Fluconazole STADA (capsules)
Single or repeated use of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone (Antipyrin) when used simultaneously.
Concomitant use of fluconazole with the following drugs is contraindicated:
Cisapride:
with the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The use of fluconazole at a dose of 200 mg once a day and cisapride at a dose of 20 mg 4 times a day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. The simultaneous use of cisapride and fluconazole is contraindicated.
Terfenadine:
With the simultaneous use of azole antifungals and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When using fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in the blood plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated (see section “Contraindications”). Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.
Astemizole:
simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Elevated concentrations of astemizole in blood plasma can lead to prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The simultaneous use of astemizole and fluconazole is contraindicated.
Pimozide:
Although appropriate in vitro or
in vivo
, the simultaneous use of fluconazole and pimozide may lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozide can lead to a prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The simultaneous use of pimozide and fluconazole is contraindicated.
Quinidine:
Although adequate in vitro or
in vivo
, concomitant use of fluconazole and quinidine may also result in inhibition of quinidine metabolism. The use of quinidine is associated with prolongation of the QT interval and, in some cases, with the development of ventricular tachysystolic arrhythmia of the “torsade de pointes” type. The simultaneous use of quinidine and fluconazole is contraindicated.
Erythromycin:
simultaneous use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (QT prolongation, torsade de pointes) and, consequently, sudden cardiac death.
The simultaneous use of fluconazole and erythromycin is contraindicated.
The following medications are not recommended:
Halofantrine:
Fluconazole may increase plasma concentrations of halofantrine due to inhibition of the CYP3A4 isoenzyme. It is possible to develop ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes) when used simultaneously with fluconazole, as well as with other azole antifungal drugs, so their combined use is not recommended.
Caution should be exercised when used simultaneously with fluconazole:
Amiodarone:
Amiodarone use has been associated with QT prolongation. Caution should be exercised when using fluconazole and amiodarone simultaneously, especially when taking a high dose of fluconazole (800 mg).
Caution and possible dosage adjustments should be used when the following drugs are used concomitantly with fluconazole:
Drugs that affect fluconazole:
Hydrochlorothiazide:
repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in the blood plasma by 40%. An effect of this severity does not require a change in the fluconazole dosage regimen in patients receiving concomitant diuretics, but the doctor should take this into account.
Rifampicin:
simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the half-life of fluconazole by 20%. In patients concomitantly taking rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.
Drugs affected by fluconazole:
Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is also an inhibitor of the CYP2C19 isoenzyme. In addition, in addition to the effects listed below, there is a risk of increased plasma concentrations of other drugs metabolized by the isoenzymes CYP2C9, CYP2C19 and CYP3A4 when used simultaneously with fluconazole. In this regard, caution should be exercised when using these drugs simultaneously, and if such combinations are necessary, patients should be under close medical supervision. It should be taken into account that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to the long half-life.
Alfentanil:
There is a decrease in clearance and volume of distribution, and an increase in the half-life of alfentanil. This may be due to inhibition of the CYP3A4 isoenzyme by fluconazole. Alfentanil dosage adjustment may be required. Amitriptyline, nortriptyline: increased effect. Concentrations of 5-nortriptyline and/or S-amitriptyline can be measured at the start of combination therapy with fluconazole and one week after initiation. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.
Amphotericin B:
In studies in mice (including those with immunosuppression), the following results were observed: small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism in systemic infection with A. fumigatus . The clinical significance of these results is unclear.
Anticoagulants:
like other antifungal agents (azole derivatives), fluconazole, when used simultaneously with warfarin, increases prothrombin time (by 12%), and therefore bleeding may develop (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena) . In patients receiving coumarin and indanedione anticoagulants and fluconazole, it is necessary to constantly monitor prothrombin time during therapy and for 8 days after simultaneous use. The feasibility of adjusting the dose of these anticoagulants should also be assessed.
Azithromycin:
with simultaneous oral use of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, no pronounced pharmacokinetic interaction has been established between both drugs.
