Fluconazole

Pharmacokinetics

After oral administration, its systemic availability is about 90%; maximum plasma concentrations are seen in 1–2 hours, its half-life is about 30 hours and steady state is reached within 5–7 days. Fluconazole has low protein binding (about 12%), is hardly metabolized, and about 80% of it is excreted in the urine. Hemodialysis reduces plasma concentrations by about half in 3 hours [ ]. Tissue and body fluid penetration is good [ , ]. The CSF concentration ratio is 0.5–0.9, the resultant concentrations being adequate for the treatment of cryptococcal meningitis [ ]. Penetration into the eye is good [ ], and fluconazole has been used successfully in fungal endophthalmitis [ ]. In a patient in whom the concentrations of fluconazole in bile were studied, the concentrations after the first dose were about the same as in serum, but 10–12 hours after the dose, bile concentrations were higher than serum concentrations [ ]. Sputum concentrations are similar to plasma concentrations. Concentrations in vaginal secretions are slightly lower than in plasma, but persist for longer [ , ].

Like ketoconazole, fluconazole is a potent inhibitor of cytochrome P450, but with much higher specificity for fungal enzymes compared with human enzymes [ , ]. Clinical interaction studies and some in vitro studies have suggested that azole antifungal drugs inhibit P glycoprotein. In a cell line in which human P glycoprotein was overexpressed, itraconazole and ketoconazole inhibited P glycoprotein function, with 50% inhibitory concentrations of about 2 and 6 μmol/l respectively; however, fluconazole had no effect [ ].

General adverse effects and adverse reactions

Fluconazole is generally well tolerated. The most common adverse reactions are nausea and vomiting. Abnormal liver function tests and slight increases in hepatic enzymes have been reported, and there have been anecdotal reports of hepatitis and hepatic failure. Early studies have shown no changes in testosterone concentrations or in the adrenal response to ACTH. Rashes and a few cases of exfoliative skin disorder have been reported [ ] and have been seen more frequently in patients with AIDS [ ]. Alopecia has been reported in a few cases with the use of high doses for prolonged periods of time [ ]. Rare instances of anaphylactoid reactions [ ] and hypersensitivity reactions [ ] have been reported. Tumor-inducing effects have not been reported.

In a study using the UK General Practice Research Database to determine rates of drug-induced, rare, serious adverse effects on the liver, kidneys, skin, or blood, occurring within 45 days of completing a prescription or refill in 54 803 users of either fluconazole or itraconazole, three had illnesses for which a fluconazole-induced cause could not be ruled out; one with thrombocytopenia, one with neutropenia, and one with an abnormal liver function test just after receiving fluconazole [ ]. The rates were 2.8 per 100 000 prescriptions (95% CI = 0.8, 10) for serious, adverse blood events and 1.4 per 100 000 prescriptions (95% CI = 0.25, 8.2) for serious, adverse liver events. These results suggest that fluconazole does not commonly have serious adverse effects on the liver, kidneys, skin, or blood.

Observational studies

The prophylactic use of oral fluconazole to prevent invasive Candida infections in 260 critically ill surgical patients has been investigated in a prospective, randomized, placebo-controlled trial in a single-center, tertiary-care surgical intensive care unit [ ]. The patients were randomly assigned to receive either oral fluconazole 400 mg/day or placebo. The risk of presumed and proven Candida infections in the patients who received fluconazole was significantly less than the risk in those who received placebo. After adjusting for several potentially confounding effects, fluconazole reduced the risk of presumed and proven fungal infection by 55%. There was no difference in death rate between fluconazole and placebo. The authors concluded that enteral fluconazole safely reduced the incidence of fungal infections in this high-risk population.

Outcomes in 20 patients with solid tumors and candidemia treated with high-dose fluconazole (at least 600 mg/day) have been reported [ ]. There were no significant adverse reactions.

