Instructions for use Fluconazole-Darnitsa capsules 150 mg No. 1
Composition
active ingredient: fluconazole;
1 capsule contains 150 mg of fluconazole;
Excipients: potato starch, lactose monohydrate, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate, gelatin, titanium dioxide (E 171).
Dosage form
Capsules.
Main physicochemical properties: hard gelatin capsules with a white body and cap. Capsule contents – white or almost white powder.
Pharmacotherapeutic group
Antifungal agents for systemic use. Triazole derivatives. ATX code J02A C01.
Pharmacological properties
Pharmacodynamics
Mechanism of action. Fluconazole, a triazole antifungal agent, is a potent and selective inhibitor of fungal enzymes required for ergosterol synthesis. Its primary mechanism of action is inhibition of fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. Accumulation of 14-alpha-methyl sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for the various mammalian cytochrome P450 enzyme systems.
In vitro susceptibility: Fluconazole demonstrates antifungal activity in vitro against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis).
C. glabrata shows a wide range of susceptibility to fluconazole, while C. krusei is resistant to it. Fluconazole also shows in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic molds Blastomices dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.
Pharmacokinetics
Absorption. Fluconazole is well absorbed after oral administration, and plasma drug levels and systemic bioavailability exceed 90% of the plasma drug levels achieved after intravenous administration. Concomitant food intake does not affect oral drug absorption. Peak plasma concentrations are achieved 0.5–1.5 hours after dosing. Plasma drug concentrations are dose-proportional. Steady-state concentrations of 90% are achieved by the second day of treatment when a loading dose of twice the usual daily dose is administered on the first day.
Distribution. The volume of distribution is approximately equal to the total body fluid content. Plasma protein binding is low (11–12%). Fluconazole penetrates well into all body fluids tested. Fluconazole levels in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole levels in the cerebrospinal fluid reach 80% of plasma concentrations.
High concentrations of fluconazole in the skin, exceeding those in serum, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum.
Biotransformation: Fluconazole is metabolized to a minor extent - only approximately 11% of fluconazole is excreted in the urine in an unchanged form. Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of CYP2C19 isoenzyme.
Excretion. The half-life of fluconazole from blood plasma is about 30 hours. Most of the drug is excreted by the kidneys, with 80% of the administered dose being found in the urine unchanged. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified. The long half-life of the drug from blood plasma allows for a single use of the drug for vaginal candidiasis, as well as the use of the drug once a week for other indications.
Pharmacokinetics in special categories of patients.
Renal insufficiency. In patients with severe renal insufficiency (glomerular filtration rate < 20 ml/min), the half-life increases from 30 hours to 98 hours. Therefore, the dose of fluconazole should be reduced in this category of patients. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal dialysis. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.
Elderly patients.
Changes in pharmacokinetics in elderly patients apparently depend on renal function parameters.
Indication
Acute vaginal candidiasis, candidal balanitis (when local therapy is not appropriate).
Contraindication
Hypersensitivity to fluconazole, other azole compounds or to other components of the drug; simultaneous use of fluconazole and terfenadine in patients receiving fluconazole multiple times at doses of 400 mg/day and above (according to the results of a multiple-dose interaction study); simultaneous use of fluconazole and other drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme (for example, cisapride, astemizole, pimozide, quinidine and erythromycin).
Interaction with other medicinal products and other types of interactions
The concomitant use of fluconazole and the following drugs is contraindicated.
Cisapride, astemizole, pimozide, quinidine, erythromycin: Concomitant use of the above drugs and fluconazole may lead to QT prolongation, torsades de pointes, and, as a result, sudden death. The combination of these drugs is contraindicated.
Terfenadine: No prolongation of the QT interval was observed when fluconazole 200 mg/day was administered concomitantly with terfenadine. Concomitant administration of fluconazole 400 mg/day and above with terfenadine significantly increases its plasma levels, which may lead to serious cardiac arrhythmias caused by prolongation of the QT interval. When fluconazole is administered concomitantly with terfenadine at doses below 400 mg/day, the patient's condition should be carefully monitored. Concomitant administration of fluconazole 400 mg/day with terfenadine is contraindicated.
Amiodarone: Concomitant use of fluconazole with amiodarone may result in inhibition of amiodarone metabolism. An association has been observed between amiodarone use and QT prolongation. Concomitant use of fluconazole and amiodarone is contraindicated.
The concomitant use of fluconazole and the following medicines is not recommended.
