconazole is also an inhibitor of CYP2C19 enzyme. It is necessary to monitor the state of the patients treated with both fluconazole and drugs with a small therapeutic window, metabolized with CYP2C9, CYP2C19 and CYP3A4.

Terfenadine.

It is necessary to carefully monitor the patients treated concurrently with terfenadine and fluconazole in a dose less than 400 mg per day due to reported cases of severe arrhythmic disorders.

In some cases, the occurrence of anaphylaxis due to the use of fluconazole was reported.

Excipients.

The medical product contains 0.9% of sodium chloride. Each dose of 200 mg (100 ml bottle) contains 15 mmol of sodium. Thus, it should be prescribed with caution to patients who are treated with a sodium-controlled diet.

Use during pregnancy and lactation.

The current data on the use of single and repeated doses of fluconazole (<200 mg / day) in several hundred pregnant women during the 1 trimester have demonstrated no adverse effects on the fetus. Numerous congenital diseases in newborns (including bradyphrenia, dysplasia of the ear, excessive anterior fontanel, curvature of the hips, humero-ulnar synostosis) whose mothers were taking fluconazole in high doses (400-800 mg per day) for at least three or more months for the treatment of coccidioidosis were reported. The connection between the use of fluconazole and these cases has not been established.

Animal testing has shown reproductive toxicity.

It is advisable not to use the usual doses of fluconazole and short-term courses of treatment with fluconazole during pregnancy, except in case of emergencies.

It is advisable not to use high doses of fluconazole and / or prolonged treatments with fluconazole during pregnancy, except for the treatment of infections which are potentially life-threatening.

Fluconazole permeates into breast milk and achieves a lower concentration than in blood plasma.

Breast-feeding can be continued after a single ordinary dose of fluconazole that makes 200 mg or less.

Breast-feeding is not recommended after repeated use of fluconazole or when using high doses of fluconazole.

 

Ability to influence reaction rate when driving or operating other machinery. 

There are no reports on the influence of the preparation on the capacity to drive or operate technical devices. The patients should be informed about the possibility of dizziness or seizures during the use of the medical preparation. It is not recommended to drive a car or operate technical devices if the symptoms occur.

Routes of administration and dosage.

The daily dose of fluconazole depends on the nature and severity of the mycotic infection. Treatment of infections, requiring repeated intake, should be continued until the clinical and laboratory effects are achieved. Insufficient time of treatment could result in renewal of the active infection process.

Fluconazole should be administrated orally or intravenously by infusion at the rate of no more than 10 ml/min. The way of administration depends on the clinical condition of the patient.

It is not necessary to change the daily dose when transferring from the intravenous to oral intake and vice versa. Therapy can be started before the results of culture and other laboratory tests, but after the results are ready, antimicrobial preparations must be also added.

Compatibility

For intravenous administration, fluconazole is compatible with the following solutions:

- Ringer’s solution;

- Hartman’s solution;

- Solution of potassium chloride in glucose;

- 4.2% and 5% sodium bicarbonate;

- 3.5% aminosyn;

- 0.9% sodium chloride;

- dialafleks (6,36% solution for intraperitoneal dialysis).

Fluconazole may be combined in an infusion system with one of the above solutions. It is not recommended to mix up the preparation with other ones before the infusion, although the cases of non-specific drug incompatibility with other preparations are not reported

The solution for intravenous infusion is intended for a single use only. Dilution should be performed under aseptic conditions. The solution must be tested for the presence of foreign particles and color changes. The solution should be used only when it is clear and free of foreign particles. Unused remainders of the drug must be destroyed.

Adults

Cryptococcosis.

In cryptococcal meningitis and cryptococcal infections of other localizations 400 mg should be administered parenterally on the first day, and then continue the treatment using doses from 200 to 400 mg once a day. Duration of therapy for cryptococcal infection depends on the clinical response, but it usually lasts at least 6 - 8 weeks for cryptococcal meningitis. For life-threating infections, the daily dose can be increased up to 800 mg.

The supporting therapy is aimed to prevent a relapse of cryptococcal meningitis in patients with high risk of its development: The recommended dose makes 200 mg per day during indefinite time.

