Fluconazole Canon (50mg, 150mg)
Single or multiple doses of fluconazole at a dose of 50 mg do not affect the metabolism of phenazone (Antipyrine) when taken simultaneously.
Concomitant use of fluconazole with the following drugs is contraindicated:
Cisapride: with simultaneous use of fluconazole with cisapride, adverse reactions from the heart are possible, including ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The use of fluconazole at a dose of 200 mg 1 time per 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. Concomitant use of cisapride and fluconazole is contraindicated.
Terfenadine: When azole antifungals are used concomitantly with terfenadine, serious arrhythmias may occur as a result of prolongation of the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole in doses
400 mg/day and above causes a significant increase in the concentration of tefenadine in the blood plasma. Concomitant use of fluconazole at a dose 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: Concomitant use of fluconazole with astemizole or other drugs metabolized 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 “torsade de pointes” type. The simultaneous use of astemizole and fluconazole is contraindicated.
Pimozide: No relevant in vitro or in vivo studies have been conducted, however, 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 no in vitro or in vivo studies have been conducted, 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, can lead to the development of ventricular tachysystolic arrhythmias of the “torsade de pointes” type. The simultaneous use of fluconazole and quinidine is contraindicated.
Erythromycin: Concomitant 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.
Amiodarone: Concomitant use of fluconazole and amiodarone may result in inhibition of amiodarone metabolism. Amiodarone use has been associated with QT prolongation. The simultaneous use of fluconazole and amiodarone is contraindicated (see section "Contraindications").
Caution and possible dosage adjustments should be used when fluconazole and the following drugs are used concomitantly
Drugs that affect fluconazole:
Hydrochlorothiazide: repeated use of hydrochlorothiazide concomitantly with fluconazole leads to an increase in plasma concentrations of fluconazole by 40%. An effect of this severity does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, however, the doctor should take this into account.
Rifampicin: Combination with rifampicin results in a 25% reduction in the area under the concentration-time curve (AUC) and a 20% reduction in the plasma half-life of fluconazole. Therefore, in patients receiving rifampicin at the same time, it is advisable to increase the dose of fluconazole.
Drugs Affected by Fluconazole
Fluconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP2C9 and CYP2C19 and a moderate inhibitor of the CYP3A4 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 taken simultaneously with fluconazole. In this regard, when using these drugs and fluconazole simultaneously, caution should be exercised; 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.
Tofacitinib: Tofacitinib exposure is increased when coadministered with drugs that are both moderate CYP3A4 inhibitors and strong CYP2C19 inhibitors (such as fluconazole). Dose adjustment of tofacitinib may be necessary.
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 the start of treatment. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.
Amphotericin B: In studies in mice (including immunosuppressed mice), the following results were observed: small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Criptococcus neoformans, and antagonism in systemic infection with A .fumigatus. The clinical significance of these results is unknown.
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 anticoagulants and fluconazole, prothrombin time must be constantly monitored during therapy and for 8 days after simultaneous use. The advisability of adjusting the warfarin dose should also be assessed.
Azithromycin: with simultaneous oral administration 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.
Benzodiazepines (short-acting): After oral administration of midazolam, fluconazole significantly increases its concentration and psychomotor effects, and this effect is more pronounced after fluconazole is administered orally 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.
When coadministered with a single dose of triazolam, fluconazole increases triazolam AUC by approximately 50%, Cmax by 25-50%, 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, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole may increase the systemic effect of calcium channel antagonists. It is recommended to monitor the development of side effects.
Cyclosporine: in kidney transplant patients, fluconazole dose
200 mg/day leads to a slow increase in plasma concentrations of cyclosporine. With repeated use of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentrations were observed in bone marrow recipients. It is recommended to monitor cyclosporine blood concentrations in patients receiving fluconazole.
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 a fatality possibly associated with the concomitant use of fluconazole and fentanyl. Fluconazole significantly prolongs the elimination time of fentanyl. Side effects may be related to fentanyl intoxication. It should be borne in mind that increased concentrations of fentanyl can lead to respiratory depression.
Halofantrine: Due to inhibition of CYP3A4, fluconazole may increase plasma concentrations of halofantrine. When used simultaneously with fluconazole and other azole antifungal drugs, the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes) is possible. Their combined use is not recommended.
HMG-CoA reductase inhibitors: with simultaneous use of fluconazole with HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 isoenzyme (for example, atorvastatin, simvastatin) or the CYP2D6 isoenzyme (fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If concomitant therapy with these drugs is necessary, patients should be monitored for symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatine kinase. If the concentration of this enzyme increases significantly or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.
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): Flubiprofen Cmax and AUC increased by 23% and 81%, respectively. With the simultaneous use of fluconazole and racemic ibuprofen
(400 mg) Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] increased by 15% and 82%, respectively. 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 increased by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.
Fluconazole may increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac), but no targeted studies have been conducted. NSAID dose adjustment may be required.
When fluconazole and NSAIDs are used concomitantly, patients should be closely monitored medically to identify and monitor NSAID-related adverse events and toxicities.