Comparative studies

Placebo-controlled studies

In a randomized, double-blind, placebo-controlled study in Saudi Arabia of oral fluconazole (200 mg/day for 6 weeks) in the treatment of cutaneous leishmaniasis, 106 patients were assigned to fluconazole and 103 to placebo [ ]. Follow-up data were available for 80 and 65 patients respectively. At the 3-month follow-up, healing of lesions was complete in 63 of the 80 patients who took fluconazole and 22 of the 65 patients who took placebo (relative risk of complete healing, 2.33; 95% CI = 1.63, 3.33). Adverse reactions were mild and similar in the two groups.

Cardiovascular

Prolongation of the QT interval is a class effect of the antifungal azoles and has occasionally been reported with fluconazole, with a risk of torsade de pointes.

• A 68-year-old woman with Candida glabrata isolated from a presacral abscess developed torsade de pointes after 8 days treatment with oral fluconazole 150 mg/day [ ]. She had no other risk factors for torsade de pointes, including coronary artery disease, cardiomyopathy, congestive heart failure, or electrolyte abnormalities. The dysrhythmia resolved when fluconazole was withdrawn, but she continued to have ventricular extra beats and non-sustained ventricular tachycardia for 6 days.

• A 59-year-old woman with liver cirrhosis and Candida peritonitis developed long QT syndrome and torsade de pointes after intravenous therapy with 400–800 mg/day of fluconazole for 65 weeks, followed by intraperitoneal administration (150 mg/day) [ ]. One day after the second intraperitoneal administration, she developed palpitation, multifocal ventricular extra beats, and syncope. In contrast to a normal electrocardiogram on admission, electrocardiography showed polymorphic ventricular extra beats, T wave inversion, alternating T wave amplitude, and a prolonged QT _c interval of 606 ms. Torsade de pointes required cardiopulmonary resuscitation. The fluconazole plasma concentration was 216 μg/ml (usual target range at 400–800 mg/day: 18–28 μg/ml). Fluconazole was withdrawn and all conduction abnormalities reversed fully within 3 weeks.

• A 33-year-old woman with systemic lupus erythematosus was given intravenous fluconazole 200 mg/day for Candida albicans pneumonia [ ]. She developed prolongation of the QT _c interval and torsade de pointes. She had also been given domperidone, and both that and the fluconazole were withdrawn, the domperidone being suspected as the causative agent. However, torsade de pointes recurred several weeks later when she was given fluconazole again and resolved on withdrawal.

• A 55-year-old woman with acute myelomonocytic leukemia with bone marrow eosinophilia who was receiving consolidation chemotherapy had an episode of prolonged QT interval and torsade de pointes after being given fluconazole [ ]. Intravenous magnesium sulfate and multiple attempts at electric cardioversion led to recovery.

• A 25-year-old woman with worsening endocarditis had a prolonged QT interval at baseline and developed monomorphic ventricular dysrhythmias, which were managed successfully with pacing and antidysrhythmic therapy, including amiodarone [ ]. Several days later, she was given high-dose fluconazole (800 mg/day) for fungemia and after 3 days had episodes of torsade de pointes.

In this case torsade de pointes developed in the presence of known risk factors—hypokalemia, hypomagnesemia, female sex, baseline QT interval prolongation, and ventricular dysrhythmias.

Antifungal azoles, as a class, can cause QT _c interval prolongation and potentially fatal cardiac dysrhythmias by a direct blocking action on IK _r channels.

• A 68-year-old woman with cerebellar and pontine cryptococcosis was given amphotericin and flucytosine but developed hypokalemia, hypomagnesemia, and atrial fibrillation [ ]. She was given electrolyte replacement and metoprolol, and conventional amphotericin was changed to amphotericin B lipid complex for 6 weeks, after which she was given high-dose oral fluconazole was initiated. However, 6 days later she had a generalized tonic–clonic seizure and cardiopulmonary arrest. Her QT _c interval was 556 msec and she had recurrent episodes of torsade de pointes. Fluconazole was withdrawn and amphotericin was reintroduced, but she died 2 days later. Autopsy showed no coronary artery disease or hemorrhagic transformation of the pontine cryptococcoma.

In some cases cardiac dysrhythmias can be precipitated by the concomitant use of other prodysrhythmic compounds.

• An 11-year-old critically ill child was given fluconazole 150 mg bd for Candida peritonitis after a perforated gastric volvulus and developed torsade de pointes after being given amiodarone [ ].