Coccidioidosis

The recommended dose makes 200-400 mg per day. Duration of the treatment makes 11-24 months or more, depending on the patient’s condition. It could be appropriate to use a dose of 800 mg per day for the treatment of some forms of infection, especially for the treatment of meningitis.

Invasive candidiasis.

In candidemia, disseminated candidiasis and other forms of invasive Candida infections, the loading dose makes 800 mg on the first day and the supportive dose - 400 mg per day parenterally. Generally, the recommended duration of the treatment of candidemia makes 2 weeks after first negative results of blood culture tests and disappearance of signs and symptoms of candidemia.

Candidiasis of mucous membranes.

- Oropharyngeal candidiasis: the loading dose makes 200-400 mg on the first day and the supportive dose of 100-200 mg per day. Duration of the treatment makes 7-21 days (before remission), but it could be increased in patients with severe immunodeficiency;

- Esophageal candidiasis: the loading dose makes 200-400 mg on the first day and the supportive dose of 100-200 mg per day. Duration of the treatment makes 14-30 days (before remission), but it could be increased in patients with severe immunodeficiency;

- Candiduria: the recommended dose makes 200-400 mg per day for 7-21 days. For the patients with severe immune deficiency, duration of the treatment can be increased;

- Chronic atrophic candidiasis: The recommended dose makes 50 mg per day for 14 days;

- Chronic candidiasis of the skin and mucous membranes: the recommended dose makes 50-100 mg per day. Duration of the treatment makes 28 days, but it could be increased depending on the severity and a type of infection or depressed immunity.

Prevention of candidiasis’ relapse of mucosal membranes in patients with HIV, who have a high risk for its development.

- Oropharyngeal candidiasis, esophageal candidiasis: the recommended dose makes 100-200 mg per day or 200 mg 3 times a week. Duration of the treatment is unlimited for patients with depressed immunity.

Prophylaxis of Candida infections in patients with prolonged neutropenia.

If there is a high risk of generalized infection (in patients with the expected, severe or prolonged neutropenia), the recommended dose makes 200-400 mg once a day. Fluconazole should be administered a few days before the expected neutropenia; after the neutrophil amount increases above 1000 in 1 mm³, the treatment should be continued for another 7 days.

Elderly patients.

The dose should be selected depending on the kidney’s state  (see. Below).

Renal failure.

Fluconazole is excreted primarily in the urine in unchanged form. Adjustment of the dose is not required for a single use. In case the repeated use of the drug is needed, the initial dose should be 50-400 mg, depending on the prescription, for the patients with renal failure (including children). Then the daily dose (according to the prescription) should be calculated according to the following table:

 

Creatinine clearance (ml / min)	The percentage from the recommended dosage
> 50	100 %
≤ 50 (no dialysis)	50 %
Regular dialysis	100 % after every dialysis

 

Patients, who have the regular dialysis, should intake 100% of the recommended dose after every dialysis. On the day when dialysis is not performed, the patient should intake a dose, adjusted according to the creatinine clearance.

Impaired liver function.

Fluconazole should be used carefully in patients with impaired liver function, because there is not enough information about the use of fluconazole in this category of patients.

Children.

Do not exceed the maximum daily dose of 400 mg.

Duration of the treatment for children as for respective infections in adults depends on the clinical and antimycotic effect.

Fluconazole should be used once a day every day.

The drug’s dosage for children with renal dysfunction is mentioned above. The pharmacokinetics of fluconazole has not been studied in children with renal failure (see below the information about the use for newborns, who frequently have primary immature kidneys).

Children under the age of 12 years.

Depending on body weight and pubertal development, a doctor should estimate what dosage (for adults or children) is optimal for the patient. Clinical data indicate that children have a higher fluconazole clearance compared to adults. The use of 100 mg, 200 mg and 400 mg for adults and 3, 6 and 12 mg / kg for children results in achievement of comparable systemic exposure.

Children in the age of 28 days to 11 years.

Mucosal candidiasis: the initial dose of 6 mg/kg per day and the supportive dose of 3 mg/kg per day. The initial dose can be used on the first day to expedite the achievement of equilibrium concentration.

