Approval Date:April 05, 2007
Revision date:April 18, 2013 December 01, 2015
Fluconazole capsule instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Fluconazole Capsules
English name: Fluconazole Capsules
Hanyu Pinyin：Fukangzuo Jiaonang
Ingredients
The main ingredient of this product is Fluconazole, whose chemical name is: α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)
The chemical name is: α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazol-1-ylethanol.
The chemical structure formula is
Molecular formula: C13H12F2N6O
Molecular weight: 306.28
Properties
This product is a capsule, the contents are white or off-white powder.
Indications】
This product is indicated for the following fungal infections.
Adults
(1) 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) where oral hygiene or topical treatment is ineffective.
Treatment of acute or recurrent vaginal candidiasis in the absence of suitable topical treatment options.
Treatment of candidal glans when appropriate local treatment options are lacking
treatment of dermatophytes 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 suitable drugs 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.
Reduction in the incidence of recurrent 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.
It is indicated for the prevention of Candida infections in immune-compromised patients.
It may 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 the judicious use of antifungal drugs.
Tinea capitis: Studies have been conducted on the use of fluconazole in the treatment of tinea capitis in children. The results showed that fluconazole was not superior to ashwagandha and that the overall success rate was less than 20%. Therefore, this product should not be used for ringworm of the head.
Cryptococcosis: There is less evidence on the efficacy of fluconazole for the treatment of cryptococcosis at other sites (e.g., pulmonary and cutaneous cryptococcosis) and therefore it is not recommended and no dosage recommendations are provided.
Endemic deep fungal disease: Evidence for the efficacy of fluconazole in the treatment of other types of endemic fungal disease (e.g., paracoccidioidomycosis, cutaneous lymphangioidomycosis, and histoplasmosis) is sparse, and therefore it is not recommended and dosage recommendations are not provided.
Specification】50mg
Dosage]
1.Dosage
The dose should be determined according to the nature and severity of the fungal infection. For infections requiring multiple doses of treatment should be continued until clinical parameters or laboratory tests indicate that the active fungal infection has subsided. Inadequate treatment may lead to recurrence of active infections.
Adult dosing.
Indication dosage regimen Cryptococcosis – Treatment of cryptococcal meningitis Loading dose: 400 mg on day 1
Follow-up dose: 200 mg to 400 mg once daily usually for at least 6-8 weeks. Daily dose may be increased to 800mg for life-threatening infections – Maintenance therapy for prevention of recurrence of cryptococcal meningitis in patients at high risk of recurrence 200mg once daily 200mg once daily continuous dosing Coccidioidomycosis 200mg to 400mg once daily for 11 months up to 24 months or longer, depending on the patient. 800mg daily may be considered for some infections, especially meningitis. Invasive Candidiasis Loading dose: 800mg on day 1
Follow-up dose: 400mg once daily The usual recommended course of treatment for Candidaemia is 2 weeks after the first negative blood culture and resolution of signs and symptoms of Candidaemia Mucocutaneous Candidiasis Treatment – Oropharyngeal Candidiasis Loading dose: 200mg to 400mg on day 1
Follow-up dose: 100mg to 200mg once daily for 7-21 days (until remission of oropharyngeal candidiasis)
Severely immunocompromised patients may require longer – Esophageal candidiasis loading dose: 200mg to 400mg on day 1
Follow-up dose: 100mg to 200mg once daily for 14-30 days (until esophageal candidiasis is in remission)
Severely immunocompromised patients may need longer- Candida urine 200mg to 400mg once daily for 7-21 days Severely immunocompromised patients may require longer- Chronic atrophic candidiasis 50mg once daily for 14 days- Chronic cutaneous mucocutaneous candidiasis 50mg to 100mg once daily for up to 28 days. Long-term treatment depends on the severity of infection or underlying immune compromise and infection prevention relapse of mucocutaneous candidiasis in HIV-infected patients at high risk of relapse- Oropharyngeal candidiasis 100mg to 200mg once daily or 200mg 3 times a week for chronic immunosuppressed patients on an irregular basis- Esophageal candidiasis 100mg to 200mg once a day or 200mg 3 times a week in chronic immunosuppressed patients – Genital Candidiasis – Acute vaginal Candida infection