• A 23-year-old woman with acute promyelocytic leukemia developed torsade de pointes after 4 weeks of concomitant treatment with arsenic trioxide and fluconazole [ ].

Arsenic trioxide can cause electrocardiographic abnormalities, such as ventricular tachycardia and prolongation of the QT interval and both arsenic trioxide and fluconazole are metabolized by cytochrome P450.

Nervous system

Central nervous system abnormalities constitute the major dose-limiting adverse reactions to fluconazole and are observed at dosages over 1200 mg/day [ ].

Dizziness, headache, and seizures were seen in 2–5% of 232 patients with severe systemic fungal infections taking fluconazole [ ]. In the same group there were three cases each of delirium and dysesthesia (1.3%). A possible effect of the underlying illness has to be considered. In 14 patients treated with fluconazole for cryptococcal meningitis, dizziness was reported in 14% [ ].

Two Japanese patients developed clonic convulsions while taking fluconazole 800 mg/day [ ].

• A 66-year-old woman with complicated invasive Candida tropicalis infection but no renal impairment took fluconazole 800 mg/day. On the 21st day she developed clonic convulsions. The fluconazole trough concentration at the time of the event was 82 μg/ml.

• A 62-year-old man with deteriorating renal and hepatic function after coronary artery bypass surgery was given fluconazole 400 mg bd for a fungal sternal wound infection. On the 15th day he developed seizures. His trough plasma fluconazole concentration was 88 μg/ml. Nineteen days after dosage adjustment to 400 mg qds, he had another seizure. The trough fluconazole concentration was 103 μg/ml, probably because of deteriorating renal function.

In both cases, the seizures abated after dosage reduction. These case reports suggest an association between trough plasma fluconazole concentrations of 80 μg/ml and central nervous system toxicity; they re-emphasize the need for careful monitoring and dosage adjustment of fluconazole in patients with reduced renal function.

Endocrine

Preliminary studies concerning a possible effect on testosterone concentrations and the adrenal response to adrenocorticotropic hormone did not show any changes. However, determinations were performed after only 14 days of fluconazole administration. In fact, antifungal azoles inhibit the production of adrenal steroids and can cause acute adrenal insufficiency, as has been reported in a 38-year-old man who was treated with fluconazole and broad-spectrum antibiotics [ ].

In a retrospective analysis of the effects of fluconazole 400 mg/day in 154 critically ill surgical patients the median plasma cortisol concentration was 158 μg/l in 79 patients randomized to fluconazole and 167 μg/l in 75 patients randomized to placebo [ ]. Patients randomized to fluconazole did not have significantly increased odds of adrenal dysfunction compared with patients randomized to placebo (OR = 0.98; 95% CI = 0.48, 2.01). Randomization to fluconazole was not associated with a significant difference in cortisol concentrations over time. Mortality was not different between patients with and without adrenal dysfunction, nor between patients with adrenal dysfunction who were randomized to fluconazole and those randomized to placebo.

• Two critically ill patients, a 77-year-old man with esophageal cancer and a 66-year-old woman with multiple organ failure, developed reversible adrenal insufficiency temporally related to the use of high-dose fluconazole (800 mg loading dose followed by 400 mg/day), as assessed by short stimulation tests with cosyntropin (ACTH) [ ]. Although anecdotal, these data suggest that the possibility that high-dose fluconazole can cause adrenal insufficiency in already compromised critically ill patients needs to be investigated further.

• A 63-year-old man received high-dose cyclophosphamide for peripheral blood stem-cell harvesting, having been taking fluconazole 200 mg/day [ ]. On day 3 he developed atrial fibrillation and his blood pressure fell to 78 mmHg. A rapid ACTH stimulation test showed a blunted adrenal response. He was suspected of having adrenal failure, and fluconazole was withdrawn. A rapid ACTH test was normal on day 14. To clarify the association between adrenal failure and fluconazole, he was rechallenged with fluconazole 400 mg/day from day 16 and a rapid ACTH test was performed on day 21; it showed a blunted adrenal response.

