DIFLUCAN 50MG CAPSULE (CAPSULE)

Dosage / Direction for Use: Adult Cryptococcal meningitis & cryptococcal infections at other sites 400 mg on the 1st day followed by 200-400 mg once daily for at least 6-8 wk. Prevention of relapse of cryptococcal meningitis in patient w/ AIDS after a full course of primary therapy Administer indefinitely at 200 mg once daily. Candidemia, disseminated candidiasis & other invasive candidal infections 400 mg on the 1st day followed by 200 mg once daily, may be increased to 400 mg once daily depending on clinical response. Oropharyngeal candidiasis 50-100 mg once daily for 7-14 days. Atrophic oral candidiasis associated w/ dentures 50 mg once daily for 14 days concurrently w/ local antiseptic measures to the denture. Other candidal infections of mucosa except genital candidiasis 50-100 mg once daily for 14-30 days. Prevention of relapse of oropharyngeal candidiasis in patient w/ AIDS after a full course of primary therapy 150 mg once wkly dose. Vag candidiasis, Candida balanitis 150 mg as single oral dose. Prevention of candidiasis 50-400 mg once daily. Recurrent vag candidiasis 150 mg once mthly. Patient at high risk of systemic infection eg, patient w/ anticipated profound or prolonged neutropenia 400 mg once daily. Tinea pedis, tinea corporis, tinea cruris & candida infections 150 mg once wkly or 50 mg once daily. Duration of therapy: 2-4 wk but tinea pedis may require for up to 6 wk. Tinea versicolor 300 mg once wkly for 2 wk. Alternate dosing regimen: 50 mg once daily for 2-4 wk. Tinea unguium 150 mg once wkly. Deep endemic mycoses 200-400 mg once daily for up to 2 yr. Duration of therapy: Coccidioidomycosis 11-24 mth; paracoccidioidomycosis 2-17 mth; sporotrichosis 1-16 mth; histoplasmosis 3-17 mth. Childn Mucosal candidiasis 3 mg/kg once daily. Loading dose: 6 mg/kg on the 1st day. Systemic candidiasis & cryptococcal infections 6-12 mg/kg once daily. Suppression of relapse of cryptococcal meningitis in childn w/ AIDS 6 mg/kg once daily. Prevention of fungal infections in immunocompromised patient considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy 3-12 mg/kg once daily. Neonate ≤4 wk 1st wk of life: Same dose w/ older childn administered every 72 hr. Wk 3 & 4 of life: Same dose should be given every 48 hr. Renal impairment in adult & childn Initial loading dose of 50-400 mg. CrCl >50 mL/min 100% recommended dose; ≤50 mL/min 50% recommended dose. Hemodialysis 100% recommended dose after each hemodialysis. Overdosage: There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior. In the event of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A 3-hour hemodialysis session decreases plasma levels by approximately 50% Administration: May be taken with or without food. Contraindications: Hypersensitivity. Co-administration w/ terfenadine & other drugs known to prolong QT interval & those metabolized via CYP3A4 enzyme eg, cisapride, astemizole, erythromycin, pimozide & quinidine. Special Precautions: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus. Effective contraceptive measures should be considered in women of child-bearing potential and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. (See Use in Pregnancy & Lactation.) Fluconazole should be administered with caution to patients with liver dysfunction. Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole. Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored (see Contraindictions and Interactions). In rare cases, as with other azoles, anaphylaxis has been reported. Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4 (see Interactions). During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsades de pointes. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Fluconazole should be administered with caution to patients with renal dysfunction (see also Dosage & Administration). Fluconazole is a moderate CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of the isoenzyme CYP2C19. Fluconazole - treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see Interactions). Adrenal insufficiency has been reported in patients receiving other azoles (e.g., ketoconazole). Reversible cases of adrenal insufficiency were reported in patients receiving fluconazole. Fluconazole (Diflucan) capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption. Effects on ability to drive and use machines: When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. Effective contraceptive measures should be considered in women of child-bearing potential and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. There have been reports of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high-dose (400 mg/day to 800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Adverse fetal effects have been seen in animals only at high-dose levels associated with maternal toxicity. There were no fetal effects at 5 mg/kg or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 mg/kg and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60 times the recommended human dose) to 320 mg/kg, embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal craniofacial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis and parturition. Case reports describe a distinctive and a rare pattern of birth defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. Use During Lactation: Fluconazole is found in human breast milk at concentrations similar to plasma (see Pharmacology: Pharmacokinetics under Actions). The elimination half-life from breast milk approximates the plasma elimination half-life of 30 hours. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration is 0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose (<2 weeks of age) or 13% of the recommended infant dose for mucosal candidiasis. Breast-feeding may be maintained after a single dose of 150 mg fluconazole. Breast-feeding is not recommended after repeated use or after high-dose fluconazole. