Fluconazole dosage

Fluconazole can increase concentrations of ciclosporin by inhibiting CYP3A4. In some studies, minimal or no effects were recorded, but in others ciclosporin concentrations were increased by fluconazole. Differences in the dosage and duration of fluconazole treatment could have explained these discrepancies (SED-12, 682) (21,84-87). For example, there was no interaction at a fluconazole dosage of 100 mg/day, but high dosages of fluconazole (400 mg/day or more) increase blood ciclosporin and tacrolimus concentrations (88,89). 

There have been few controlled studies that assess the effectiveness of antifungals. Doubling of the fluconazole dosage to 400 or 800 mg/day may be effective in some patients with infection caused by Candida of intermediate resistance, although the response may be only transient. Fluconazole oral suspension may be beneficial in some patients because of increased salivary concentrations obtained when the suspension is taken with the swish-and-swaUow technique. Itraconazole oral suspension is effective in 55% to 70% of patients however, the benefit is short-lived if chronic suppressive therapy is not maintained, and there is a high likelihood of the development of itraconazole resistance. Amphotericin B oral suspension is limited primarily to use in azole-refractory patients It has broad spectrum... 

The interaction between rifampicin and fluconazole appears to be established and of clinical importance. Although rifampicin has only a modest effect on fluconazole, the cases of relapse cited above and the need for an increased dosage indicate that this interaction can be clinically important. Monitor concurrent use and increase the fluconazole dosage if necessary. One study suggests a 30% increase in fluconazole dose may be considered for serious infections during concurrent rifampicin therapy. This may be especially important during prophylaxis of cryptococcal meningitis with lower doses of fluconazole, such as 200 mg daily. ... 

The manufacturer notes that, in 13 healthy subjects, hydrochlorothiazide 50 mg daily increased the AUC and plasma levels of fluconazole 100 mg daily for 10 days by about 40%. They attribute these changes to a reduction in the renal clearance of fluconazole. However they say it is unlikely that a change in the fluconazole dosage will be needed in patients taking diuretics, but that the interaction should be borne in mind. Any interaction is almost certainly of no relevance in patients taking a single dose of fluconazole for genital candidiasis. 

Disseminated histoplasmosis Acute (Infantile) Subacute Progressive histoplasmosis (immunocompetent patients and immunosuppressed patients without AIDS) 0.02-0.05 Disseminated histoplasmosis Untreated mortality 83% to 93% relapse 5% to 23% in non-AIDS patients therapy is recommended tor all patients Nonimmunosuppressedpatients Ketoconazole 400 mj day orally x 6-12 months or amphotericin B 35 mg/kg IV Immunosuppressed patients (non-AIDS) or endocarditis or CNS disease Amphotericin B >35 mg/kg x 3 months followed by fluconazole or itraconazole 200 mg orally twice daily x 12 months Life-threatening disease Amphotericin B 0.7-1 mg/kg/day IV for a total dosage of 35 mj kg over 2-4 months once the patient is afebrile, able to take oral medications, and no longer requires blood pressure or ventilatory support therapy can be changed to itraconazole 200 mg orally twice daily for 6-18 months Non-life-threatening disease Itraconazole 200-400 mg orally daily for 6-18 months fluconazole therapy 400-800 mg daily should be reserved for patients intolerant to itraconazole, and the development of resistance can lead to relapses... 

Specific antifungals (and their usual dosages) for the treatment of coccidioidomycosis include amphotericin B IV (0.5 to 1.5 mg/kg/day), ketocona-zole (400 mg orally daily), IV or oral fluconazole (usually 400 to 800 mg daily, although dosages as high as 1,200 mg/day have been utilized without complications), and itraconazole (200 to 300 mg orally twice daily as either capsules or solution). If itraconazole is used, measurement of serum concentrations may be helpful to ascertain whether oral bioavailability is adequate. 

Cryptococcal meningitis 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on the patient s response to therapy. The duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. 

Fluconazole is an inhibitor of the cytochrome P450 3A4 and 2C9 enzyme systems. Coadministration of fluconazole with other drugs metabolized by the same enzyme system may result in increased plasma concentrations of the drugs, which could increase or prolong therapeutic and adverse effects. Unless otherwise specified, dosage adjustment may be necessary. 

Hypertension PO 50 mg once a day. If 50 mg once a day produces an inadequate BP response, may increase dosage to 50 mg twice a day. If patient is concurrently receiving erythromycin, saquinavir, verapamil, or fluconazole, reduce initial dose to 25 mg once a day. 

