Dosing and uses of Diflucan (fluconazole)
Adult dosage forms and strengths
injected solution
- 2mg/mL
oral suspension
- 10mg/mL
- 40mg/mL
tablets
- 50mg
- 100mg
- 150mg
- 200mg
Oropharyngeal Candidiasis
200 mg PO on Day 1, THEN 100 mg qDay
Dosing considerations
- Treatment should be continued for at least 2 weeks to decrease likelihood of relapse
Esophageal Candidiasis
200 mg PO on Day 1, THEN 100 mg qDay; doses up to 400 mg/day may be used based on patient’s response
Dosing considerations
- Treat for a minimum of 3 weeks and for at least 2 weeks following resolution of symptoms
Cryptococcal Meningitis
400 mg PO on Day 1, THEN 200 mg PO qDay
Dosage of up to 400 mg qDay may be used based on patient’s response
Suppression of relapse in patients with AIDS: 200 mg PO qDay
Dosing considerations
- Recommended duration of therapy is 10-12 weeks after cerebrospinal fluid becomes culture negative
Prophylaxis of Candidiasis with BMT
Prevention of candidiasis incidence in patients undergoing bone marrow transplant
400 mg PO qDay
Dosing considerations
- Patients who are anticipated to have severe granulocytopenia should start prophylaxis several days before anticipated onset of neutropenia and continue for 7 days after neutrophil count rises >1000 cells per mm³
Vaginal Candidiasis
Uncomplicated: 150 mg PO as a single dose
Complicated: 150 mg PO q72hr for 3 doses
Recurrent: 150 mg PO qDay for 10-14 days followed by 150 mg once weekly for 6 months
Candida UTI/Peritonitis
50-200 mg PO qDay
Dosage modifications
Hepatic impairment: Not studied
Renal impairment
- Percent of recommended dose:
- -CrCl >50 mL/min: 100% of dose
- -CrCl ≤50 mL/min: 50% dose
- -Regular dialysis: 100% dose after each dialysis; on nondialysis days, reduce dose according to creatinine clearance
Pediatric dosage forms and strengths
injected solution
- 2mg/mL
oral suspension
- 10mg/mL
- 40mg/mL
tablets
- 50mg
- 100mg
- 150mg
- 200mg
Oropharyngeal Candidiasis
6 mg/kg PO on Day 1, THEN 3 mg/kg qDay; not to exceed 600 mg/day
Dosing considerations
- Treatment should be administered for at least 2 weeks to decrease likelihood of relapse
Esophageal Candidiasis
Esophageal candidiasis: 6 mg/kg PO on Day 1, THEN 3 mg/kg qDay
Doses up to 12 mg/kg/day may be used, based on patient’s response
Dosing considerations
- Treat for a minimum of 3 weeks and for at least 2 weeks following resolution of symptoms
Systemic Candida Infections
6-12 mg/kg/day PO/IV; not to exceed 600 mg/day
Cryptococcal Meningitis
12 mg/kg PO/IV on Day 1, THEN 6 mg/kg qDay
Dose of 12 mg/kg once daily may be used, based on patient’s response
Suppression in children with AIDS: 6 mg/kg once daily
Dosing considerations
- Recommended duration of therapy is 10-12 weeks after cerebrospinal fluid becomes culture negative
Premature Neonates
26-29 weeks' gestation:: 6-12 mg/kg IV/PO
Maintenance: 3-6 mg/kg IV/PO qDay
Maintenance dose intervaL
- 26-29 weeks' gestation: q72hr; administer q24hr after 2 weeks of life
Diflucan (fluconazole) adverse (side) effects
>10%
Headache (2-13%)
1-10%
Nausea (2-7%)
Abdominal pain (2-6%)
Diarrhea (2-3%)
Rash (2%)
Vomiting (2-5%)
Frequency not defined
QT prolongation
Torsades de pointes
Alopecia
Anaphylactic reactions
Angioedema
Cholestasis
Dizziness
Dyspnea
Hepatic failure
Hepatitis
Hypertriglyceridemia
Hypokalemia
Increased alkaline phosphatase
Increased ALT/ASt
Jaundice
Leukopenia
Pallor
Seizures
Stevens-Johnson syndrome
Taste perversion
Thrombocytopenia
Toxic epidermal necrolysis
Warnings
Contraindications
Hypersensitivity
Pregnancy
Concurrent QT-prolonging drugs that are metabolized via the enzyme CYP3A4 (cisapride, erythromycin, pimozide, and quinidine)
Cautions
Hypersensitivity to other azoles
Use caution in proarrhythmic conditions and renal impairment
Use extreme caution or avoid in congenital long-QT patients and patients with conditions that increase QT-prolongation risk
Fluconazole inhibits CYP2C9, CYP2C19, and CYP3A4 isoenzymes; coadministration with drugs that are substrates if these isoenzymes may be contraindicated or warrant dosage modifications
Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
Powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption or sucrase-isomaltase deficiency
Syrup contains glycerol; may cause headache, stomach upset, and diarrhea
Hepatotoxicity reported with use; use with caution in patients with hepatic impairment
Rare exfoliative skin disorders reported; monitor closely if rash develops and discontinue if it progresses
When driving vehicles or operating machines, it should be taken into account that dizziness or seizures may occasionally occur
Candida krusei is inherently resistant
