Approval Date:
Revision Date.
Fluconazole Tablets Instructions
Please read the instruction manual carefully and use under the guidance of your physician
[Drug Name].
Generic Name: Fluconazole Tablets
Trade Name: Elicom
English name: Fluconazole Tablets
Hanyu Pinyin: Fukangzuo Pian
[Ingredients
The main ingredient of this product is Fluconazole.
Chemical name: a-(2,4-difluorophenyl)-a-(1H-1,2,4-triazol-1-ylmethyl)-1H-1, 2,4-triazol-1-ylethanol.
Chemical structure formula.
Molecular formula: C13H12F2N6O
Molecular weight: 306.28
[Properties
This product is a white or off-white tablet.
[Indications].
This product is indicated for the following fungal infections.
Adults
This product is indicated for the treatment of the following fungal infections in adult patients
Cryptococcal meningitis.
Coccidioidomycosis.
Invasive candidiasis.
Mucocutaneous candidiasis, including oropharyngeal and esophageal candidiasis, candiduria and chronic cutaneous mucocutaneous candidiasis.
Chronic atrophic oral candidiasis (denture stomatitis) in which oral hygiene or local treatment is ineffective.
Treatment of acute or recurrent vaginal candidiasis in the absence of appropriate topical treatment options.
Treatment of Candida glabrata in the absence of appropriate topical treatment options.
Treatment of dermatophytosis including tinea pedis, tinea corporis, tinea cruris, lichen planus, and cutaneous Candida infections when systemic therapy is indicated.
Treatment of ringworm of the fingernails (nail fungus) when other appropriate agents are lacking.
2) This product is indicated for the prevention of the following fungal infections in adult patients.
Recurrence of cryptococcal meningitis in patients at high risk of recurrence.
Recurrence of oropharyngeal or esophageal candidiasis in patients at high risk of recurrence with HIV infection.
Reducing the incidence of recurrence of vaginal candidiasis (four or more episodes a year).
Candida infection in patients with neutropenia (e.g., patients with malignant hematologic disease receiving chemotherapy or patients receiving hematopoietic stem cell transplantation).
2. Full-term newborns, infants, toddlers, children and adolescents aged 0 to 17 years
This product is indicated for the treatment of mucocutaneous candidiasis (oropharynx, esophagus), invasive candidiasis, and cryptococcal meningitis.
This product is indicated for the prevention of Candida infections in immunocompromised patients.
This product can be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in pediatric patients at high risk of recurrence.
Instructions for use:
This product may be initiated before culture results and other laboratory studies are known; however, once results are available, anti-infective therapy should be adjusted accordingly.
Official guidelines should be consulted for judicious use of antifungal drugs.
Tinea capitis: Studies of fluconazole for the treatment of tinea capitis in children have been conducted. The results showed that fluconazole was not superior to ashwagandha and the overall success rate was less than 20%. Therefore, this product should not be used for tinea capitis.
Cryptococcosis: There is less evidence on the efficacy of fluconazole for the treatment of cryptococcosis at other sites (eg, pulmonary and cutaneous cryptococcosis) and therefore it is not recommended and no dosage recommendations are provided.
Endemic deep fungal disease: Fluconazole has less evidence of efficacy for the treatment of other types of endemic fungal disease (eg, paracoccidioidomycosis, cutaneous lymphangioidomycosis, and histoplasmosis) and therefore is not recommended and no dosage recommendations are provided.
[Specification
(1) 50 mg; (2) 150 mg
[Dosage].
1. Dosage
Dosage should be determined according to the nature and severity of the fungal infection. For infections requiring multiple doses of therapy the drug should be continued until clinical parameters or laboratory tests indicate that the active fungal infection has resolved. Inadequate regimens may lead to recurrence of active infection.
Adult Dosing.
IndicationsdosageCourse of treatmentCryptococcosis- Treatment of cryptococcal meningitisLoad dose: 400mg on day 1
Follow-up dose: 200mg to 400mg once dailyUsually for at least 6-8 weeks. The daily dose can be increased to 800 mg for life-threatening infections- Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk of recurrence200mg once daily200mg daily continuous medicationCoccidioidomycosis 200mg to 400mg once daily11 months up to 24 months or longer, depending on the patient. Some infections may be considered at 800 mg daily, especially meningitis. Invasive Candidiasis Load dose: 800mg on day 1
Follow-up dose: 400mg once dailyThe usual recommended course of treatment for Candidaemia is 2 weeks after the first negative blood culture and resolution of signs and symptoms of CandidaemiaMucocutaneous Candidiasis Treatment- Oropharyngeal candidiasisLoad dose: 200mg to 400mg on day 1
Follow-up dose: 100mg to 200mg once daily7-21 days (until oropharyngeal candidiasis is in remission).
Patients with severe immune compromise may take longer- Esophageal CandidiasisLoad dose: 200mg to 400mg on day 1
Follow-up dose: 100mg to 200mg once daily14-30 days (until esophageal candidiasis is in remission).