Halofantrine: Fluconazole may increase plasma concentrations of halofantrine due to inhibition of CYP3A4. Concomitant use of these drugs has the potential to lead to cardiotoxicity (QT prolongation, torsades de pointes) and, consequently, sudden cardiac death. The combination of these drugs should be avoided.
Concomitant use of fluconazole and the following drugs requires caution and dose adjustment.
Effects of other medicinal products on fluconazole: Interaction studies have shown that concomitant food intake, administration of cimetidine, antacids or subsequent total body irradiation for bone marrow transplantation have no clinically significant effect on the absorption of fluconazole when administered orally.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole. An increase in the dose of fluconazole may be required when these drugs are used concomitantly.
Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple hydrochlorothiazide to healthy volunteers receiving fluconazole increased the plasma concentrations of fluconazole by 40%. These interaction parameters do not require changes in the dosing regimen of fluconazole in patients receiving concomitant diuretics.
The effect of fluconazole on other drugs.
Medicinal products metabolised by CYP2C9 and CYP3A4: Fluconazole is a potent inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of CYP2C19. There is a risk of increased plasma concentrations of other compounds metabolised by CYP2C9 and CYP3A4 when co-administered with fluconazole, including vinca alkaloids, alfentanil, calcium channel blockers, everolimus, sirolimus (also via inhibition of P-glycoprotein), tacrolimus, non-steroidal anti-inflammatory drugs metabolised by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac, flurbiprofen), saquinavir (also via inhibition of P-glycoprotein). Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolised by CYP3A4. Fluconazole has the potential to increase the systemic exposure of calcium channel blockers. Close monitoring for adverse reactions is recommended. Increased plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine) have been associated with neurotoxic effects. Elevated tacrolimus levels have been associated with nephrotoxicity. Such combinations should be used with caution and patients should be closely monitored. The enzyme inhibitory effect of fluconazole persists for 4–5 days after administration due to its long half-life. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more severe.
Voriconazole, zidovudine, carbamazepine, methadone, rifabutin, celecoxib, cyclosporine, phenytoin (intravenously): simultaneous use of fluconazole and the above drugs increases Cmax (for phenytoin Cmin) and AUC of the latter; drugs can be used simultaneously, provided that the dose of the above drugs is adjusted depending on the plasma concentration. Fluconazole inhibits the metabolism of carbamazepine and causes an increase in the serum level of carbamazepine by 30%. There is a risk of developing toxicity from carbamazepine. It may be necessary to adjust the dose of carbamazepine depending on its concentration and the effect of the drug. Cases of uveitis have been reported with the simultaneous use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be taken into account. Phenytoin serum concentration should be monitored to avoid the development of phenytoin toxicity.
Tofacitinib: The exposure of tofacitinib is increased when co-administered with medicinal products that result in moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g. fluconazole). Therefore, it is recommended to reduce the dose of tofacitinib to 5 mg once daily in combination with these medicinal products.
Azithromycin: In an open-label, randomized, three-way crossover study in 18 healthy volunteers, the effects of azithromycin and fluconazole on the pharmacokinetics of each other were evaluated when administered orally at single doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed between them.
Alfentanil: Co-administration of alfentanil 20 mcg/kg and fluconazole 400 mg in healthy volunteers resulted in a two-fold increase in AUC10, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.
Amitriptyline/nortriptyline: Fluconazole enhances the effect of amitriptyline/nortriptyline. When using these drugs simultaneously, it is recommended to monitor the concentrations of 5-nortriptyline and/or S-amitriptyline at the beginning of combination therapy, after 1 week and, if necessary, adjust their dose.
Amphotericin B: In preclinical studies, concomitant administration of fluconazole and amphotericin B to immunocompetent and immunocompromised mice resulted in the following results: a small additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism of the two drugs in systemic A. fumigatus infection; the clinical significance of these results is unknown.
Anticoagulants: As with other azole antifungals, bleeding events (hematoma, epistaxis, gastrointestinal bleeding, haematuria and melena) in association with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time has been observed with concomitant use of fluconazole and warfarin, presumably due to inhibition of warfarin metabolism by CYP2C9. Careful monitoring of prothrombin time and, if necessary, adjustment of the warfarin dose are recommended when the medicinal products are used concomitantly.
Short-acting benzodiazepines (e.g. midazolam, triazolam): Administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentrations and increased psychomotor effects. Close monitoring of the patient and reduction of the benzodiazepine dose are recommended when these drugs are used concomitantly. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in a 3.7- and 2.2-fold increase in AUC and half-life, respectively. Administration of fluconazole 200 mg/day and triazolam 0.25 mg orally resulted in a 4.4- and 2.3-fold increase in AUC and half-life, respectively. Potentiation and prolongation of the effects of triazolam were observed when fluconazole and triazolam were administered concomitantly.