– Candida glabrata 150mg
Single dose administration- Treatment and prevention of recurrence incidence of vaginal candidiasis (4 or more episodes a year) 150mg every 3 days for a total of 3 doses (day 1, day 4 and day 7), followed by a maintenance dose of 150mg weekly Continuous treatment: 6 months Dermatophytosis- Tinea pedis
– Tinea corporis
– Tinea corporis
– Candida infection
Tinea pedis 150mg once a week or 50mg once a day for 2-4 weeks, Tinea pedis may require up to 6 weeks of treatment- Tinea pedis 300mg-400mg once a week for 1-3 weeks 50mg once a day for 2-4 weeks- Tinea nail (nail fungus) 150mg once a week maintenance therapy until infected nails are covered (normal nails grow out). Usually it takes 3 to 6 months for finger nails and 6 to 12 months for toe nails to re-grow. However, the rate of growth varies greatly with the age of the individual. Occasionally, nails may remain deformed after successful treatment of long-term chronic infections. Prevention of Candida infection in neutropenic patients 200 mg to 400 mg once daily treatment should be started a few days before the expected onset of neutropenia and continued for 7 days after recovery (elevated neutrophil count above 1000/mm3)
Special Population Dosing.
Elderly
Dose should be adjusted according to renal function (see “Impaired Renal Function”).
Impaired renal function
This product is primarily excreted 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 should be determined according to the following table (depending on the indication).
Creatinine clearance (ml/min) % of recommended dose >50100% ≤ 50 (not on hemodialysis) 50% hemodialysis 100% after each 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.
Hepatic Impairment
There are limited data on dosing in patients with impaired liver function; therefore, fluconazole should be used with caution in patients with hepatic insufficiency (see [Adverse Reactions] and [Precautions]).
Pediatric Population
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.
For the use in pediatric patients with impaired renal function, see the section on “Impaired Renal Function”. Fluconazole has not been studied pharmacokinetically 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).
Indication dosage recommendation – Mucocutaneous candidiasis initial dose: 6mg/kg
Follow-up dose: 3 mg/kg once daily on the first day of use to reach steady-state levels more quickly – Invasive candidiasis
– Cryptococcal meningitis dose: 6-12 mg/kg once daily depending on severity of disease – Maintenance therapy for prevention of recurrence of Cryptococcal meningitis in pediatric patients at high risk of recurrence dose: 6 mg/kg once daily depending on severity of disease – Prevention of immune compromise Dose for Candida infection in patients: 3-12 mg/kg once daily depending on the degree and duration of induced neutropenia (see adult dosage)
Adolescents (12-17 years).
Depending on body 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 obtain 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 necessary for the treatment of 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 is little pharmacokinetic data to support the dosage in term neonates.
Age group dosage recommendations for full-term neonates (0-14 days) The maximum dose of mg/kg given every 72 hours should not exceed 12 mg/kg every 72 hours for full-term neonates (15-27 days) The maximum dose of mg/kg given every 48 hours should not exceed 12 mg/kg every 48 hours for infants, toddlers, and children
2.Dosing method
This product can be administered orally (capsules, oral dry suspension powder and syrup) or by intravenous infusion (infusion solution), the route of administration depends on the clinical status of the patient. No change in daily dose is required when switching from intravenous to oral administration and vice versa.
The physician should prescribe the most appropriate dosage form and size based on age, weight and dose. Capsules are not intended for use in infants and children; this population is better suited to fluconazole oral liquid systemic dosing.
The entire capsule should be swallowed and is not dependent on food intake.
[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 (available information cannot be confirmed).