Patients with severe immune compromise may take longer- Candiduria200mg to 400mg once daily7-21 days. Severely immunocompromised patients may take longer- Chronic Atrophic Candidiasis50mg once daily14 days- Chronic cutaneous mucocutaneous candidiasis50mg to 100mg once dailyUp to 28 days. Long-term treatment depends on the severity of the infection or underlying impaired immune function and infectionPrevention of mucocutaneous candidiasis recurrence in HIV-infected patients at high risk of recurrence – Oropharyngeal candidiasis100mg to 200mg once a day or 200mg 3 times a weekIrregular dosing in patients with chronic immunosuppression – Esophageal Candidiasis100mg to 200mg once a day or 200mg 3 times a weekIrregular dosing in patients with chronic immunosuppressionGenital Candidiasis- Acute vaginal Candida infection
– Candida glabrata150mg
Single dose administration- Treatment and prevention of recurrence incidence of vaginal candidiasis (4 or more episodes a year)Dose 150 mg every 3 days for a total of three doses (day 1, day day 4 and day 7), followed by a maintenance dose of 150 mg per weekContinuing treatment: 6 monthsDermatophytosis – Tinea pedis
– Tinea corporis
– Tinea corporis
– Candida infection
150mg once a week, or 50mg once a day2-4 weeks, tinea pedis may require up to 6 weeks of treatment- Pemphigus foliaceusOnce a week at 300mg-400mg1-3 weeks50mg once a day2-4 weeks2-4 weeks- Nail Fungus (Nail Fungus)150mg once a weekMaintain treatment until infected nails are covered (normal nails grow out). It usually takes 3 to 6 months and 6 to 12 months for fingernail and toenail regrowth, respectively. However, the rate of growth varies greatly with the age of the individual. Occasionally, nails may remain deformed after successful treatment of a long-term chronic infection. Preventing Candida infections in neutropenic patients 200mg to 400mg once a dayTreatment should be started several days before the expected onset of neutropenia and 7 days after recovery (neutrophil count elevated to 1000/mm3 or more)
Medication for Special Populations.
Geriatric
Dose should be adjusted based on renal function (see “Impaired Renal Function”).
Impaired renal function
The product is excreted primarily in the urine as a prototype active substance. No dose adjustment is required for single-dose therapy. In patients with impaired renal function (including children) receiving multiple doses of fluconazole, the initial dose should be 50 mg to 400 mg, depending on the recommended daily dose for the indication. After the initial loading dose, the daily dose (depending on the indication) should be determined according to the following table.
Creatinine clearance (ml/min)Percentage of recommended dose>50100%≤50 (not on hemodialysis)50%HemodialysisEach 100% after hemodialysis
Patients undergoing hemodialysis should receive 100% of the recommended dose after each hemodialysis session; patients on non-dialysis days may receive a lower dose based on creatinine clearance.
Impaired liver function
Data on dosing in patients with impaired hepatic function are limited; therefore, fluconazole should be used with caution in patients with hepatic insufficiency (see [Adverse Reactions] and [Precautions]).
Children
The maximum dose for the pediatric population should not exceed 400 mg daily.
As with similar infections in adults, the duration of therapy is based on clinical and fungal response. This product is administered once daily.
See the “Renal Impairment” section for dosing in pediatric patients with impaired renal function. Pharmacokinetics of fluconazole have not been studied in children with renal insufficiency (see below for dosing in “term neonates” who primarily exhibit renal immaturity).
Infants, toddlers, and children (28 days to 11 years of age).
IndicationsDosageRecommendation- Mucocutaneous CandidiasisInitial dose: 6mg/kg
Follow-up dose: 3mg/kg once dailyFirst day with initial dose to reach steady-state levels faster- Invasive Candidiasis
– Cryptococcal meningitisDose: 6-12mg/kg once dailyDepending on the severity of the disease- Prevention of relapse risk maintenance treatment for recurrence of cryptococcal meningitis in pediatric patients with a high risk of recurrenceDose: 6mg/kg once dailyDepending on the severity of the disease-Preventing Candida infections in immune-compromised patients Dose: 3-12mg/kg once dailyDepends on the degree and duration of induced neutropenia (see adult dosage)
Adolescents (12-17 years).
Depending on weight and pubertal development, prescribers need to evaluate which dosage (adult or pediatric) is most appropriate. Clinical data show that fluconazole clearance is higher in children than in adults. Corresponding pediatric doses that approximate systemic exposure to adult doses of 100, 200, and 400 mg are 3, 6, and 12 mg/kg.
The safety and efficacy of the genital candidiasis indication in the pediatric population have not been established. The available safety information for other pediatric indications can be found in [Adverse Reactions]. If it is necessary to treat genital candidiasis in adolescents 12 to 17 years of age, the dose used may be the same as the adult dose.
Full-term neonates (0 – 27 days).
Neonates excrete fluconazole at a slower rate. There are few pharmacokinetic data to support the dosage in full-term neonates.
Age groupDosageRecommendationsFull-term newborns (0-14 days)Give the same mg/kg dose every 72 hours as infants, toddlers and childrenThe maximum dose should not exceed 12mg/kg every 72 hoursFull-term newborns (15-27 days)Give the same mg/kg dose every 48 hours as infants, toddlers and childrenThe maximum dose should not exceed 12mg/kg every 48 hours
2. Method of administration
This product may be administered by oral or intravenous drip, the route of administration depending on the clinical status of the patient. No change in daily dose is required when switching from intravenous to oral administration, and vice versa.
Physicians should prescribe the most appropriate dosage form and size based on age, weight, and dose. Capsules and tablets are not indicated for infants and children, and fluconazole oral liquid formulations are more appropriate for this population.
The entire tablet should be swallowed and is not dependent on feeding.
[Adverse Reactions].
The most commonly reported (>1/10) adverse reactions were headache, abdominal pain, diarrhea, nausea, vomiting, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated blood alkaline phosphatase, and rash.
The following table shows the adverse reactions observed during fluconazole treatment and their frequency: very common (≥1/10); common (≥1/100 to <1/10); rare (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Unknown (not confirmed by available information).