Vitamin A: A patient receiving all-trans retinoic acid (the acid form of vitamin A) and fluconazole was reported to have experienced a central nervous system (CNS) adverse reaction in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. The drugs may be used concomitantly, taking into account the risk of CNS adverse reactions.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which accounts for much of the angiotensin II receptor antagonism of losartan. Monitoring of blood pressure in patients is recommended.
Prednisone: A case report has been made of a liver transplant patient receiving prednisone who developed acute adrenal insufficiency following discontinuation of a three-month course of fluconazole. Discontinuation of fluconazole is likely to have resulted in increased CYP3A4 activity, leading to increased metabolism of prednisone. Monitoring of patients for the development of adrenal insufficiency following discontinuation of fluconazole is recommended.
Sulfonylureas: Fluconazole prolonged the elimination half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide) when administered concomitantly in healthy volunteers. Monitoring of glucose levels is recommended and, if necessary, dose adjustment of fluconazole is recommended.
Theophylline: In a drug-drug interaction study, fluconazole 200 mg for 14 days decreased the mean plasma clearance of theophylline by 18%. Patients receiving high doses of theophylline or who are otherwise at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity. The drug should be discontinued if signs of toxicity occur.
Fentanyl: One fatal case of fentanyl intoxication has been reported following the interaction of fentanyl and fluconazole. Studies have shown that fluconazole significantly delayed the elimination of fentanyl. Increased fentanyl concentrations may lead to respiratory depression. Careful monitoring of the patient is recommended during concomitant use of these drugs, and adjustment of the fentanyl dose as necessary.
Cyclophosphamide: Concomitant use of cyclophosphamide and fluconazole has been shown to increase serum bilirubin and creatinine levels. The drugs may be used concomitantly, given the risk of increased serum bilirubin and creatinine concentrations.
Methadone: Fluconazole may increase the serum concentration of methadone. Methadone dose adjustment may be necessary when methadone and fluconazole are used concomitantly.
Non-steroidal anti-inflammatory drugs (NSAIDs): When co-administered with fluconazole, the Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, when co-administered with racemic ibuprofen (400 mg), the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen were increased by 15% and 82%, respectively, compared to racemic ibuprofen alone.
Although no specific studies have been performed, fluconazole has the potential to increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be necessary.
Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator enhancer, increases ivacaftor exposure by 3-fold and hydroxymethylivacaftor (M1) by 1.9-fold. For patients concomitantly taking moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.
Application features
Insufficient duration of treatment may lead to the resumption of the active infectious process.
Use in deep endemic mycoses, cryptococcosis, dermatophytosis. Evidence of the effectiveness of fluconazole for the treatment of cryptococcosis and other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis and cutaneous-lymphatic sporotrichosis, is insufficient, therefore there are no recommendations for a dosage regimen for the treatment of such diseases. According to the results of a study of fluconazole for the treatment of dermatophytosis in children, fluconazole is not more effective than griseofulvin, therefore fluconazole should not be used for the treatment of dermatophytosis.
Effects on the urinary system. The drug should be used with caution in patients with impaired renal function (see section "Method of administration and dosage").
Adrenal insufficiency: Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rare. Adrenal insufficiency associated with concomitant prednisone treatment is described in the section “Effect of fluconazole on other medicinal products” above.
The drug should be used with caution in patients with impaired liver function. Patients should be informed of symptoms that may indicate serious liver damage (severe asthenia, anorexia, persistent nausea, vomiting and jaundice). In such cases, fluconazole should be discontinued immediately and a doctor should be consulted.
Cardiovascular effects. Some azoles, including fluconazole, have been associated with QT prolongation on the electrocardiogram. Very rare cases of QT prolongation and torsades de pointes have been reported with fluconazole. These cases have occurred in severely ill patients with multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other drugs that affect the QT interval.
The drug should be used with caution in patients at risk of developing arrhythmias. Concomitant use with drugs that prolong the QT interval and are metabolized by the cytochrome P450 enzyme CYP3A4 is contraindicated.
Effects on the cytochrome P450 system. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme.
Patients should be carefully monitored when co-administering fluconazole with drugs with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4.
Dermatological reactions: Exfoliative skin reactions such as malignant exudative erythema (Stevens-Johnson syndrome) and toxic epidermal necrolysis (Lyell's syndrome) have been reported rarely with fluconazole. AIDS patients are more prone to severe skin reactions with many drugs.