Systemic organ classification Common Rare Rare Unknown Blood and lymphatic system disorders Anemia Granulocyte deficiency, leukopenia, thrombocytopenia, neutropenia Immune system disorders Allergic reactions Metabolic and nutritional disorders Appetite loss Hypercholesterolemia, hypertriglyceridemia, hypokalemia Psychiatric disorders Narcolepsy, insomnia Neurologic disorders Headache Epileptic seizures, sensory abnormalities, dizziness, taste inversion tremor Ear and Labyrinthine disorders Vertigo Cardiac disorders Ventricular tachycardia, prolonged QT interval Gastrointestinal disorders Abdominal pain, vomiting, diarrhea, nausea and constipation, dyspepsia, flatulence, dry mouth Hepatobiliary disorders Elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated blood alkaline phosphatase Cholestasis, jaundice, elevated bilirubin Liver failure, hepatocyte necrosis, hepatitis, hepatocellular damage Skin and subcutaneous tissue disorders rash drug rash*, urticaria, pruritus, increased sweating toxic necrolytic epidermolysis bullosa, Stevens-Johnson syndrome, acute generalized eruptive impetigo, exfoliative dermatitis, angioedema, facial edema, hair loss eosinophilia and reactions to drugs with systemic symptoms (DRESS) skeletal muscle and connective tissue disorders myalgia systemic disorders and administration site conditions Fatigue, malaise, malaise, fever * including fixed drug rash
Pediatric population
The types and incidence of adverse reactions and abnormal laboratory tests recorded in pediatric patients in clinical studies other than those for the indication of genital candidiasis were approximately the same as in adult patients.
Suspected Adverse Reaction Reporting
It is important to report suspected adverse reactions after a drug is licensed so that the benefit/risk balance of the drug can be monitored on an ongoing basis. Healthcare professionals are required to report any suspected adverse reactions.
Contraindications
Contraindicated in patients with hypersensitivity to fluconazole, its inactive ingredients, or 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 prohibited in patients receiving fluconazole therapy.
Precautions]
Renal system
This product should be used with caution in patients with renal insufficiency.
Adrenal cortical insufficiency
Ketoconazole is known to cause adrenocortical insufficiency. Although rare, fluconazole is also indicated. See [Drug Interactions] for adrenocortical insufficiency associated with prednisone combination.
Hepatobiliary System
Fluconazole should be used with caution in patients with hepatic insufficiency.
Serious hepatotoxicity, including lethal hepatotoxicity, has occasionally occurred in patients following fluconazole use, 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.
Adverse Skin Reactions
Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermolysis bullosa have occasionally occurred in patients during fluconazole treatment. 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 closely monitored and fluconazole should be discontinued as soon as maculopapular lesions or erythema multiforme develop.
Terfenadine
Concomitant use of terfenadine in patients taking fluconazole (<400 mg daily) should be closely monitored (see [Contraindications] and [Drug Interactions]).
Hypersensitivity reactions
Anaphylactic shock reactions have been reported rarely.
Cardiovascular system
Certain azole antifungals, including fluconazole, are associated with prolongation of the QT interval in the ECG. Fluconazole causes prolongation of the QT interval by inhibiting rectifier potassium channel currents (Ikr). Prolongation of the QT interval caused by other drugs (e.g., amiodarone) can be amplified by inhibition of cytochrome P450 (CYP) 3A4. Post-marketing safety monitoring of patients on fluconazole found that very few cases reported QT interval prolongation and tip-twisting 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 arrhythmogenic conditions. Concomitant use of other drugs known to prolong the QT interval or 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 to avoid concomitant use of fluconazole with halofantrine (see [Drug Interactions]).
Cytochrome P450
Fluconazole is an intermediate inhibitor of CYP2C9 and CYP3A4. Fluconazole is also a potent inhibitor of the CYP2C19 isoenzyme. Patients treated with fluconazole need to be monitored closely if concomitant use of drugs that are metabolized by CYP2C9, CYP2C19 and CYP3A4 and have a narrow therapeutic window (see [Drug Interactions]).
Excipients
Capsules contain lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactolytic enzyme deficiency, or impaired glucose-galactose absorption problems should not take this product.
Effects on the ability to drive and operate machinery
Trials of the effects of fluconazole on the ability to drive or operate machinery have not been performed. Patients should be warned of the possibility of vertigo or seizures during fluconazole administration and advised to stop driving or operating machinery if any of these symptoms occur.