Fluconazole is well absorbed following oral administration, with a plasma half-life of 30 hours. In view of this long half-life, daily doses of 100 mg are sufficient to treat mucocutaneous candidiasis alternate-day doses are sufficient for dermatophyte infections. The plasma half-life of itraconazole is similar to that of fluconazole, and detectable therapeutic concentrations remain in the stratum corneum for up to 28 days following termination of therapy. Itraconazole is effective for the treatment of onychomycosis in a dosage of 200 mg daily taken with food to ensure maximum absorption for 3 consecutive months. Recent reports of heart failure in patients receiving itraconazole for onychomycosis have resulted in recommendations that it not be given for treatment of onychomycosis in patients with ventricular dysfunction. 

The protease inhibitor saquinavir, propofol, and fluconazole (53,58,59) increased the systemic availability and peak plasma concentrations and prolonged the half-life of midazolam, thus increasing its sedative effects. The dosage of midazolam should be reduced in patients taking these drugs. 

Central nervous system abnormahties constitute the major dose-limiting adverse effects of fluconazole and are observed at dosages over 1200 mg/day (35). 

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). 

A patient developed a longitudinal band of pigmentation in the diseased nail after fluconazole therapy for onychomycosis at a dosage of 150 mg once a week for 4 weeks (56). 

The potential ability of fluconazole to modulate pheny-toin teratogenesis has been studied in Swiss mice (59). Pretreatment with a non-embryotoxic dosage of fluconazole (10 mg) potentiated phenytoin teratogenesis combined treatment of fluconazole 50 mg with phenytoin resulted in a significant increase in embryo deaths. The mechanism of this teratological interaction remains to be established. 

In a group of children with fever, neutropenia, and neoplastic disease, there was an increase in renal fluconazole clearance (45). In infants and children, the volume of distribution of fluconazole is significantly higher and falls with age. With the exception of infants, who have a slower clearance rate, children clear the compound more rapidly (61). However, a second larger study reported slower elimination in children under 1 year of age, requiring dosage adjustments (62). Low birth-weight neonates have a particularly low clearance rate, which increases within weeks (63). 

The use of fluconazole in 726 children under 1 year of age, reported in 78 publications, has been reviewed (64). They received a wide range of dosages for up to 162 days. Fluconazole was well tolerated and efficacious in the therapy of systemic candidiasis and candidemia in children under 1 year of age, including neonates and very low birth-weight infants. The daily dosage recommended by the manufacturers is 6 mg/kg, to be reduced in patients with impaired renal function in accordance with the guidelines given for adults. 

The safety profile of fluconazole has been assessed in 562 children (aged 0-17 years 323 boys and 239 girls), enrolled into 12 clinical studies of prophylactic or therapeutic fluconazole in predominantly immunocompromised patients (66). Most of the children received multiple doses of fluconazole 1-12 mg/kg, given as oral suspension or intravenously. Overall, 58 children reported 80 treatment-related adverse effects. The most common adverse effects were associated with the gastrointestinal tract (7.7%), the skin (1.2%), or the liver and biliary system (0.5% or three patients). Overall, 18 patients discontinued treatment owing to adverse effects, mainly gastrointestinal. Dosage and age did not affect the incidence and pattern of adverse effects. Treatment-related... 

Since tacrolimus (FK506) is metabolized by intestinal and hepatic CYP3A4, drugs that inhibit CYP3A4 can reduce the metabolism of tacrolimus and increase tacrolimus blood concentrations (111). The effect of fluconazole on the blood concentrations of tacrolimus have been investigated in eight liver transplant patients in whom prophylactic fluconazole (200 mg/day) was withdrawn because of rises in hepatic transaminases (n = 6), renal dysfunction, or eosinophilia (n = 1 each) (112). Calculated tacrolimus concentrations fell by 13-81% (median 41%) between the fourth and ninth days after withdrawal of fluconazole. Tacrolimus blood concentrations should be carefully monitored and dosages increased as necessary after withdrawal of fluconazole. 

Pittrow L, Penk A. Dosage adjustment of fluconazole during continuous renal replacement therapy (CAVH, CVVH, CAVHD, CVVHD). Mycoses 1999 42(1-2) 17-19. 

In studies of combining ritonavir with fluconazole (2) and ritonavir with mefloquine (3) there were no significant effects, and dosage adjustment is not warranted. 

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