• Adrenal insufficiency occurred in a 38-year-old man with obstructive sleep apnea and polycythemia who received fluconazole plus broad-spectrum antibiotics for pulmonary infiltrates during ventilation; he recovered after fluconazole was stopped [ ].

The authors concluded that adrenal suppression attributable to fluconazole may be under-recognized and that critically ill patients who are given fluconazole should be monitored.

Mineral balance

Hypokalemia was observed in only a few patients taking fluconazole, which contrasts with experience with itraconazole [ ]. However, hyperkalemia was reported in one paper [ ].

Hematologic

Cytopenias occur but seem to be mild. Occasionally, more marked changes have been described, but these could have been connected with the underlying disease [ , ]. In a single placebo-controlled study of fluconazole prophylaxis using a relatively high dose of 400 mg/day, a post-hoc analysis suggested prolongation of granulocytopenia after intensive chemotherapy for hematological neoplasms in the fluconazole group. This may have been due to an interaction with the antineoplastic drug [ ].

Leukopenia with eosinophilia has been attributed to fluconazole [ ].

• A 75-year-old man with non-Hodgkin’s lymphoma and cryptococcal meningoencephalitis developed neutropenia with eosinophilia associated with fluconazole. After 1 week of fluconazole 400 mg/day his total leukocyte count began to fall and his eosinophil count increased. Concurrent medications included levothyroxine, famotidine, and co-trimoxazole. The last two drugs were withdrawn and he was given G-CSF. However, his leukocyte count continued to fall and 4 days later reached a nadir of 700 × 10 ⁶ /l; the platelet count remained normal. The leukopenia and eosinophilia resolved promptly after withdrawal of fluconazole.

Since the leukopenia and eosinophilia did not resolve until fluconazole was withdrawn, an effect of the compound was plausible. This case and two other reported cases [ , ] emphasize the importance of recognizing fluconazole as a rare but potential cause of bone marrow suppression in patients in whom drug-induced agranulocytosis is suspected.

In one study in patients with AIDS taking prophylactic maintenance fluconazole for cryptococcal meningitis, there was a higher rate of hematological toxicity with fluconazole than with placebo, but this probably reflected the greater proportional and absolute amounts of zidovudine used in the fluconazole group; there was no serious hematotoxicity [ ].

Mouth

An oral fixed drug eruption has been attributed to fluconazole [ ].

• A 19-year-old boy developed redness and swelling over the hard palate 7–8 hours after a dose of fluconazole 150 mg. There was mild pain and hypersalivation and the lesion gradually progressed to superficial erosion. He had had a similar episode about 1 year before after taking fluconazole for tinea cruris; he had stopped taking fluconazole and the oral lesion had healed by itself. The new erosion healed in about 15 days after treatment with chlorhexidine mouth rinse 0.12% 10 ml bd, warm saline rinses, oral cetirizine 10 mg/day, and topical triamcinolone in Orabase. Four weeks after the oral lesion had healed, oral provocation with fluconazole 50 mg caused the lesion to reappear in about 3 hours.

Gastrointestinal

Nausea and vomiting are mentioned in most reports of patients taking fluconazole, with an incidence of 10–15% [ , , , ]. Anorexia, mild abdominal pain, and diarrhea have been reported, but none was severe.

Liver

Raised liver enzyme activities have been reported in most studies. In some articles this effect was described as transient, in others as disappearing after withdrawal. The incidence varies from a few percent of cases to 35–45%, but occasionally the effect has been recorded in all cases treated. A temporal relation between these liver function changes and fluconazole treatment has been shown in many cases. Severe liver toxicity has not been reported [ ]. While asymptomatic rises in transaminases were noted in some children with neoplastic disease who were treated concomitantly with fluconazole in a small study [ ], there were no significant changes in a larger study in cancer patients treated with placebo or fluconazole 400 mg [ ].

• A 45-year-old woman with protracted cryptococcal meningoencephalitis developed fulminant hepatic failure secondary to high fluconazole serum concentrations, possibly precipitated by renal dysfunction induced by concomitant amphotericin therapy or concomitant therapy with lisinopril, atenolol, or amlodipine [ ]. Four days after the withdrawal of fluconazole 400 mg/day the serum concentration of fluconazole was 40 μg/ml.