Pregnant women and nursing mothers
Use during pregnancy
An observational study showed an increased risk of spontaneous abortion with fluconazole in women in the first trimester of pregnancy.
Multiple congenital anomalies (including short head malformation, ear hypoplasia, large fontanelle, femoral archification, and brachioradialis fusion) were reported in infants of mothers with coccidioidomycosis who received high doses of fluconazole (400 to 800 mg daily) for 3 months or more. Whether these anomalies are associated with the use of fluconazole is unknown.
Animal studies have shown reproductive toxicity of this product.
Short-term administration of standard doses of fluconazole should be avoided during pregnancy unless clearly indicated.
High-dose and/or long-term treatment with fluconazole should be avoided during pregnancy unless a potentially life-threatening infection occurs.
Dosing 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 be continued. After multiple doses or high doses of fluconazole, it is recommended that breastfeeding be discontinued. 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 has no effect on fertility in male or female rats.
Pediatric Use]
See [Dosage and Administration] Special Populations and [Pharmacokinetics] Pharmacokinetics in Children.
Geriatric use
See [Dosage] Special Populations and [Pharmacokinetics] Pharmacokinetics in the Elderly.
Drug Interactions
1. The combination of this product with the following drugs is prohibited
Cisapride: Concomitant use of fluconazole and cisapride has been reported to cause cardiac adverse events, including tip-twisting ventricular tachycardia. A controlled study showed that the combination of fluconazole (200 mg once daily) and cisapride (20 mg four times daily) caused a significant increase in cisapride blood levels and a significant prolongation of the QTc interval. The combination of cisapride is contraindicated in patients treated with fluconazole (see [Contraindications]).
Terfenadine: Several drug interaction studies have been conducted because the combination of azole antifungals and terfenadine 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 a daily dose of 400 mg or more significantly increased the blood levels of terfenadine. The combination of fluconazole with terfenadine is prohibited at doses of 400 mg or more per day (see [Contraindications]). If fluconazole is administered at doses below 400 mg daily and is co-administered with terfenadine, the blood levels of terfenadine should be monitored closely.
Astemizole: The combination of astemizole and fluconazole may slow the clearance of astemizole, whose elevated blood levels may lead to prolonged QT interval and rare tip-twisting ventricular tachycardia. Therefore, co-administration 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 may lead to QT interval prolongation and rare tip-turn 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 use of the latter is associated with prolonged QT interval and rare tip-turn ventricular tachycardia. The combination of quinidine and fluconazole is contraindicated (see [Contraindications]).
Erythromycin: The combination of fluconazole and 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
Halofantrine: Fluconazole inhibits CYP3A4 and therefore may increase the blood concentration of halofantrine. Combination of fluconazole and halofantrine 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]).
3. Combination of drugs should be used with caution
Amiodarone: Combined use of fluconazole and amiodarone may increase QT interval prolongation. Caution must be exercised if fluconazole and amiodarone must be used in combination, especially when high doses of fluconazole (800 mg) are used.
4. Caution and dose adjustment should be exercised when combined with the following drugs
(1) Effects of other drugs on fluconazole
Rifampin: The combination of fluconazole and rifampin can reduce the area under the curve (AUC) of fluconazole by 25% and the half-life by 20%. Patients treated with rifampicin in combination should consider an appropriate increase in fluconazole dosing.
Results of drug interaction studies have shown no significant impairment of fluconazole absorption when fluconazole was administered orally with food, cimetidine, and antacids, or when patients received fluconazole after systemic radiotherapy for bone marrow transplantation.
Hydrochlorothiazide: In a pharmacokinetic interaction study, the combination of multiple doses of hydrochlorothiazide in healthy subjects treated with fluconazole resulted in a 40% increase in fluconazole blood levels. The effect of this magnitude 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 an intermediate inhibitor of cytochrome P450 (CYP) isoenzymes 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 AUC10 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 the inhibition of CYP3A4 by fluconazole.