System organ classificationCommonRarely seenRareunknownHematologic and lymphatic disorders Hematologic and lymphatic disorders AnemiaGranulocyte deficiency, leukopenia, thrombocytopenia, neutropenia Immune system disorders Allergic reactions Metabolic and Nutritional Disorders Loss of appetiteHypercholesterolemia, hypertriglyceridemia, hypokalemia Psychiatric disorders Drowsiness, insomnia Neurological disordersHeadacheEpileptic seizures, sensory abnormalities, dizziness, taste inversionsTremors Ear and Labyrinthine Disorders Glare Heart disease Tip-torsional ventricular tachycardia with prolonged QT interval Gastrointestinal disordersAbdominal pain , vomiting, diarrhea, nauseaConstipation, indigestion, flatulence, dry mouth Hepatobiliary diseaseElevated alanine aminotransferase, elevated aspartate aminotransferase elevated, elevated blood alkaline phosphataseCholestasis, jaundice, elevated bilirubinLiver failure, hepatocyte necrosis, hepatitis, hepatocellular damage Dermal and subcutaneous tissue disordersRashDrug rash*, hives, itching, increased sweatingToxic epidermolysis bullosa, Stevens-Johnson syndrome, acute generalized eruptive pustulosis, exfoliative dermatitis, angioedema, facial edema, alopeciaEosinophilia and Drug Reactions with Systemic Symptoms (DRESS)Skeletal muscle and connective tissue disorders Myalgia Systemic disease and site of administration condition Fatigue, malaise, weakness, fever * Including fixed drug rash
Pediatric population
The types and incidence of adverse reactions and abnormal laboratory tests documented in pediatric patients in clinical studies other than those with genital candidiasis indications were approximately the same as in adult patients.
Suspected Adverse Reactions Reported
It is important to report suspected adverse reactions after a drug has been licensed so that the benefit/risk balance of the drug can be monitored on an ongoing basis. Healthcare professionals are asked to report any suspected adverse reactions.
[Contraindications].
It is contraindicated in patients with hypersensitivity to fluconazole and its inactive ingredients, or to other azoles.
Concomitant administration of terfenadine is contraindicated in patients receiving multiple doses of fluconazole at 400 mg daily or higher, based on the results of a multiple-dose drug interaction study.
Concomitant administration of drugs that prolong the QT interval and are metabolized by cytochrome P450 CYP3A4 enzymes, such as cisapride, astemizole, pimozide, quinidine, and erythromycin, is contraindicated in patients receiving fluconazole.
[Caution].
Renal system
This product should be used with caution in patients with renal insufficiency.
Adrenocortical insufficiency
Ketoconazole is known to cause adrenocortical insufficiency. Although rare, fluconazole is also indicated. Adrenocortical insufficiency associated with prednisone combination see [Drug Interactions]. .
Hepatobiliary System
Fluconazole should be used with caution in patients with hepatic insufficiency.
Severe hepatotoxicity, including lethal hepatotoxicity, has occasionally occurred in patients on fluconazole, primarily in those with severe underlying disease or conditions. Hepatotoxicity following fluconazole use in patients has not been observed in relation to their daily dose, duration of therapy, gender, and age. The hepatotoxicity is usually reversible after discontinuation of fluconazole.
Patients with abnormal liver function during fluconazole use should be closely monitored for the development of more severe liver damage. Patients should be informed of symptoms suggestive of a severe hepatic reaction (severe malaise, loss of appetite, persistent nausea, vomiting, and jaundice). Patients should discontinue fluconazole therapy immediately and consult with their physician.
Dermal Adverse Reactions
Exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermolysis bullosa, have occasionally occurred in patients during fluconazole therapy. Patients with AIDS are more susceptible to severe skin reactions to multiple drugs. If a rash develops after administration of fluconazole in a patient with a superficial fungal infection, the drug should be discontinued. If a rash develops in patients with invasive/systemic fungal infections, they should be monitored closely and fluconazole should be discontinued as soon as maculopapular damage or erythema multiforme develops.
Tefenadine
Tefenadine should be monitored closely in patients taking fluconazole (
Hypersensitivity reactions
Rare anaphylactic shock reactions have been reported.
Cardiovascular system
Some azole antifungals, including fluconazole, are associated with prolongation of the QT interval in the ECG. Fluconazole causes QT interval prolongation by inhibiting rectifier potassium channel currents (Ikr). QT interval prolongation caused by other drugs (eg, amiodarone) can be amplified by inhibition of cytochrome P450 (CYP) 3A4. Post-marketing safety monitoring of patients on fluconazole has found that very few cases have reported QT interval prolongation and tip-twist ventricular tachycardia. These reports include critical cases with multiple complex risk factors (e.g., organic heart disease, electrolyte disturbances and combined medications that may lead to the above conditions). Patients with hypokalemia and advanced heart failure are at higher risk for life-threatening ventricular arrhythmias and tip-twisting ventricular tachycardia.
Fluconazole should be used with caution in patients with pre-existing potentially arrhythmia-inducing conditions. Concomitant use of other drugs that are known to prolong the QT interval or are metabolized by cytochrome P450 (CYP) 3A4 is contraindicated in patients receiving fluconazole therapy.
Halofantrine
Halofantrine prolongs the QTc interval at recommended therapeutic doses and is a substrate for CYP3A4. Therefore, it is recommended that fluconazole be avoided with halofantrine (see [Drug Interactions]).
Cytochrome P450
Fluconazole is a neutral inhibitor of CYP2C9 and CYP3A4. Fluconazole is also a potent inhibitor of CYP2C19 isoenzyme. Patients treated with fluconazole need to be monitored closely if they are using concomitant drugs that are metabolized by CYP2C9, CYP2C19, and CYP3A4 and have a narrow therapeutic window (see [Drug Interactions]).
Effect on ability to drive and operate machinery
Fluconazole has not been tested for effects on the ability to drive or operate machinery. Patients should be warned of the possibility of vertigo or seizures during fluconazole dosing and advised to stop driving or operating machines if any of these symptoms occur.
[Medication for Pregnant and Lactating Women]
Medication in Pregnancy
An observational study showed an increased risk of spontaneous abortion with fluconazole in women in the first trimester of pregnancy.
Mothers with coccidioidomycosis who received high-dose fluconazole (400 to 800 mg daily) for 3 months or more have been reported to have infants with multiple congenital anomalies (including short head deformity, ear hypoplasia, large fontanelle, femoral arching, and brachioradialis fusion). Whether these anomalies were associated with fluconazole use is unclear.
Animal studies have shown reproductive toxicity.
Short-term use of standard-dose fluconazole should be avoided during pregnancy unless clearly needed.
High-dose and/or long-term treatment with fluconazole should be avoided during pregnancy unless a potentially life-threatening infection occurs.