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. With daily dosing of 200 mg fluconazole, the AUCs of ethinyl estradiol and levonorgestrel increased by 40% and 24%, respectively; with 300 mg fluconazole once weekly, the AUCs of ethinyl estradiol and northethindrone increased by 24% and 13%, respectively. Thus, repeated use of fluconazole in the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.
Phenytoin: Concomitant use of fluconazole and phenytoin may increase plasma phenytoin concentrations to a clinically significant extent. Therefore, if it is necessary to use these drugs together, it is necessary to monitor phenytoin concentrations with dose adjustment in order to maintain drug concentrations within the therapeutic interval.
Prednisone: there is a report of the development of acute adrenal insufficiency in a patient after liver transplantation while fluconazole was discontinued 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 may be accompanied by an increase in the serum concentration of the latter by up to 80%. Cases of uveitis have been described with the simultaneous use of fluconazole and rifambutin. Patients receiving rifabutin and fluconazole concomitantly should be closely monitored.
Saquinavir: When used together, the AUC of saquinavir increases by approximately 50%, Cmax by 55%, and clearance decreases by 50% due to inhibition of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. Dose adjustment of saquinavir may be necessary.
Sirolimus: with simultaneous use, an increase in the concentration of sirolimus in the blood plasma is observed, probably associated with 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 increases the plasma half-life of oral hypoglycemic agents - sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide, tolbutamide). The combined use of fluconazole and oral hypoglycemic agents in patients with diabetes mellitus is permitted, but the physician must be aware of the possibility of developing hypoglycemia. Regular monitoring of blood glucose levels and, if necessary, dose adjustment of sulfonylurea drugs is necessary.
Tacrolimus: when used concomitantly, fluconazole increases the concentration of tacrolimus (orally) in the blood plasma by 5 times due to inhibition of the metabolism of tacrolimus occurring in the intestine with the participation of the CYP3A4 isoenzyme. In this regard, the risk of nephrotoxicity increases. Patients taking tacrolimus by mouth should be closely monitored. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood. When tacrolimus is administered intravenously, no significant changes in the pharmacokinetics of the drug are observed.
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%. Patients receiving high doses of theophylline or who are at risk of developing theophylline toxicity should be monitored for early detection of symptoms of theophylline overdose. If necessary, therapy should be adjusted accordingly.
Vinca alkaloid: Fluconazole may increase plasma concentrations of vinca alkaloids (vincristine and vinblastine) and contribute to neurotoxicity. This may be due to inhibition of the CYP3A4 isoenzyme, however, targeted studies have not been conducted.
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 simultaneous use of fluconazole with all-trans retinoic acid, which disappeared after discontinuation of fluconazole. The use of this combination is possible, but the possibility of developing adverse reactions from the central nervous system should be taken into account.
Zidovudine: In patients receiving a combination of fluconazole and zidovudine, there is an increase in Cmax and AUC of zidovudine by 84% and 74%, respectively, which is caused by a decrease in the conversion 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. Increased side effects of zidovudine should be expected when used together.
Nevirapine: Concomitant use of fluconazole and nevirapine results in an approximately 100% increase in nevirapine exposure. If these drugs are used together and there is a risk of increased exposure to nevirapine, use caution and monitor patients closely. There was no clinically significant effect of nevirapine on fluconazole.
Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): simultaneous use of fluconazole and 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 every day). first day, then 200 mg twice daily for 4 days) increased voriconazole concentrations 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.
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 (M1) exposure. For patients taking moderate CYP3A inhibitors concomitantly, such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.
Studies of the interaction of fluconazole when taken simultaneously with food, cimetidine, antacids, and also 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
Antifungal agent. A triazole derivative exhibits an antifungal effect by blocking the biosynthesis of ergosterol in the cell membrane of fungi. The “target” for the action of the drug is the enzyme 14-α-demethylase.
14-α-demethylase is part of a group of enzymes known collectively as cytochrome P450. All enzymes of the cytochrome P450 group contain hematinic iron-containing pigment. Fluconazole binds to the iron atom of the hematin group and inactivates 14-α-demethylase, which leads to disruption of ergosterol synthesis and accumulation of lanosterol and other sterols. Their inclusion in the membrane instead of ergosterol significantly disrupts the structure and function of the fungal cell membrane.
A decrease in ergosterol synthesis, as well as the accumulation of 14α-methylsterols, destroys the tightly packed acyl chains of fungal membrane phospholipids. Destabilization of the fungal membrane leads to dysfunction of membrane enzymes, including those involved in the electron transport chain, and ultimately to cell death.
Used for systemic mycoses: candidiasis, cryptococcosis, blastomycosis, histoplasmosis, coccidioidomycosis, as well as dermatomycosis. The relatively low toxic profile and high penetration into the cerebrospinal fluid make fluconazole the drug of choice for systemic candidiasis and cryptococcal meningitis. Because of complications associated with intrathecal amphotericin B, fluconazole is the first-line drug for coccidioidal meningitis. Although fluconazole is active against the causative agents of blastomycosis, histoplasmosis, and sporotrichosis, it is inferior in effectiveness against the causative agents of these infections to itraconazole. Fluconazole is not effective against aspergillosis.