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for fluconazole (Diflucan) and any potential adverse effects on the breastfed child from fluconazole (Diflucan) or from the underlying maternal condition. Caution for Usage: Incompatibilities: Fluconazole intravenous infusion is compatible with the following administration fluids: Dextrose 20%, Ringer's solution, Hartmann's solution, Potassium chloride in dextrose, Sodium bicarbonate 4.2%, Aminofusin, Normal saline. Fluconazole may be infused through an existing line with one of the above listed fluids. Although no specific incompatibilities have been noted, mixing with any other drug prior to infusion is not recommended. Side Effects / Adverse Reactions: Headache; abdominal pain, diarrhea, nausea, vomiting; increased ALT, AST & blood alkaline phosphatase; rash. Interactions: May increase plasma levels of cisapride & terfenadine. May decrease clearance of astemizole, saquinavir & theophylline. May inhibit metabolism of pimozide, quinidine, carbamazepine & losartan. Increased risk of cardiotoxicity w/ erythromycin. Increased QT prolongation w/ amiodarone. May increase plasma conc w/ hydrochlorothiazide. Decreased AUC & shorter t1/2 w/ rifampicin. Risk of increased plasma conc of other compd metabolized by CYP2C9, CYP2C19 & CYP3A4; halofantrine; olaparib. May reduce clearance, distribution vol & t1/2 of alfentanil. Increased effect of amitriptyline & nortriptyline. Increased prothrombin time w/ warfarin. May increase conc & psychomotor effects of midazolam. May increase systemic exposure of Ca channel antagonist. Increased Cmax & AUC of celecoxib, flurbiprofen, ibuprofen; saquinavir; miconazole, zidovudine. May increase conc & AUC of cyclosporine. May delay elimination of fentanyl. Risk of increased serum bilirubin & creatinine w/ cyclophosphamide. Increased risk of myopathy & rhabdomyolysis w/ HMG-CoA reductase inhibitors. May enhance serum conc of methadone. May inhibit hepatic metabolism of phenytoin. Patient on long-term treatment w/ prednisone should be monitored when fluconazole is discontinued. May increase serum levels of rifabutin. May prolong serum t1/2 of oral sulfonylureas. May increase plasma conc of sirolimus & tacrolimus. May increase exposure of tofacitinib. May increase plasma levels of vinca alkaloids (eg, vincristine & vinblastine) & lead to neurotoxicity. May develop CNS effects in the form of pseudotumor cerebri w/ all trans-retinoid acid (vit A). Mechanism of Action Pharmacotherapeutic group: Triazole derivatives, ATC code J02AC. Pharmacology: Pharmacodynamics: Fluconazole, a triazole antifungal agent, is a potent and specific inhibitor of fungal sterol synthesis. Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp., including systemic candidiasis in immunocompromised animals; with C. neoformans, including intracranial infections; with Microsporum spp.; and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitidis; with Coccidioides immitis, including intracranial infection; and with Histoplasma capsulatum in normal and immunosuppressed animals. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50 mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on adrenocorticotropic hormone (ACTH) stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism. Pharmacokinetics: The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. After oral administration, fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by Days 4 to 5 with multiple once-daily dosing. Administration of loading dose (on Day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by Day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11%-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the cerebrospinal fluid (CSF) are approximately 80% the corresponding plasma levels. High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 μg/g, and 7 days after cessation of treatment the concentration was still 5.8 μg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on Day 7 was 23.4 μg/g, and 7 days after the second dose was still 7.1 μg/g. Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 μg/g in healthy and 1.8 μg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single-dose therapy for vaginal candidiasis, once-daily and once-weekly dosing for other indications. A study compared the saliva and plasma concentrations of a single fluconazole 100 mg dose administered in a capsule or in an oral suspension* by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations. *Fluconazole oral suspension is not available locally. A pharmacokinetic study in 10 lactating women, who had temporarily or permanently stopped breast-feeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours following a single 150 mg dose of fluconazole (Diflucan). Fluconazole was detected in breast milk at an average concentration of approximately 98% of those in maternal plasma. The mean peak breast milk concentration was 2.61 mg/L at 5.2 hours post-dose. In premature newborns (gestational age around 28 weeks), intravenous administration of fluconazole of 6 mg/kg was given every third day for a maximum of five doses while the premature newborns remained in the intensive care unit. The mean half-life (hours) was 74 (range 44-185) on Day 1, which decreased with time to a mean of 53 (range 30-131) on Days 7 and 47 (range 27-68) on Day 13. The AUC (μg.h/mL) was 271 (range 173-385) on Day 1, which increased with a mean of 490 (range 292-734) on Day 7 and decreased with a mean of 360 (range 167-566) on Day 13. The volume of distribution (mL/kg) was 1183 (range 1070-1470) on Day 1, which increased with time to a mean of 1184 (range 510-2130) on Day 7 and 1328 (range 1040-1680) on Day 13. Pharmacokinetics in Elderly: A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 μg h/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 μg.h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter the AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hours, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject's terminal elimination half-life versus creatinine clearance compared to the predicted half-life-creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life-creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared to normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Toxicology: Preclinical safety data: Carcinogenesis: Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Mutagenesis: Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of Salmonella typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Impairment of Fertility: Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5 mg/kg, 10 mg/kg or 20 mg/kg or with parenteral doses of 5 mg/kg, 25 mg/kg or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg orally. In an intravenous perinatal study in rats at 5 mg/kg, 20 mg/kg and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see Pharmacology: Pharmacodynamics previously).