Use during lactation
Fluconazole is secreted via breast milk, and milk concentrations are similar to plasma concentrations (see [Pharmacokinetics]). If a single dose of fluconazole 150 mg is administered, lactation may continue. Discontinuation of breastfeeding is recommended after multiple doses or high doses of fluconazole. The developmental health benefits of breastfeeding should be weighed against the clinical need of the mother for this product and the potential adverse effects on the breastfed child from this product or the mother’s underlying disease.
Fertility
Fluconazole had no effect on fertility in male or female rats. .
[Pediatric use].
See [Dosage]Medication for Special Populations – Pediatric Population and [Pharmacokinetics]Pharmacokinetics in Children.
[Geriatric Use
See [Dosage]Medication for Special Populations – Elderly and [Pharmacokinetics]Pharmacokinetics in the Elderly.
[Drug Overdose]
Fluconazole overdose has been reported to be accompanied by hallucinations and paranoid behavior.
Patients who overdose should be treated symptomatically (supportive therapy and gastric lavage if necessary).
The majority of fluconazole is excreted in the urine, and forced volume expansion diuresis may increase its clearance. 3 hours of hemodialysis treatment may reduce the plasma concentration of fluconazole by approximately 50%.
[Drug interactions].
1. The combination of this product with the following drugs is prohibited
Cisapride: Concomitant use of fluconazole with cisapride has been reported to cause cardiac adverse events, including tip-twisting ventricular tachycardia. A controlled study showed that combined administration of fluconazole (200 mg once daily) with cisapride (20 mg four times daily) caused a significant increase in cisapride blood levels as well as a significant prolongation of the QTc interval. The combination of cisapride is contraindicated in patients treated with fluconazole (see [Contraindications]).
Tefenadine: Several drug interaction studies have been conducted because the combination of azole antifungals with tefenadine can cause prolongation of the QTc interval and secondary severe arrhythmias. One study of fluconazole at a dose of 200 mg daily did not detect QTc interval prolongation. Another study of fluconazole administered at 400 mg and 800 mg daily confirmed that the combination of fluconazole at 400 mg daily or higher significantly increased the blood levels of terfenadine. Co-administration of fluconazole with terfenadine is contraindicated at doses of 400 mg or more daily (see [CONTRAINDICATIONS]). When fluconazole is administered at doses below 400 mg daily and is co-administered with terfenadine, the blood levels of terfenadine should be monitored closely.
Aspemidazole: The combination of aspemidazole and fluconazole may slow clearance of aspemidazole, whose elevated blood levels may lead to prolonged QT interval and rare tip-twisting ventricular tachycardia. Therefore, coadministration of astemizole with fluconazole is contraindicated (see [Contraindications]).
Pimozide: Although in vitro and in vivo studies are lacking, the combination of these two drugs may inhibit pimozide metabolism, and elevated blood levels of the latter can lead to QT interval prolongation and rare tip-twisting ventricular tachycardia. The combination of pimozide and fluconazole is contraindicated (see [Contraindications]).
Quinidine: Although in vitro and in vivo studies are lacking, the combination of these two drugs may inhibit quinidine metabolism, and the use of the latter is associated with QT interval prolongation and rare tip-twisting ventricular tachycardia. The combination of quinidine and fluconazole is contraindicated (see [Contraindications]).
Erythromycin: Co-administration of fluconazole with erythromycin may increase the risk of cardiotoxicity (QT interval prolongation, tip-twisting ventricular tachycardia) and therefore may increase the risk of sudden cardiac death. The combination of these two drugs should be avoided (see [Contraindications]).
2. The combination of this product with the following drugs is not recommended
Halfantrine: Fluconazole inhibits CYP3A4 and therefore increases blood levels of halofantrine. The combination of fluconazole and halofantrine may increase the risk of cardiotoxicity (prolonged QT interval, tip-twisting ventricular tachycardia) and therefore may increase the risk of sudden cardiac death. The combination of these two drugs should be avoided (see [Contraindications]).
3. Combinations should be used with caution
Amiodarone: Combining fluconazole and amiodarone may increase QT interval prolongation. Caution must be exercised if fluconazole and amiodarone must be used in combination, especially at high doses (800 mg).
4. Caution and dose adjustments should be made when combining with the following drugs
1) Effects of other drugs on fluconazole
Rifampin: The combination of fluconazole and rifampin reduced the area under the drug-time curve (AUC) of fluconazole by 25% and the half-life by 20%. Patients treated with rifampin in combination should be considered for appropriate higher fluconazole dosing.
The results of the drug interaction study showed no significant impairment of fluconazole absorption when fluconazole was given orally with food, cimetidine, and antacids, or when patients received fluconazole after systemic radiation therapy for bone marrow transplantation.
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple doses of hydrochlorothiazide in healthy subjects treated with fluconazole resulted in a 40% increase in fluconazole blood levels. This magnitude of effect suggests that no dose adjustment of fluconazole dosing is required in patients who are coadministered with diuretics.
2) Effect of fluconazole on other drugs
Fluconazole is a neutral inhibitor of cytochrome P450 (CYP) isozymes 2C9 and 3A4. Fluconazole is also a potent inhibitor of the isoenzyme CYP2C19. In addition to the interactions observed or documented below, fluconazole may increase the blood levels of other drugs metabolized by CYP2C9, CYP2C19 or CYP3A4 when used in combination with these drugs. Therefore, the combination of these drugs should be used with caution and closely monitored. Fluconazole has a long half-life, so enzyme inhibition by fluconazole may persist for 4 to 5 days after discontinuation (see [Contraindications]).
Alfentanil: Alfentanil AUC 10 was elevated 2-fold during concurrent treatment with fluconazole (400 mg) and intravenous alfentanil (20 μg/kg) in healthy volunteers. The mechanism of action for this effect may be inhibition of CYP3A4 by fluconazole.
This situation may require adjustment of the dose of alfentanil.