Side effects
Side effects are possible when using the drug Fluconazole
- From the immune system: hypersensitivity (cross with all azoles), other anaphylactic, anaphylactoid and allergic reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria).
- From the nervous system: headache, dizziness, peripheral neuropathy, paresthesia, excessive fatigue, rarely - convulsions.
- From the digestive system: loss of appetite, dryness of the oral mucosa, changes in taste, abdominal pain, vomiting, nausea, diarrhea, flatulence, rarely - impaired liver function (jaundice, hepatitis, hepatonecrosis, hyperbilirubinemia, increased activity of alanine aminotransferase, aspartate aminotransferase, increased alkaline phosphatase activity, hepatocellular necrosis), including severe.
- From the hematopoietic organs: rarely - leukopenia, thrombocytopenia (bleeding, petechiae), neutropenia, agranulocytosis.
- From the cardiovascular system: increased duration of the QT interval, ventricular fibrillation/flutter, torsades de pointes.
- Metabolism: hypercholesterolemia, hypertriglyceridemia, hypokalemia, hyperglycemia.
- From the musculoskeletal system: myalgia.
- Other: weakness, asthenia, peripheral edema, neutropenia, itching, pulmonary edema, fever, excessive sweating, vertigo.
special instructions
Treatment with fluconazole may be initiated pending the results of cultures and other laboratory tests, but therapy should be adjusted accordingly once the results of these tests are available.
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.
Treatment must be continued until clinical and hematological remission occurs (an exception is acute vaginal candidiasis). Premature cessation of treatment leads to relapses.
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 occurs in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme occur.
In rare cases, the use of fluconazole has been accompanied by toxic changes in the liver, including death, 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.
Contraindications for use
Medical contraindications for taking Fluconazole capsules are pathological and physiological processes in the patient’s body, which include:
- Simultaneous use of the drug terfinadine, astemizole, as well as other drugs that lead to prolongation of the QT interval on the electrocardiogram (especially when using Fluconazole capsules in a daily dosage exceeding 400 mg).
- Children up to 4 years old.
- Individual intolerance to the main active ingredient or additional substances of this medication.
The drug is used with caution in case of concomitant liver or renal failure, the appearance of a skin rash in patients with generalized systemic fungal infections, simultaneous use of the drug in a daily dosage of less than 400 mg with terfenadine, chronic alcoholism, in the case of the use of drugs that have a hepatotoxic effect, and also in patients with a high risk of developing arrhythmia (disturbance in the rhythm and frequency of heart contractions) against the background of organic heart pathology, electrolyte imbalance in the body. The drug is also used with caution in pregnant women. Before prescribing Fluconazole capsules, the doctor makes sure that the patient has no contraindications.
Use during pregnancy and lactation
There have been no adequate and controlled studies of the use of fluconazole in pregnant women. Several cases of multiple congenital defects have been described in newborns whose mothers received high-dose fluconazole therapy (400-800 mg/day) for most or all of the first trimester. The following developmental disorders were noted: brachycephaly, impaired development of the facial part of the skull, impaired formation of the cranial vault, cleft palate, curvature of the femurs, thinning and elongation of the ribs, arthrogryposis and congenital heart defects. Currently, there is no evidence of a connection between the listed congenital anomalies and the use of low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.
During pregnancy, the use of fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections when the expected benefit of treatment to the mother outweighs the possible risk to the fetus. Women of childbearing age should use contraception.
Since the concentration of fluconazole in breast milk and plasma is the same, the use of the drug during breastfeeding is contraindicated.
Indications for use
Indications for the use of Fluconazole capsules are:
- Cryptococcal infection, including specific damage to the membranes of the brain (cryptococcal meningitis) in patients with immunodeficiency or with a normal state of functional immune activity.
- A severe form of candidiasis with generalization of the infectious process and damage to a significant amount of tissue (mucous membranes of various organs, skin, peritoneum, endocardium, eyes, respiratory and urinary tracts). In most cases, the infection develops against the background of a pronounced decrease in the functional activity of the immune system during malignant neoplasms, treatment with cytostatics, immunosuppressants, as well as in patients who have been in the intensive care unit for a long time.
- Localized candidiasis, developing on the mucous membranes of the oral cavity and upper digestive tract, on the structures of the urogenital tract - the drug in dosage form for systemic use is used in case of insufficient effectiveness of ointment or cream for topical use.
- Dermatomycosis, which is localized on the skin of the feet, torso, and groin area.
- Pityriasis (multi-colored) lichen.
- Fungal infection of the nail plates (onychomycosis).
- Deep endemic mycoses, which may include paracoccidioidomycosis, coccidioidomycosis, histoplasmosis in patients with normal functional immune activity.
The drug is also used to prevent the development of fungal infections in patients with normal or impaired immunity.