Benzodiazepines (short-acting):
After oral administration of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after oral administration of fluconazole than when administered intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to assess the appropriateness of an appropriate reduction in the benzodiazepine dose.
With simultaneous use of a single dose of triazolam, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 20-32% and half-life by 25-50% due to inhibition of triazolam metabolism. Triazolam dose adjustment may be necessary.
Carbamazepine:
fluconazole inhibits the metabolism of carbamazepine and increases the serum concentration of carbamazepine by 30%. The risk of carbamazepine toxicity must be taken into account. The need for carbamazepine dose adjustment based on concentration/effect should be assessed.
Calcium channel blockers:
Some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by the CYP3A4 isoenzyme. Fluconazole increases the systemic exposure of calcium channel antagonists. Monitoring for the development of side effects is recommended.
Nevirapine:
Coadministration of fluconazole and nevirapine increases nevirapine exposure by approximately 100% compared with control data for nevirapine alone. Due to the risk of increased excretion of nevirapine during concomitant use of drugs, some precautions and careful monitoring of patients are necessary.
Cyclosporine:
in patients with a transplanted kidney, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine concentrations. However, with repeated use of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentrations were observed in bone marrow recipients. When using fluconazole and cyclosporine simultaneously, it is recommended to monitor the concentration of cyclosporine in the blood.
Cyclophosphamide:
with simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is observed. This combination is acceptable given the risk of increased bilirubin and creatinine concentrations.
Fentanyl:
There has been a report of one death possibly related to the concomitant use of fentanyl and fluconazole. The disturbances are believed to be related to fentanyl intoxication. Fluconazole has been shown to significantly prolong the clearance time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to depression of respiratory function.
HMG-CoA reductase inhibitors:
When fluconazole is used concomitantly with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the CYP2D6 isoenzyme (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If simultaneous therapy with these drugs is necessary, patients should be monitored to identify symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. If there is a significant increase in creatinine kinase concentrations or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.
Ibrutinib:
Moderate CYP3A4 inhibitors such as fluconazole increase ibrutinib plasma concentrations and may increase the risk of toxicity. If the use of drugs in combination cannot be avoided, the dose of ibrutinib should be reduced as indicated in the ibrutinib prescribing information and close clinical monitoring should be ensured.
Losartan:
fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with angiotensin-II receptor antagonism. Regular monitoring of blood pressure is necessary.
Methadone:
Fluconazole may increase plasma concentrations of methadone. Methadone dose adjustment may be necessary.
Nonsteroidal anti-inflammatory drugs (NSAIDs):
Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg).
With simultaneous use of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg, the Cmax and AUC of celecoxib increase by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.
Although there are no targeted studies, fluconazole may increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). NSAID dose adjustment may be necessary.
When NSAIDs and fluconazole are used concomitantly, patients should be closely monitored medically to identify and monitor NSAID-related adverse events and toxicities.
Olaparib:
Moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of olaparib. Their simultaneous use is not recommended. If concomitant use cannot be avoided, reduce the dose of olaparib to 200 mg twice daily.
Oral contraceptives:
with simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, while with daily intake of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and when taking 300 mg of fluconazole once a day week, the AUC of ethinyl estradiol and norethindrone increased by 24% and 13%, respectively. Thus, repeated use of fluconazole at the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.
Phenytoin:
simultaneous use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentrations. If concomitant use of both drugs is necessary, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic serum concentrations.
Ivacaftor:
When coadministered with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) stimulator, there was a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl-ivacaftor (Ml) exposure. For patients concomitantly taking moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.
Prednisone:
There is a report of the development of acute adrenal insufficiency in a patient after liver transplantation upon discontinuation of fluconazole after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to increased metabolism of prednisone.
Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to evaluate the condition of the adrenal cortex.
Rifabutin:
simultaneous use of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter by up to 80%. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.
Saquinavir:
AUC increases by approximately 50%, Cmax by 55%, clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. Dose adjustment of saquinavir may be necessary.