Convenience and efficacy of single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against acceptability of higher incidence of drug related adverse events with fluconazole (26%) versus intravaginal agents (16%)
Pregnancy and lactation
Pregnancy
Single maternal PO dose of 150 mg for vaginal candidiasis
- Results of a Danish study concludes there is a possible increased risk of miscarriage; women who are pregnant or actively trying to get pregnant should ask their physician about alternative treatments
- Spontaneous abortion between 7 and 22 weeks' gestation occurred significantly more often in women exposed to oral fluconazole than unexposed pregnancies (4.43% vs. 4.25%; hazard ratio, 1.48); fluconazole was also compared with intravaginal azole antifungals to account for confounding by candidiasis, again, the oral drug was associated with significantly increased risk for spontaneous abortion - JAMA. 2016;315(1):58-67
- CDC guidelines recommend only using topical antifungal products to treat pregnant women with vulvovaginal yeast infections, including for longer periods than usual if these infections persist or recur
All other indications
- A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester
- Reported anomalies are similar to those seen in animal studies and consist of brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease
Lactation
Enters breast milk; use caution (AAP Committee states "compatible with nursing")
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Diflucan (fluconazole)
Mechanism of action
Highly selective inhibitor of fungal cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase
Subsequent loss of normal sterols correlates with accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole
Absorption
Bioavailability: >90% (oral)
Peak plasma time: 1-2 hr (PO)
Distribution
Vd: 0.6 L/kg; widely distributed throughout body, with good penetration into CSF, eye, peritoneal fluid, sputum, urine and skin
CSF to blood level ratio: 50-90% (normal meninges); >70-80% (inflamed meninges)
Relative diffusion blood into CSF: Adequate with or without inflammation (exceeds MICs)
Protein bound: 11-12%
Metabolism
Liver, partially
Enzymes inhibited: Hepatic CYP2C9 (potent); CYP3A4 (moderate)
Elimination
Half-life: 30 hr (range: 20-50 hrs); 46 hr (elderly)
Excretion: Urine 80% (unchanged drug), 11% (metabolites)
Administration
IV Incompatibilities
Additive: TMP-SMX
Y-site: Amphotericin B, amphotericin B cholesteryl sulfate, ampicillin, calcium gluconate, cefotaxime, ceftazidime(?), ceftriaxone, cefuroxime, chloramphenicol, clindamycin, co-trimoxazole, diazepam, digoxin, erythromycin lactobionate, furosemide, haloperidol, hydroxyzine, imipenem/cilastatin, pentamidine, piperacillin, ticarcillin, TMP-SMX
IV Compatibilities
Solution: D5W, Lr
Additive: Acyclovir, amikacin, amphotericin B, cefazolin, ceftazidime, ciprofloxacin, clindamycin, gentamicin, heparin, meropenem, metronidazole, morphine, piperacillin, potassium chloride, ranitidine with ondansetron, theophylline
Y-site: Acyclovir, aldesleukin, allopurinol, amifostine, amikacin, aminophylline, amiodarone, ampicillin-sulbactam, aztreonam, benztropine, bivalirudin, cefazolin, cefepime, cefotetan, cefoxitin, cefpirome, chlorpromazine, cimetidine, cisatracurium, dexamethasone sodium phosphate, dexmedetomidine, diltiazem, diphenhydramine, dobutamine, docetaxel, dopamine, doxorubicin liposomal, droperidol, etoposide PO4, famotidine, fenoldopam, filgrastim, fludarabine, foscarnet, ganciclovir, gatifloxacin, gemcitabine, gentamicin, granisetron, heparin, hetastarch, hydrocortisone, immune globulin, leucovorin, linezolid, lorazepam, melphalan, meperidine, meropenem, metoclopramide, metronidazole, midazolam, morphine, nafcillin, nitroglycerin, ondansetron, oxacillin, paclitaxel, pancuronium, penicillin G, phenytoin, piperacillin-tazobactam, prochlorperazine, promethazine, propofol, quinupristin-dalfopristin, ranitidine, remifentanil, sargramostim, tacrolimus, teniposide, theophylline, thiotepa, ticarcillin-clavulanate, tobramycin, vancomycin, vecuronium, vinorelbine, zidovudine
IV Preparation
Standard diluent: 200 mg/100 mL NS (premixed); 200 mg/200 mL NS (premixed)
Do not use if cloudy or precipitated
IV Administration
IV infusion over approximately 1-2 hr
Maximum infusion rate: 200 mg/hr
To prevent air embolism, do not connect in series with other infusions
Storage
Tablets: Store below 86° F (30° C)
Dry powder: Store below 86° F (30° C); reconstituted suspension should be stored between 86° F (30° C) and 41° F (5° C), and unused portion should be discarded after 2 weeks; protect from freezing
Injection (glass bottles): Store between 86° F (30° C) and 41° F (5° C); protect from freezing
Injection (Viaflex Plus plastic containers): Store between 77° F (25° C) and 41° F (5° C); protect from freezing