Dose adjustment of alfentanil administration may be required in this case.
Amitriptyline, nortriptyline: Fluconazole may increase the efficacy of amitriptyline and nortriptyline. Blood levels of 5-nortriptyline and/or S-amytriptyline may need to be measured at the beginning 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 infections with Candida albicans; no change in efficacy for intracranial infections with Cryptococcus novelis; and antagonism between the two drugs for systemic infections with Aspergillus fumigatus. The clinical significance of the above findings is unclear.
Anticoagulants: Post-marketing clinical reports suggest that, similar to other azole antifungals, patients treated with fluconazole and concomitant warfarin therapy may experience bleeding adverse events (subcutaneous ecchymosis, epistaxis, gastrointestinal bleeding, hematuria, and black stools) with prolonged prothrombin time. Prothrombin time should be closely monitored in patients receiving concomitant coumarin or indandione anticoagulant therapy. Dose adjustment of anticoagulants may be required for combination therapy.
Benzodiazepines (short-acting) i.e. midazolam, triazolam: administration of fluconazole after oral midazolam may cause a significant increase in midazolam blood levels and a psychomotor reaction. 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 to adjust the dose of carbamazepine may be determined by the results of drug concentration monitoring 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 the above 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 of the normal recommended dose when combined.
Cyclophosphamide: The combination of cyclophosphamide and fluconazole may result in increased blood bilirubin and creatinine concentrations. Therefore, the risks associated with elevated 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 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.
HMG-CoA reductase inhibitors: Some HMG-CoA reductase inhibitors are metabolized by CYP3A4 (e.g., atorvastatin, simvastatin) and some by CYP2C9 (e.g., fluvastatin); these drugs can increase the risk of myopathy and rhabdomyolysis when used in combination with fluconazole. If the combination is necessary, patients should be observed for symptoms associated with myopathy and rhabdomyolysis, and creatinine kinase levels should be monitored closely. If a significant increase in creatinine kinase levels is detected, or if a diagnosis of myopathy/rhabdomyolysis is confirmed/proposed, the HMG-CoA reductase inhibitor must be discontinued.
Olaparib: CYP3A4 intermediate-acting inhibitors (e.g., fluconazole) increase plasma concentrations of olaparib; therefore, coadministration is not recommended. If combination dosing cannot be avoided, limit the dose of olaparib 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/day) and cyclosporine (2.7 mg/kg/day). The dose of cyclosporine can be reduced according to the blood concentration of cyclosporine.
Everolimus: Although no in vitro or in vivo studies are available, fluconazole inhibits CYP3A4 and thereby increases the blood concentration of everolimus.
Sirolimus: Fluconazole may increase the blood concentration of sirolimus, and the mechanism may be due to the inhibition of sirolimus metabolism through CYP3A4 and P-glycoprotein. The dose of sirolimus can be adjusted according to the clinical efficacy or blood concentration monitoring results when co-administered.
Tacrolimus: Fluconazole can inhibit the metabolism of tacrolimus through CYP3A4 in the intestinal tract, so the combination with oral tacrolimus can increase the blood concentration of the latter by up to 5 times. No significant pharmacokinetic changes were observed when tacrolimus was administered intravenously. Elevated tacrolimus blood concentrations were associated with nephrotoxicity. Therefore, when fluconazole is co-administered with oral tacrolimus, the dose should be reduced appropriately according to the tacrolimus blood concentration.
Cloxacin: Fluconazole inhibits the metabolism of cloxacin to the active metabolite (E-31 74), which plays a major role in the antagonism of angiotensin II receptors. Therefore patients who combine these two drugs need to have their blood pressure levels continuously monitored.
Methadone: Fluconazole may increase the blood levels of methadone, and the dose of methadone may need to be adjusted when co-administered.
NSAIDs: The peak blood concentration and area under the drug-time curve for the combination of flurbiprofen and fluconazole increased by 23% and 81%, respectively, compared to flurbiprofen monotherapy. Similarly the peak blood concentration and the area under the drug-time curve of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, when racemic ibuprofen (400 mg) was co-administered with fluconazole compared to racemic ibuprofen monotherapy.