This case points to the potential risks of fluconazole therapy in the setting of renal insufficiency, in particular with higher dosages (400 mg/day and more).

The hepatotoxicity of antifungal medications in bone marrow transplant recipients has been analysed in a retrospective matched-control study [ ]. The unadjusted incidence of hepatotoxicity was 0.98 cases per 100 patient-days of exposure to fluconazole (OR = 1.99; 95% CI = 1.21, 3.26). In the follow-up analysis of patients who developed hepatotoxicity and who continued to take antifungal medications, 8% of those who took fluconazole developed marked increases in serum bilirubin concentration. Thus, fluconazole was associated with an increased risk of hepatotoxicity, independent of other treatments or patient characteristics. However, patients who develop hepatotoxicity appear to tolerate continued therapy with fluconazole.

Hepatotoxicity with azoles is not necessarily a class effect.

• A 32-year-old Hispanic man with type I diabetes mellitus and coccidioidal meningitis developed increased hepatic transaminases when given fluconazole but subsequently tolerated voriconazole [ ]. Rechallenge with fluconazole again led to increased transaminases, which normalized when voriconazole was reinstated.

This report suggests that voriconazole may be cautiously substituted for fluconazole in patients with fluconazole-induced hepatatotoxicity who require azole therapy.

Biliary tract

The use of fluconazole prophylaxis for 6 weeks has been studied in a historical comparison in infants of extremely low birth weight [ ]. During prophylaxis, 60/140 infants developed conjugated hyperbilirubinemia compared with 12/137 who did not have prophylaxis. However, fluconazole prevented several cases of candidiasis (none versus nine in the two groups) and the benefit to harm balance is probably favorable.

Urinary tract

In a randomized, blind, multicenter comparison of fluconazole 800 mg/day plus placebo and fluconazole plus amphotericin B deoxycholate 0.7 mg/kg/day, with the placebo/amphotericin component given only for the first 5–6 days, as therapy for candidemia due to species other than Candida krusei in 219 adults without granulocytopenia, success rates on day 30 were 57% for fluconazole plus placebo and 69% for fluconazole plus amphotericin [ ]. Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients) respectively; the bloodstream infection failed to clear in 17% and 6% of subjects respectively. Renal dysfunction led to a reduction in drug dosage in 3% and 23% but was the primary cause of study failure in only 5% and 3% of subjects respectively. There were no differences in mortality within 90 days of starting therapy. Thus, in non-neutropenic subjects, the combination of fluconazole plus amphotericin was not antagonistic compared with fluconazole alone, and the combination tended to produce improved success and more rapid clearance from the bloodstream. Nevertheless, the combination also was associated with a higher rate of nephrotoxicity.

A patient developed recurrent episodes of membranous nephropathy after taking fluconazole repeatedly [ ].

Skin

Rashes of several types occur with fluconazole and are more frequent in immunocompromised patients.

The risk of serious skin disorders has been estimated in 61 858 users of oral antifungal drugs, aged 20–79 years, identified in the UK General Practice Research Database [ ]. They had received at least one prescription for oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. The background rate of serious cutaneous adverse reactions (corresponding to non-use of oral antifungal drugs) was 3.9 per 10 000 person-years (95% CI = 2.9, 5.2). Incidence rates for current use were 15 per 10 000 person-years (1.9, 56) for itraconazole, 11.1 (3.0, 29) for terbinafine, 10 (1.3, 38) for fluconazole, and 4.6 (0.1, 26) for griseofulvin. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.

Pruritus has been reported [ ].

Erythema multiforme associated with fluconazole has been reported [ ], as has Stevens–Johnson disease [ , ].

Fixed drug eruption caused by systemic fluconazole has been reported [ ].

• A 36-year-old woman with a history of atopy and recurrent Candida vaginitis developed a fixed drug eruption while taking fluconazole 150 mg/day [ ]. Local provocation with 10% fluconazole in petrolatum applied at the site of a previous site of fixed drug eruption reproduced the eruption clinically and histopathologically.

In cases of hypersensitivity, desensitization has reportedly been used with success [ ].