Invasive candidiasis, cryptococcal meningitis: the dose makes 6-12 mg/kg per day depending on the severity of the disease.

The supporting therapy is aimed to prevent the relapse of cryptococcal meningitis in children with a high risk of its development: dose of 6 mg/kg per day depending on the severity of the disease.

Prophylaxis of candidiasis in immunocompromised patients: the dose makes 3-12 mg/kg per day depending on the severity and duration of the induced neutropenia (see Dosage for adults).

Children in the age of 0 to 27 days.

Fluconazole is excreted slowly in newborns. Pharmacokinetic data are listed below, see "Pharmacokinetics".

 

• – Full-term infants in the age of 0 to 14 days: The doses, same as the mentioned above for children in the age of 28 days to 11 years, should be used every 72 hours. Do not exceed the maximum dosage that makes 12 mg/kg every 72 hours.
• – Full-term infants in the age of 15 to 27 days: The doses, same as the mentioned above for children in the age of 28 days to 11 years, should be used every 48 hours. Do not exceed the maximum dosage that makes 12 mg/kg every 48 hours.

Children.

The medical preparation could be used for children from birth.

Overdose.

Hallucinations and paranoid behavior may occur.

In case of overdose, it is necessary to carry out symptomatic supportive therapy. Gastric lavage might be necessary.

Fluconazole is mostly excreted in the urine; forced diuresis can accelerate the excretion of the medical preparation. A 3-hour hemodialysis session decreases the level of fluconazole in blood plasma by approximately 50%.

Side effects.

The most common adverse reactions (> 1/10) are headache, abdominal pain, diarrhea, nausea, vomiting, rash, increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase levels.

In some patients, especially those who suffer from serious diseases (AIDS or cancer), there were observed changes of blood indicators, kidney and liver function, but clinical presentations of these changes and their connection with the use of fluconazole solution have not been established.

Central nervous system: headache, dizziness, cramps, taste disorder, paraesthesia, and tremor.

Digestive system: abdominal pain, diarrhea, flatulence, nausea, indigestion, vomiting, constipation, dyspepsia, and dry mouth.

Liver/biliary system: toxic liver damage, including rare fatalities, increase of levels of alkaline phosphatase, bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), cholestasis, liver failure, hepatitis, hepatocellular necrosis, jaundice, and hepatocellular injury.

Skin: rash, alopecia, exfoliative skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, itching, drug-induced dermatitis, urticaria, increased sweating, acute generalized exanthematous pustulosis, angioedema, face edema, and exfoliative dermatitis.

Blood and lymphatic system: leucopenia, including neutropenia and agranulocytosis, thrombocytopenia, and anaemia.

Immune system: anaphylaxis, including angioneurotic edema, swelling of the face and skin’s itching; urticaria.

Metabolic processes / eating habits: hypercholesterolemia, hypertriglyceridemia, hypokalemia, decreased appetite.

Psychiatric disorders: insomnia and somnolence.

Cardiovascular system: prolongation of QT interval, paroxysmal ventricular tachycardia of the "pirouette" type.

Hearing and vestibular apparatus: vertigo.

Musculoskeletal system and connective tissue: myalgia.

General disorders and reactions in the injection site: increased fatigue, malaise, fatigue and fever.

Children. The frequency and nature of side effects and abnormalities of laboratory tests in clinical trials involving children are comparable with clinical trials of adults.

Storage life. 2 years. 

Storage conditions.

Keep out of reach of children in the original package at temperature below 25 ^°С. Unused remaining medical preparation must be destroyed.

Incompatibility.

The features of incompatibility of the drug were not noticed. Medical preparation should not be mixed with other medicinal products in intravenous introduction except those referred to in the "Dosage and Administration" section.

Packaging.

100 ml of the preparation in every container. 1 container in a PVC film with the package leaflet in the box.

Terms of dispensing. On prescription.

Manufacturer.

Eurolife Healthcare Pvt. Ltd.

Manufacturer’s registered address.

Hashra No 520, Bhagwanpur, Ruhr, Haridwar, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, SW6 2PY, London, United Kingdom.

Date of last review.

03.09.2015.