If a rash occurs that may be associated with fluconazole, the drug should be discontinued in patients with superficial fungal infections. If a rash occurs that may be associated with fluconazole, patients with invasive/systemic fungal infections should be closely monitored, and if bullous rashes or erythema multiforme develop, the drug should be discontinued.
Hypersensitivity reactions: Anaphylactic reactions have been reported rarely with fluconazole.
The medicinal product contains lactose, therefore patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of fluconazole on the ability to drive or use machines have not been conducted. Patients should be informed of the possibility of dizziness or convulsions while taking the drug. If such symptoms develop, it is not recommended to drive or use machines.
Use during pregnancy or breastfeeding
Data obtained from single or repeated administration of fluconazole at usual doses (< 200 mg/day) to several hundred pregnant women during the first trimester of pregnancy have not shown any adverse effects on the fetus. Numerous congenital anomalies have been reported in newborns (including bradyphrenia, auricular dysplasia, excessive enlargement of the anterior fontanelle, hip dysplasia, brachiocephalic synostosis) when pregnant women received high doses of fluconazole (400–800 mg/day) for at least 3 months for the treatment of coccidioidomycosis. The relationship between the use of fluconazole and these cases has not been established.
Animal studies have shown reproductive toxicity.
Normal doses of fluconazole and short courses of fluconazole should not be used during pregnancy unless clearly necessary.
High doses of fluconazole and/or long courses of fluconazole treatment should not be used during pregnancy, except for the treatment of potentially life-threatening infections.
Fluconazole passes into breast milk and reaches lower concentrations than in blood plasma. Breastfeeding can be continued after a single dose of fluconazole, which is 200 mg or less.
Breastfeeding is not recommended with repeated use of fluconazole or when using high doses of fluconazole.
Method of administration and doses
The drug is administered orally in a single dose of 150 mg. The capsules should be swallowed whole, regardless of meals.
Elderly patients.
In the absence of signs of renal dysfunction, the drug should be used in the usual adult dose for the treatment of this category of patients.
Patients with impaired renal function.
When administered once daily to patients with mild or moderate renal impairment, no dose adjustment is required.
Patients with impaired liver function.
The drug should be used with caution, as there is insufficient information on the use of fluconazole in this category of patients.
The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite comprehensive data on the use of fluconazole in children. If there is an urgent need to use the drug in adolescents (aged 12 to 17 years), the usual adult doses should be used.
Overdose
Fluconazole overdose has been reported to cause hallucinations and paranoid behavior.
Treatment: symptomatic supportive therapy, if necessary - gastric lavage. Fluconazole is largely excreted in the urine, so forced diuresis can accelerate the elimination of the drug. A 3-hour hemodialysis session reduces the level of fluconazole in the blood plasma by approximately 50%.
Adverse reactions
The most commonly (> 1/10) reported adverse reactions were: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase in the blood.
The following classification is used to estimate the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
From the side of the organs of hearing and vestibular apparatus:
Uncommon: vertigo.
From the gastrointestinal tract:
Common: abdominal pain, diarrhea, nausea, vomiting.
Uncommon: constipation, dyspepsia, flatulence, dry mouth.
From the liver and biliary tract:
Common: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase.
Uncommon: cholestasis, jaundice, increased plasma bilirubin.
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage.
From the side of metabolism:
Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia.
Uncommon: decreased appetite.
From the nervous system:
Common: headache.
Uncommon: convulsions, dizziness, paresthesia, taste disturbance.
Rare: tremor.
From the psyche:
Uncommon: insomnia, drowsiness.
From the cardiovascular system:
Rare: paroxysmal torsades de pointes, QT prolongation.
Blood and lymphatic system disorders:
Uncommon: anemia.
Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.
On the part of the immune system:
Rare: anaphylaxis.
Skin and subcutaneous tissue disorders:
hypersensitivity reactions, including:
Common: rash.
Uncommon: itching, flushing, drug dermatitis, urticaria, increased sweating.
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioedema, facial edema, anaphylactic shock, alopecia.
Not known: drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders:
Uncommon: myalgia.
General disorders:
Uncommon: fatigue, malaise, asthenia, fever.
Children.
The frequency and nature of adverse reactions and laboratory abnormalities in clinical trials in children were comparable to those in adults.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
1 capsule in a contour blister pack; 1 contour blister pack in a pack.
Vacation category
Without a prescription.
Producer
PrJSC "Pharmaceutical Company "Darnitsa".
Location of the manufacturer and its business address
Ukraine, 02093, Kyiv, Boryspilska St., 13.