Amitriptyline, nortriptyline: Fluconazole may increase the efficacy of amitriptyline and nortriptyline. Blood levels of 5-demethylphenidate and/or S-amytriptyline may need to be measured initially and after 1 week of combination dosing. The dose of amitriptyline/nortriptyline may be adjusted if necessary.
Amphotericin B: The combination of fluconazole and amphotericin B in normal and immunosuppressed mouse models of fungal infection showed the following results: a slight increase in antifungal efficacy for systemic infection with Candida albicans; no change in efficacy for intracranial infection with Cryptococcus neoformans; and antagonism between the two drugs for systemic infection with Aspergillus fumigatus. The clinical significance of these findings is unclear.
Anticoagulants: Postmarketing clinical reports suggest that, similar to other azole antifungals, bleeding adverse events (subcutaneous ecchymosis, epistaxis, gastrointestinal bleeding, hematuria, and black stools) can occur with prolonged prothrombin time in patients treated with fluconazole and concomitant warfarin therapy. Prothrombin time should be closely monitored in patients receiving concomitant coumarin or indandione anticoagulant therapy. Dose adjustment of the anticoagulant may be required for the combination.
Benzodiazepines (short-acting), ie, midazolam, triazolam: Administration of fluconazole after oral midazolam can cause a significant increase in midazolam blood levels and a psychomotor response. Concomitant oral administration of 200 mg fluconazole and 7.5 mg midazolam increased midazolam AUC and half-life by 3.7-fold and 2.2-fold, respectively. Concomitant oral administration of 200 mg/day fluconazole and 0.25 mg triazolam increased the AUC and half-life of the latter by 4.4-fold and 2.3-fold, respectively. The effects of triazolam were enhanced and prolonged when administered concomitantly with fluconazole. This effect of midazolam was more pronounced in patients receiving oral fluconazole than in patients receiving intravenous fluconazole. If a patient requires concomitant treatment with fluconazole and benzodiazepines, a reduction in the dose of benzodiazepines should be considered and the patient should be appropriately monitored.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine, increasing the blood concentration of carbamazepine by 30%, and therefore carries the risk of causing increased carbamazepine toxicity. The need for carbamazepine dose adjustment may be determined based on drug concentration monitoring results or clinical efficacy.
Calcium channel blockers: Some calcium channel blockers (nifedipine, irradipine, amlodipine, verapamil, felodipine) are metabolized by CYP3A4. Fluconazole may have the potential effect of increasing systemic exposure to these calcium channel blockers, and therefore close monitoring for adverse events is recommended.
Celecoxib: When fluconazole (200 mg once daily) was combined with celecoxib (200 mg), the peak blood concentration and area under the drug-time curve of celecoxib increased by 68% and 134%, respectively. Therefore, the dose of celecoxib can be adjusted to half the normal recommended dose when combined.
Cyclophosphamide: Coadministration of cyclophosphamide with fluconazole may result in increased blood bilirubin and creatinine concentrations. Therefore, the risks associated with increased blood bilirubin and creatinine concentrations need to be considered when co-administering the drug.
Fentanyl: One case of death has been reported that may be related to the fentanyl-fluconazole drug interaction. In healthy volunteers, fluconazole significantly delayed the elimination of fentanyl. Elevated fentanyl blood levels may lead to respiratory depression. Patients should be carefully monitored for potential risk of respiratory depression. Fentanyl dose adjustment may be necessary.
Olaparib: CYP3A4 mid-acting inhibitors (e.g., fluconazole) increase plasma concentrations of olaparib; therefore, coadministration is not recommended. If combination dosing cannot be avoided, limit olaparib dosing to 200 mg twice daily.
3) Immunosuppressants (i.e., cyclosporine, everolimus, sirolimus, tacrolimus)
Cyclosporine: Fluconazole significantly increases the drug concentration and area under the drug-time curve of cyclosporine. The AUC of cyclosporine was increased 1.8-fold during concomitant treatment with fluconazole (200 mg daily) and cyclosporine (2.7 mg/kg/day). The dose of cyclosporine can be reduced according to the blood concentration of cyclosporine.
Everolimus: Although there are no in vitro studies, fluconazole inhibits CYP3A4 and thus increases everolimus blood levels.
Sirolimus: Fluconazole increases sirolimus blood concentrations, possibly due to inhibition of sirolimus metabolism via CYP3A4 and P-glycoprotein. The dose of sirolimus may be adjusted according to clinical efficacy or blood concentration monitoring when co-administered.
Closartan: Fluconazole inhibits the metabolism of cloxartan to the active metabolite (E-31 74), which plays a major role in antagonizing the angiotensin II receptor. Therefore patients on the combination of these two drugs require continuous monitoring of blood pressure levels.
Methadone: Fluconazole increases methadone blood levels, and the dose of methadone may need to be adjusted when co-administered.
Nonsteroidal anti-inflammatory drugs: Peak blood concentrations and area under the drug-time curve were increased by 23% and 81%, respectively, with the combination of flurbiprofen and fluconazole compared with flurbiprofen monotherapy. Similarly the peak blood concentration and area under the drug-time curve of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, when eliminated ibuprofen (400 mg) was coadministered with fluconazole compared with eliminated ibuprofen monotherapy.
Although not specifically studied, fluconazole has the potential to increase systemic exposure to other NSAIDs metabolized by CYP2C9 (eg, naproxen, clonoxicam, meloxicam, diclofenac). Close monitoring for adverse events and toxicity associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required for co-administration.
Phenytoin: Fluconazole inhibits the metabolism of phenytoin in the liver. Concurrent multiple intravenous doses of fluconazole 200 mg and phenytoin 250 mg increased phenytoin AUC24 and Cmin by 75% and 128%, respectively. Phenytoin blood levels need to be tested during coadministration to prevent the development of phenytoin toxicity.