Sirolimus:
an increase in the concentration of sirolimus in the blood plasma, presumably due to inhibition of the metabolism of sirolimus through inhibition of the CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.
Sulfonylureas:
Fluconazole, when used concomitantly, leads to an increase in the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus can be prescribed the combined use of fluconazole and oral sulfonylureas, but the possibility of hypoglycemia should be taken into account, in addition, regular monitoring of blood glucose is necessary and, if necessary, dose adjustment of sulfonylureas.
Tacrolimus:
simultaneous use of fluconazole and tacrolimus (orally) leads to an increase in serum concentrations of the latter by 5 times due to inhibition of the metabolism of tacrolimus occurring in the intestine through the CYP3A4 isoenzyme. No significant changes in the pharmacokinetics of the drugs were observed when tacrolimus was administered intravenously. Cases of nephrotoxicity have been described. Patients receiving oral tacrolimus and fluconazole concomitantly should be monitored closely. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.
Theophylline:
when used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of developing theophylline toxicity, monitor for symptoms of theophylline overdose and, if necessary, adjust therapy accordingly.
Tofacitinib:
The exposure of tofacitinib increases when it is co-administered with drugs that are both moderate inhibitors of CYP3A4 and CYP2C19 isoenzymes (for example, fluconazole). Dose adjustment of tofacitinib may be necessary.
Vinca alkaloid:
Although targeted studies are lacking, it is suggested that fluconazole may increase plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) and thus lead to neurotoxicity, possibly due to inhibition of CYP3A4.
Vitamin A:
There is a report of one case of the development of adverse reactions from the central nervous system (CNS) in the form of pseudotumor cerebri with the simultaneous use of all-trans retinoic acid and fluconazole, which disappeared after discontinuation of fluconazole. The use of this combination is possible, but one should remember the possibility of adverse reactions from the central nervous system.
Zidovudine:
with simultaneous use with fluconazole, an increase in Cmax and AUC of zidovudine was observed by 84% and 74%, respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was found.
Patients receiving this combination should be monitored for side effects of zidovudine.
Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes):
simultaneous use of voriconazole (400 mg 2 times a day on the first day, then 200 mg twice a day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) in 8 healthy male subjects resulted in an increase in voriconazole Cmax and AUC by 57% and 79%, respectively. It has been shown that this effect persists when the dose is reduced and/or the frequency of administration of any of the drugs is reduced. Concomitant use of voriconazole and fluconazole is not recommended.
Studies of the interaction of oral forms of fluconazole when taken simultaneously with food, cimetidine, antacids, as well as after total body irradiation in preparation for bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.
The listed interactions were established with repeated use of fluconazole; There are no known drug interactions resulting from a single dose of fluconazole.
Doctors should note that interactions with other drugs have not been specifically studied, but are possible.
Pharmacodynamics
An antifungal agent that has a highly specific effect, inhibiting the activity of fungal enzymes dependent on cytochrome P450. Blocks the conversion of lanosterol from fungal cells into the membrane lipid - ergosterol; increases the permeability of the cell membrane, disrupts its growth and replication.
Fluconazole, being highly selective for fungal cytochrome P450, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole, it suppresses cytochrome P450-dependent oxidative processes in human liver microsomes to a lesser extent). Does not have antiadrogenic activity.
Active against opportunistic mycoses, incl. caused by Candida spp. (including generalized forms of candidiasis due to immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp.; for endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).
Pharmacokinetics
After oral administration, fluconazole is well absorbed; food intake does not affect the rate of absorption of fluconazole, its bioavailability is 90%.
The time to reach maximum concentration after oral administration of 150 mg of the drug on an empty stomach is 0.5–1.5 hours, Cmax is 90% of the plasma concentration when administered intravenously at a dose of 2.5–3.5 mg/l. T1/2 of fluconazole is 30 hours. Communication with plasma proteins is 11–12%. Plasma concentration is directly dependent on dose. A 90% level of equilibrium concentration is achieved by the 4th–5th day of treatment with the drug (when taken once a day).