Although not specifically studied, fluconazole has the potential to increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, clonoxicam, meloxicam, diclofenac). Close monitoring for adverse events and toxicity associated with NSAIDs is recommended. Adjustment of the dose of NSAIDs may be required for co-administration.
Phenytoin: Fluconazole inhibits the metabolism of phenytoin in the liver. Concurrent intravenous administration of fluconazole 200 mg and phenytoin 250 mg can increase phenytoin AUC24 and Cmin by 75% and 128%, respectively. Phenytoin blood levels need to be tested when co-administered to prevent the occurrence of phenytoin toxicity.
Prednisone: One case reported acute adrenocortical insufficiency in a liver transplant patient treated with prednisone after a 3-month discontinuation of 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.
Rifabutin: Drug interactions have been reported with the combination of fluconazole and rifabutin, resulting in increased serum concentrations of rifabutin (its AUC increased up to 80%). The combination of fluconazole and rifabutin has been reported to cause uveitis. Symptoms of rifabutin toxicity should be considered with combination therapy.
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%. 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 co-administration.
Sulfonylureas: Combination studies have demonstrated that fluconazole prolongs the half-life of oral sulfonylureas (e.g., chlorosulfonylurea, glibenclamide, glipizide, mebendazole) in healthy subjects. Close monitoring of blood glucose levels and moderate reduction of sulfonylurea dosage is recommended for combination dosing.
Theophylline: A placebo-controlled drug interaction study showed that fluconazole 200 mg for 14 days resulted in an 18% reduction in mean plasma elimination of theophylline. Patients treated with high doses of theophylline or at risk for other theophylline toxicities should be observed for symptoms of theophylline toxicity when fluconazole is co-administered; if patients develop symptoms of toxicity, the treatment regimen should be adjusted accordingly.
Tofacitab: Tofacitab is associated with increased exposure when co-administered with CYP3A4 intermediate inhibitors and CYP2C19 potent inhibitors (e.g., fluconazole). Therefore, when co-administered with such drugs, it is recommended to reduce the dose of tofacitib to 5 mg once daily.
Vincristine analogues: Although not studied, fluconazole may increase blood levels and cause neurotoxicity of vincristine analogues (e.g., vincristine, perphenazine), which may be associated with inhibition of CYP3A4.
Vitamin A: In a case report, one 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): concomitant oral administration of 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 a total of 4 days) in 8 healthy male subjects resulted in a mean increase in voriconazole Cmax and AUCτ were elevated by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. Reduced dose and/or frequency of voriconazole and fluconazole dosing that would eliminate this effect has not been identified. Monitoring for voriconazole-related adverse events is recommended if voriconazole is administered after fluconazole.
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. A reduction in the dose of zidovudine may be considered if necessary.
Azithromycin: An open, randomized, 3-crossover pharmacokinetic study was conducted in 18 healthy subjects to evaluate the interaction of azithromycin (1200 mg oral single dose) with fluconazole (800 mg oral single dose). The results showed no significant pharmacokinetic interactions between azithromycin and fluconazole.
Oral contraceptives: There have been two pharmacokinetic studies on the combination of multiple doses of fluconazole with oral contraceptives. In one study with a fluconazole dose of 50 mg, there was no significant association between hormone levels and the drug, while 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 coadministration with ivacaftor, a cystic fibrosis transmembrane transduction regulator (CFTR) potentiator, resulted in a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl ivacaftor (M1) exposure. For patients who are using a combination of CYP3A intermediate-acting inhibitors such as fluconazole and erythromycin, it is recommended that the ivacaftor dose be reduced to 150 mg once daily.
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).
Fluconazole is mostly excreted in urine, and its clearance may be increased by forced volume expansion diuresis. 3 hours of hemodialysis treatment may reduce the plasma concentration of fluconazole by about 50%.
[Clinical Trials
No relevant study data are available.