Prednisone: One case reported acute adrenocortical insufficiency in a liver transplant patient treated with prednisone after discontinuation of 3-month fluconazole therapy. This may be related to increased CYP3A4 activity caused by fluconazole discontinuation, which in turn leads to an accelerated rate of prednisone metabolism. Patients receiving long-term fluconazole in combination with prednisone should be closely monitored for the development of adrenocortical insufficiency after fluconazole discontinuation.
Saquinavir: Fluconazole inhibits the hepatic metabolism of saquinavir via CYP3A4 and P-glycoprotein, thus increasing the area under the drug-time curve of saquinavir by approximately 50% and the peak blood concentration by approximately 55%, and the interaction between fluconazole and saquinavir/ritonavir has not been studied and may be more pronounced. Adjustment of the dose of saquinavir may be required for coadministration.
Sulfonylureas: Co-administration studies have demonstrated that fluconazole prolongs the half-life of oral sulfonylureas (e.g., chlorosulfonylurea, glibenclamide, glipizide, toluenesulfonylurea) in healthy subjects. Close monitoring of blood glucose levels and moderate reduction of sulfonylurea dosage is recommended for co-administration.
Tofacitab: Tofacitab is associated with increased exposure when co-administered with CYP3A4 intermediate inhibitors and CYP2C19 potent inhibitors (e.g., fluconazole). Therefore, a reduction in the dose of tofacitab to 5 mg once daily is recommended when coadministered with such drugs.
Vincristine analogs: Although not studied, fluconazole may increase blood concentrations of vincristine analogs (eg, vincristine, perphenazine) and cause neurotoxicity, which may be related to inhibition of CYP3A4.
Vitamin A: In one case report, a patient receiving a combination of all-trans retinoic acid (an acid form of vitamin A) and fluconazole experienced CNS-related adverse effects (manifested as pseudotumor cerebri syndrome) that resolved after discontinuation of fluconazole. Such drugs can be used in combination, but the occurrence of their CNS-related adverse reactions should be kept in mind.
Voriconazole: (CYP2C9, CYP2C19, and CYP3A4 inhibitors): 8 healthy male subjects received oral voriconazole (400 mg Q12h for 1 day; followed by 200 mg Q12h for 2.5 days) and fluconazole (400 mg on day 1; followed by 200 mg Q24h for for a total of 4 days) resulted in an average increase in voriconazole Cmax and AUCτ of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. Reduced dose and/or frequency of voriconazole and fluconazole administration that would eliminate this effect have not been identified. If voriconazole is administered after fluconazole, monitoring for voriconazole-related adverse events is recommended.
Zidovudine: Fluconazole in combination with oral zidovudine reduces the clearance rate of the latter by approximately 45% and therefore increases the peak blood concentration and area under the drug-time curve of zidovudine by 84% and 74%, respectively. At the same time, the half-life of zidovudine was prolonged by about 128%. Therefore, the occurrence of zidovudine-related adverse reactions should be closely monitored when co-administering the drug. If necessary, consider reducing the dose of zidovudine.
Azithromycin: An open, randomized, 3-crossover pharmacokinetic study was conducted in 18 healthy subjects to evaluate the interaction of azithromycin (oral single dose 1200 mg) with fluconazole (oral single dose 800 mg). The results showed no significant pharmacokinetic interaction between azithromycin and fluconazole.
Oral contraceptives: There have been two pharmacokinetic studies of multiple doses of fluconazole in combination with oral contraceptives. In one study with a fluconazole dose of 50 mg, there was no significant association between hormone levels and the drug; whereas in the study with a fluconazole dose of 200 mg, the area under the drug-time curve increased by 40% and 24% for ethinyl estradiol and levonorgestrel, respectively. Thus these doses of fluconazole administered in multiple doses had little effect on the efficacy of oral contraceptives.
Ivacaftor: Fluconazole coadministered with the cystic fibrosis transmembrane transduction regulator (CFTR) potentiator ivacaftor resulted in a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl ivacaftor (M1) exposure. For patients who are on a combination of CYP3A mid-activity inhibitors such as fluconazole and erythromycin, a reduction in ivacaftor dose to 150 mg once daily is recommended.
[ Pharmacological Toxicology]
Pharmacological effects
1)Mechanism of action
Fluconazole is a triazole antifungal drug. Its primary mechanism of action is the inhibition of fungal cytochrome P-450-mediated demethylation of 14α-lanosterol, a key step in fungal ergosterol biosynthesis. 14α-methylsterol accumulation is associated with subsequent ergosterol loss from fungal cell membranes, which may account for fluconazole’s ability to exert antifungal activity. Fluconazole has a higher selectivity for fungal cytochrome P-450 enzymes compared to the mammalian cytochrome P-450 enzyme system.
2)In vitro sensitivity
In in vitro tests, fluconazole showed antifungal activity against most clinically common Candida species, including Candida albicans, Candida subtilis, and Candida tropicalis. Smooth Candida showed broad susceptibility to fluconazole, whereas Candida klebsiella was resistant to fluconazole.
Fluconazole also has antifungal activity in in vitro assays against Cryptococcus neoformans and Cryptococcus, as well as endemic mycobacterial dermatophytes, Clostridium vulgaris, Entamoeba histolytica, and Bacillus brasiliensis.
3)Pharmacokinetics/Pharmacodynamic relationships
In animal trials, there was a correlation between MIC values and the efficacy of anti-Candida-induced experimental fungal disease. In clinical trials, there was an almost linear 1:1 relationship between AUC and fluconazole dose. a similar direct (although imperfect) relationship exists between AUC or dose and clinical cure of oral candidiasis, and to some extent with clinical treatment of candidemia. Similarly, clinical cure is likely to be less for infections caused by strains with higher fluconazole MICs.
4)Drug resistance mechanisms
Candida has developed a large number of resistance mechanisms to azole antifungal drugs. Strains with one or more resistance mechanisms are generally thought to exhibit higher MIC values to fluconazole, which can affect in vivo and clinical efficacy. Serious infections with Candida (other than Candida albicans) have been reported, and these strains tend to be inherently insensitive to fluconazole (e.g., Candida klebsiella), in which case other antifungal agents may be chosen.