Administration of a loading dose (on the first day), 2 times higher than the usual daily dose, allows one to achieve a concentration level corresponding to 90% of the equilibrium concentration by the second day.
Fluconazole penetrates well into all biological fluids of the body. Concentrations of the active substance in breast milk, joint fluid, saliva, sputum and peritoneal fluid are similar to its levels in plasma. Constant values in vaginal secretions are achieved 8 hours after oral administration and are maintained at this level for at least 24 hours. Fluconazole penetrates well into the cerebrospinal fluid (CSF) - with fungal meningitis, the concentration in the CSF is about 85% of its level in plasma. In sweat fluid, epidermis and stratum corneum (selective accumulation) concentrations exceeding serum levels are achieved. After oral administration of 150 mg on the 7th day, the concentration in the stratum corneum of the skin is 23.4 mcg/g, and 1 week after taking the second dose - 7.1 mcg/g; concentration in nails after 4 months of use at a dose of 150 mg once a week is 4.05 mcg/g in healthy and 1.8 mcg/g in affected nails. The volume of distribution approaches the total water content of the body.
It is an inhibitor of the CYP2C9 isoenzyme in the liver. It is excreted primarily by the kidneys (80% unchanged, 11% in the form of metabolites). Fluconazole clearance is proportional to creatinine clearance. No fluconazole metabolites were detected in peripheral blood.
The pharmacokinetics of fluconazole depends significantly on the functional state of the kidneys, and there is an inverse relationship between the half-life and creatinine clearance. After hemodialysis for 3 hours, the concentration of fluconazole in plasma decreases by 50%.
Side effects
From the digestive system: decreased appetite, taste changes, abdominal pain, vomiting, nausea, diarrhea, flatulence, rarely - impaired liver function (jaundice, hepatitis, hepatonecrosis, hyperbilirubinemia, increased activity of alanine aminotransferase, aspartate aminotransferase, increased activity of alkaline phosphatase, hepatocellular necrosis ), incl. heavy.
From the nervous system: headache, dizziness, excessive fatigue, rarely - convulsions.
From the hematopoietic organs: rarely - leukopenia, thrombocytopenia (bleeding, petechiae), neutropenia, agranulocytosis.
Allergic reactions: skin rash, rarely - exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching) .
From the cardiovascular system: increased duration of the QT interval, ventricular fibrillation/flutter.
Other: rarely - renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.
special instructions
Treatment must be continued until clinical and hematological remission occurs. Premature cessation of treatment leads to relapses.
During treatment, it is necessary to monitor blood counts, kidney and liver function. If renal and liver dysfunction occurs, you should stop taking the drug.
In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, incl. with a fatal outcome, mainly in patients with serious concomitant diseases. In the case of hepatotoxic effects associated with fluconazole, there was no obvious dependence on the total daily dose, duration of therapy, gender and age of the patient. The hepatotoxic effects of fluconazole were usually reversible; its signs disappeared after cessation of therapy. If clinical signs of liver damage that may be associated with fluconazole appear, the drug should be discontinued.
People with AIDS are more likely to develop severe skin reactions when taking many drugs. In cases where a rash develops in patients with a superficial fungal infection and is assessed as definitely related to fluconazole, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be carefully monitored and fluconazole should be discontinued if bullous changes or erythema multiforme occur.
Caution should be exercised when taking fluconazole concomitantly with cisapride, rifabutin or other drugs metabolized by the cytochrome P 450 system.
Contraindications
hypersensitivity to the drug (including a history of other azole antifungal drugs);
simultaneous use of terfenadine (while constantly taking fluconazole at a dose of 400 mg/day or more) or astemizole, as well as other drugs that prolong the QT interval;
children under 4 years of age.
With caution: liver and/or renal failure, the appearance of a rash during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg/day, simultaneous use of potentially hepatotoxic drugs, alcoholism, potentially proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs that cause arrhythmias), pregnancy.