Pharmacology and Toxicology
Pharmacological effects
1) Mechanism of action
Fluconazole is a triazole antifungal drug. Its main mechanism of action is the inhibition of fungal cytochrome P-450-mediated 14α-lanosterol demethylation, which is a key step in fungal ergosterol biosynthesis. 14α-lanosterol accumulation is associated with subsequent ergosterol loss in fungal cell membranes, which may be the reason why fluconazole can exert antifungal activity. Compared with the mammalian cytochrome P-450 enzyme system, fluconazole has a higher selectivity for fungal cytochrome P-450 enzymes.
2) In vitro sensitivity
In in vitro tests, fluconazole showed antifungal activity against most clinically common Candida species (including Candida albicans, Candida subsmoothis, and Candida tropicalis). Candida smoothus showed broad susceptibility to fluconazole, while Candida klebsiella was resistant to fluconazole.
Fluconazole also has antifungal activity in in vitro tests against Cryptococcus neoformans and Cryptococcus, as well as endemic mycobacterial dermatophytes, Clostridium vulgaris, entrapped Histoplasma capsulatum, and Bacillus brasiliensis.
3) Pharmacokinetic/pharmacodynamic relationship
In animal tests, there was a correlation between MIC values and efficacy against experimental fungal diseases caused by Candida. In clinical trials, there was an almost linear 1:1 relationship between AUC and fluconazole dose. the same 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) Mechanisms of drug resistance
Candida has developed a large number of resistance mechanisms to azole antifungal drugs. Strains with one or more resistance mechanisms are generally considered to exhibit high MIC values to fluconazole, which can affect in vivo and clinical efficacy. Serious infections with Candida (except 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 selected.
5) Fold point (according to EUCAST criteria)
Based on the analysis of pharmacokinetic/pharmacodynamic (PK/PD) data, in vitro susceptibility and clinical response, EUCAST-AFST (European Committee for Pharmacokinetic Testing – Antifungal Susceptibility Testing Sub-Committee) determined the fold points for fluconazole against Candida species (EUCAST Fluconazole Rationalization Document (2007) version 2). These include non-strain-related and strain-related fold points. The non-strain-related folds are mainly based on PK/PD data and are not related to the MIC distribution of specific strains; the strain-related folds are mainly for the most frequently infected strains in humans. These folds are shown in the following table.
Antifungal Strain-Related Fold Points (S≤/R>) Non-Strain-Related Fold Points A
S≤/R> Candida albicans Candida smoothus Candida klebsiella Candida subsmoothus Candida tropicalis Fluconazole 2/4IE – 2/42/42/4S = sensitive, R = resistant
A. = non-strain related fold point determined primarily based on PK/PD data, independent of the MIC distribution of the specific strain. Only used for strains without characteristic fold points.
— = Not recommended for drug sensitivity testing because the strain is not an ideal target for treatment with this product.
IE = Insufficient evidence that the strain is an ideal target for treatment with this product.
Toxicological studies
Genotoxicity
The results of the following genotoxicity tests using fluconazole were negative.
●
Salmonella typhimurium revertant mutation test
●
Mouse lymphoma L5178Y cell mutation test
● In vitro chromosomal aberration test of human lymphocytes
Human lymphocyte in vitro chromosome aberration test
● In vitro human lymphocyte chromosome aberration test
Bone marrow micronucleus test in mice in vivo
Reproductive toxicity
No effects on fertility were observed 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 tests, oral administration of fluconazole at doses of 5, 10, and 20 mg/kg and 5, 25, and 75 mg/kg during organogenesis was observed in pregnant rabbits. At 75 mg/kg (approximately 4 times the human clinical dose of 400 mg, based on body surface area), abortion was observed.
In several rat embryo-fetal developmental toxicity tests, fluconazole was administered 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, and anatomical variations (multiple ribs, dilated renal pelvis) and delayed ossification were seen at 25 and 50 mg/kg or higher, and at doses of 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 were associated with inhibition of estrogen synthesis in rats and may be the result of the known effects of low estrogen levels on pregnancy, organogenesis, and delivery.