5) fold (according to EUCAST family:Arial”>standard)
Fold points for fluconazole against Candida species were determined by EUCAST-AFST (European Committee for Pharmacokinetic Testing – Antifungal Susceptibility Testing Branch) based on the analysis of pharmacokinetic/pharmacodynamic (PK/PD) data, in vitro susceptibility and clinical response (EUCAST Fluconazole Rationalization Document (2007) version 2). These include non-strain-related and strain-related fold points. The non-strain-related fold points are mainly based on PK/PD data and are not related to the MIC distribution of specific strains; the strain-related fold points are mainly for the most frequently infected strains in humans. See the following table for these folds.
Antifungals Strain-related fold (S≤/R>)Non-strain-related foldA
S≤/R> Candida albicansSmooth CandidaClaudia candidaCandida subsmoothisCandida tropicalis Fluconazole2/4IE –2/42/42/4S = Sensitive,R = resistant
A. = Non-strain related folds based mainly onPK/PDdata determined independently of the strain-specificMICdistribution. Only used for strains without characteristic fold points.
— = Sensitivity testing is not recommended because this strain is not an ideal target for treatment with this product. .
IE = The evidence for this strain as an ideal target for this treatment is insufficient.
Toxicological studies
Genotoxicity
In The following genotoxicity assays using fluconazole have shown negative results. .
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Salmonella typhimurium reversion mutation test
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Mouse lymphomaL5178Ycell mutation assay
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In vitro chromosomal aberration test on human lymphocytes
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In vivo bone marrow micronucleus test in mice
Reproductive toxicity
No effect on fertility was seen in female and male rats given fluconazole 5, 10, 20 mg/kg/day or by the non-intestinal route at 5, 25, 75 mg/kg/day; however, a dose of 20 mg/kg/day (administered orally) resulted in a slight delay in the time to delivery.
In two rabbit embryo-fetal development toxicity trials, oral administration of fluconazole at doses of 5, 10, and 20 mg/kg and 5, 25, and 75 mg/kg during the organogenesis phase was seen in pregnant rabbits, respectively, and maternal weight gain was slowed at all doses (approximately 0.25 to 4 times the human clinical dose of 400 mg converted to body surface area) and at the 75 mg/kg The dose of 75 mg/kg (approximately 4 times the human clinical dose of 400 mg, based on body surface area) was associated with abortion, and no adverse effects on fetuses were observed.
In several rat embryo-fetal development toxicity tests, fluconazole was given orally to pregnant rats during the organogenesis phase. Maternal weight gain effects and increased placental weight were seen at 25 mg/kg; no effects on fetuses were seen at 5 and 10 mg/kg, anatomical variations (multiple ribs, dilated renal pelvis) and increased delayed ossification were seen in fetuses at 25 and 50 mg/kg or higher, and at 80-320 mg/kg (approximately 2-8 times the human clinical dose of 400 mg, based on body surface area). At doses of 80-320 mg/kg (about 2-8 times the human clinical dose of 400 mg), rats showed increased stillbirth rate and developmental abnormalities of fetuses such as undulating ribs, cleft palate and abnormal craniofacial ossification were observed. These abnormalities are associated with inhibition of estrogen synthesis in rats and may be the result of the known effects of low estrogen levels on gestation, organogenesis, and delivery.
In a perinatal toxicity test in rats given fluconazole 20 (approximately 5-15 times the recommended human dose), 40 mg/kg intravenously, obstructed labor and prolonged labor were seen in several females, whereas this response was not seen at the 5 mg/kg dose. A slight increase in the number of stillbirths and a decrease in the number of live births were also seen at these doses where labor disturbances occurred. The effect of high doses of fluconazole on labor in rats is related to its species-specific property of reducing estrogen levels. Such alterations in hormone levels have not been observed in women treated with fluconazole.
Carcinogenicity
In a 24-month oral administration carcinogenicity test in mice and rats, fluconazole was administered at doses of 2.5, 5, and 10 mg/kg/day (approximately 2 to 7 times the recommended human dose), and no evidence of potential carcinogenicity of fluconazole was seen. An increased incidence of hepatocellular adenomas was seen in male rats given fluconazole 5 and 10 mg/kg orally. .
[Pharmacokinetics].
The pharmacokinetic properties of fluconazole administered intravenously are similar to those of oral administration.
Absorption
Fluconazole is well absorbed orally and plasma concentrations (and systemic bioavailability) can reach more than 90% of the concentration after intravenous administration of the same dose of drug. Oral absorption is not affected by food intake. Under fasting conditions, plasma concentration peaks 0.5-1.5 hours after administration of fluconazole, with a plasma elimination half-life approaching 30 hours. The plasma concentration is proportional to the administered dose. Fluconazole reaches 90% of its steady-state concentration after 4 to 5 days of once-daily administration. After administration of a saturating dose of fluconazole (day 1), which is equivalent to 2 times the regular daily dose, its plasma concentration approaches 90% of its steady-state concentration on the second day.
Distribution
Apparent volume of distribution approximates total body water. The plasma protein binding of fluconazole is low (11-12%).
Studies have shown that fluconazole penetrates well into various body fluids. Fluconazole concentrations in saliva and sputum were similar to plasma concentrations. In the cerebrospinal fluid of patients with fungal meningitis, fluconazole concentrations were about 80% of the plasma concentrations at the same time.
Fluconazole is found in the cutaneous stratum corneum, epidermal dermis, and secreted The sweat of the skin can reach high concentrations, even exceeding its serum concentration. Fluconazole can accumulate in the stratum corneum. Fluconazole 50 mg once a day was 73 μg/g after 12 days of dosing and remained at 5.8 μg/g after 7 days of discontinuation. fluconazole 150 mg once a week was 23.4 μg/g in the stratum corneum on day 7 of dosing and remained at 7.1 μg/g after a second dose of 7 days.
Fluconazole 150 mg once a week for 4 months resulted in concentrations of 4.05 μg/g in normal and 1.8 μg/g in patient nails; and fluconazole was still detectable in nails 6 months after the end of treatment.
Biotransformation
The degree of fluconazole metabolism was low. Only 11% of the radiologically active agent volume is converted and excreted in the urine. Fluconazole is a moderately selective inhibitor of the isoenzymes CYP2C9 and CYP3A4 (see [Drug Interactions]). Fluconazole is also a potent inhibitor of the isoenzyme CYP2C19.
Elimination
The plasma elimination half-life of fluconazole is long, about 30 hours. The primary route of excretion of fluconazole is the kidney, with close to 80% of the dose excreted in the urine in its native form. The clearance of fluconazole is proportional to creatinine clearance. No metabolites of fluconazole were found in the blood circulation.
The longer plasma elimination half-life provides the rationale for single-dose therapy for vaginal candidiasis, with once-daily or weekly dosing for other indications.
Pharmacokinetics in people with impaired renal function
The half-life in patients with severe renal insufficiency (GFR<20 ml/min) increases from 30 hours to 98 hours in vivo. Therefore dose reduction is required. Fluconazole can be eliminated by hemodialysis, and peritoneal dialysis elimination is worse than hemodialysis. About 50% of fluconazole is eliminated from the blood 3 hours after initiation of hemodialysis.
Pharmacokinetics during lactation
A pharmacokinetic study was conducted in 10 lactating women who had temporarily or permanently stopped breastfeeding their infants to assess plasma and breast milk fluconazole concentrations 48 hours after a single dose of 150 mg of this product. The mean fluconazole concentration detected in breast milk was approximately 98% of the mother’s plasma concentration. The mean peak concentration in breast milk 5.2 hours after administration was 2.61 mg/L. Based on the mean peak breast milk concentration, the estimated daily dose of fluconazole received by the infant through breast milk (assuming a mean consumption of 150 ml/kg/day) was 0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose for mucocutaneous candidiasis (<2 weeks of age) or 13%.
Children’s pharmacokinetics
Pharmacokinetic data from 113 pediatric patients in 5 trials, including 2 single-dose trials, 2 multi-dose trials, and a premature neonatal trial, were evaluated. Data from one trial could not be interpreted because of changes in the route of formulation during the trial.
After administration of fluconazole at doses of 2 to 8 mg/kg in pediatric patients (aged 9 months to 15 years), the corresponding AUC was 38 μg× h/ml per 1 mg/kg dose. The mean plasma elimination half-life of fluconazole was 15 to 18 hours. The volume of distribution after multiple doses is approximately 880 ml/kg. the plasma elimination half-life of fluconazole after a single dose is longer, approximately 24 hours. It is similar to the plasma elimination half-life of fluconazole after a single intravenous dose (3 mg/kg) in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mg/kg.
Experience with fluconazole in neonates is limited to a pharmacokinetic trial in premature neonates. The mean age of the 12 preterm neonates at the time of the first dose was 24 hours (range of variation 9 to 36 hours), mean birth weight was 0.9 kg (range of variation 0.75 to 1.10 kg), and mean gestational age was approximately 28 weeks. 7 patients completed the regimen; no more than 5 fluconazole intravenous infusions (6 mg/kg) were administered every 72 hours. The mean half-life (hours) on day 1 was 74 (range of variation 44 to 185), decreasing over time to 53 (30 to 131) (day 7) and 47 (27 to 68) (day 13). The area under the curve (mg×h/ml) was 271 (range of variation 173 to 385) on day 1, increased to a mean value of 490 (range of variation 292 to 734) on day 7, and decreased to a mean value of 360 (range of variation 167 to 566) on day 13. The volume of distribution (ml/kg) was 1183 (range of variation 1070 to 1470) on day 1 and increased over time, reaching a mean value of 1184 (range of variation 510 to 2130) on day 7 and 1328 (range of variation 1040 to 1680) on day 13.
Geriatric pharmacokinetics
Twenty-two elderly subjects aged 65 years and older received a single oral dose of fluconazole 50 mg, 10 of whom were also taking a diuretic. Pharmacokinetic results showed that peak blood concentration was reached 1.3 hours after administration at 1.54 mcg/ml, with a mean area under the drug-time curve of 76.4 ± 20.3 mcg×h/ml and a mean elimination half-life of 46.2 hours. This pharmacokinetic parameter was higher than those reported in the literature for healthy young male volunteers. Concomitant administration of diuretics had no significant effect on the area under the drug-time curve and peak blood concentrations. In addition, the creatinine clearance of 74 ml/min, urinary excretion of 22% of the drug in its original form within 24 hours, and renal clearance of 0.124 ml/min/kg were lower in the elderly than in the younger volunteers. Therefore, the differences in fluconazole pharmacokinetic parameters in the elderly compared with the young may be related to reduced renal function in the elderly.
Other.
Fluconazole 50 mg daily for 28 days had no effect on plasma testosterone concentrations in men or plasma steroid concentrations in women of childbearing age. Fluconazole 200 to 400 mg daily had no significant effect on endogenous steroid levels or pro-adrenocorticotropic stimulatory effects in healthy male volunteers. Drug interaction studies with antipyrine have shown that single or multiple doses of fluconazole 50 mg do not affect the in vivo metabolism of antipyrine.
[Storage] Store below 30°C.
[Package] Aluminum-plastic blister pack.
50mg: 3 tablets/plate. 10 tablets/plate.
150mg:3tablets/plate. .
[Expiration date] 24 months
[Executive Standard
[Approval Number
[Manufacturer
Enterprise name: Shijiazhuang Four Medicine Co.
Production Address: No. 288 Zhujiang Avenue, Shijiazhuang High-Tech Industrial Development Zone
Postal Code: 050035
Phone number: (0311) 67167185 67167186 67167158
Fax number: (0311) 67167215
Website: www.sjzsiyao.com