In a perinatal toxicity test in rats, fluconazole 20 (approximately 5-15 times the recommended human dose), 40 mg/kg was given intravenously to females, and 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 24-month oral administration carcinogenicity tests 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 observed. An increased incidence of hepatocellular adenoma was seen in male rats given fluconazole 5 and 10 mg/kg orally.
Pharmacokinetics]
The pharmacokinetic properties of fluconazole are similar between intravenous and 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. Oral absorption is not affected by food intake. Under fasting conditions, plasma concentration peaks 0.5 to 1.5 hours after administration of fluconazole, with a plasma elimination half-life approaching 30 hours. 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 (first day), i.e., equivalent to twice the regular daily dose, its plasma concentration approaches 90% of its steady-state concentration on the second day.
Distribution
The apparent volume of distribution is close to the 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 are 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 can reach high concentrations in the cutaneous stratum corneum, epidermal dermis and secreted sweat, even exceeding their serum concentrations. Fluconazole can accumulate in the stratum corneum. Fluconazole 50mg, once a day, after 12 days of administration, its concentration was 73μg/g, and after 7 days of discontinuation, its concentration was still 5.8μg/g. Fluconazole 150mg, once a week, on the 7th day of administration, the concentration of the drug in the stratum corneum was 23.4μg/g, and after 7 days of the second administration, the concentration of the drug still reached 7.1μg/g.
Fluconazole 150 mg once a week for 4 months resulted in concentrations of 4.05 μg/g and 1.8 μg/g in the nails of normal subjects and patients, respectively; and it was still detectable in the nails 6 months after the end of treatment.
Biotransformation
Fluconazole was metabolized to a low degree. Only 11% of the radiologically active dose 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
Fluconazole has a long plasma elimination half-life of approximately 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 original 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 a 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 in vivo half-life increases from 30 to 98 hours in patients with severe renal insufficiency (GFR<20 ml/min). Therefore, dose reduction is required. Fluconazole can be eliminated by hemodialysis and is less effectively eliminated by peritoneal dialysis than by hemodialysis. Approximately 50% of fluconazole is eliminated from the blood 3 hours after initiation of hemodialysis.
Pharmacokinetics during breastfeeding
A pharmacokinetic study was conducted in 10 lactating women who had temporarily or permanently discontinued 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%.
Pharmacokinetics in children
Pharmacokinetic data from 113 pediatric patients in five trials, including two single-dose trials, two multi-dose trials, and one premature neonatal trial, have been evaluated. Data from one trial could not be interpreted due to changes in the route of formulation during the trial.
Pediatric patients (aged 9 months to 15 years) received fluconazole at doses of 2 to 8 mg/kg, corresponding to an AUC of 38 μg x h/ml per 1 mg/kg dose. The mean plasma elimination half-life of fluconazole was 15 to 18 hours, with a volume of distribution of approximately 880 ml/kg after multiple doses. the plasma elimination half-life of fluconazole after a single dose was 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 is approximately 950 mg/kg.
Experience with fluconazole in neonates is limited to pharmacokinetic trials conducted 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 intravenous fluconazole 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 diuretics. The pharmacokinetic results showed that the peak blood concentration of 1.54 mcg/ml was reached 1.3 hours after administration, and the mean area under the drug-time curve was 76.4 ± 20.3 mcg × h/ml, with 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, 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 to 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 on the stimulatory effects of adrenocorticotropic hormones in healthy male volunteers. Drug interaction studies with antipyrine showed that single or multiple doses of fluconazole 50mg did not affect the in vivo metabolism of antipyrine.
Storage】Seal and store in a dry place.
Package】Packaged in aluminum-plastic blister (PTP-PVC/PVDC), 6 capsules/plate×1 plate/box.
Expiration date】12 months
Execution Standard
【Manufacturing Company】.
Company Name: Chengdu Bite Pharmaceutical Co.
Production address: Chengdu Shuangliu Southwest Airport Economic Development Zone, No. 1166, Airport Road 4
Zip code: 610207
Telephone number: 400-800-6276
Fax number: 028-85919027
Website: http://www.btyy.com