Antifungals, Azole (Systemic)

This monograph includes information on the following:

1) Fluconazole
2) Itraconazole
3) Ketoconazole

VA CLASSIFICATION
Fluconazole
Primary: AM700

Itraconazole
Primary: AM700

Ketoconazole
Primary: AM700
Secondary: HS900; AN900


Commonly used brand name(s): Diflucan1; Diflucan-1501; Nizoral3; Sporanox2.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiadrenal; antineoplastic (systemic)—Ketoconazole;

Antifungal (systemic)—Fluconazole; Itraconazole; Ketoconazole;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Aspergillosis (treatment)—Itraconazole is indicated in the treatment of aspergillosis caused by Aspergillus species in patients who are intolerant of or refractory to amphotericin B therapy in both immunocompromised and non-immunocompromised patients. {75} {76} {77} {78} {95} {173}{208}

Blastomycosis (treatment)—Itraconazole is indicated for the treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatiditis in immunocompromised and nonimmunocompromised patients. {61} {67} Ketoconazole1 is also indicated in the treatment of blastomycosis. {106} {163}

Candidiasis (prophylaxis)—Fluconazole is indicated for the prophylaxis of candidiasis in patients undergoing bone marrow transplant who receive cytotoxic chemotherapy and/or radiation therapy. {174} {175} {182}

Candidiasis, esophageal (treatment) or
Candidiasis, oropharyngeal (treatment)—Fluconazole, itraconazole, and ketoconazole are indicated for the treatment of esophageal and oropharyngeal candidiasis (thrush) caused by Candida species. {14} {19} {74} {86} {87} {88} {106} {107} {163} {178}

Candidiasis, disseminated (treatment)—Fluconazole and ketoconazole are indicated for the treatment of serious infections, including peritonitis, pneumonia, and urinary tract infections, caused by susceptible Candida species. [Fluconazole]1is also indicated for the treatment of systemic infections caused by Candida species in neonates.{206} {19} {49} {106} {107}

Candidiasis, mucocutaneous, chronic (treatment)—[ Fluconazole]1, [ itraconazole]1 , and ketoconazole are indicated in the treatment of severe, chronic extensive mucocutaneous candidiasis caused by Candida species. {106} {107} {162}

Candidiasis, vulvovaginal (treatment)—Fluconazole, [itraconazole]1 , and [ketoconazole]1 are indicated in the treatment of vulvovaginal candidiasis caused by Candida species. {89} {90} {91} {92} {104} {119} {120} {121} {142} {148} {176}

Chromomycosis (treatment)—[Itraconazole ] and ketoconazole are indicated as secondary agents in the treatment of chromomycosis caused by Cladosporium carrioni , Exophiala dermatitidis , Fonsecaea pedrosi , Fonsecaea compactum , Phialophora verrucosa , Rhinocladiella aquaspersa , and Rhinocladiella cerophilum . {106} {107} {162} {163}

Coccidioidomycosis (treatment)—[ Fluconazole]1 and [ itraconazole]1 are indicated in the treatment of pulmonary and disseminated coccidioidomycosis caused by Coccidioides immitis . {70} {71} {72} {73} {162} Ketoconazole is indicated as a secondary agent in the treatment of severe coccidioidomycosis. {106} {107}

Histoplasmosis (treatment)—Itraconazole is indicated for the treatment of histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal disease caused by Histoplasma capsulatum , in immunocompromised and nonimmunocompromised patients. {61} {67} Ketoconazole is also indicated in the treatment of pulmonary and disseminated histoplasmosis caused by H. capsulatum . {106} {107}

Meningitis, cryptococcal (treatment) or
Meningitis, cryptococcal (suppression)—Fluconazole is indicated for the treatment and suppression of cryptococcal meningitis. {04} {10} {13} {15} {16} {17} [ Itraconazole]1 is indicated as an alternative agent as suppressive, maintenance therapy for cryptococcal meningitis. {77} {80} {81}
—Preliminary studies indicate that amphotericin B plus flucytosine are more efficacious than fluconazole in the primary treatment of cryptococcal meningitis in patients with acquired immunodeficiency syndrome (AIDS), although there was a greater incidence of toxicity with this combination. Another study found that amphotericin B alone was superior to fluconazole in the treatment of acute cryptococcal meningitis; however, fluconazole was better tolerated for maintenance therapy. {34} {35} {41}

Onychomycosis (treatment)—[Fluconazole ], itraconazole1 , and [ ketoconazole] are indicated in nonimmunocompromised patients for the treatment of onychomycosis caused by Trichophyton species and Candida species. {83} {84} {85} {153} {162} {163} {179}

Paracoccidioidomycosis (treatment)—[ Itraconazole] and ketoconazole are indicated in the treatment of paracoccidioidomycosis caused by Paracoccidioides brasiliensis . {106} {107} {163}

Pityriasis versicolor (treatment)
Tinea corporis (treatment)
Tinea cruris (treatment) or
Tinea pedis (treatment)—Ketoconazole is indicated in the treatment of recalcitrant or very severe disfiguring or disabling pityriasis versicolor, tinea corporis, tinea cruris, and tinea pedis infections unresponsive to griseofulvin, or in patients allergic to or unable to tolerate griseofulvin. {101} {106} {107} {135} [Fluconazole]1 and [itraconazole] are used in the treatment of tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin; jock itch), and tinea pedis (ringworm of the foot; athlete's foot). {96} {97} {98} {99} {164} {180}

[Carcinoma, prostatic (treatment) ]1—High-dose ketoconazole is indicated as a secondary antiandrogen agent in the treatment of advanced prostatic carcinoma. {116} {122} {159} {162}

[Cryptococcosis (treatment)]1—Fluconazole and itraconazole are indicated in the treatment of extrameningeal cryptococcosis caused by Cryptococcus neoformans . {79} {81} {82} {162}

[Cushing's syndrome (treatment)]1—High-dose ketoconazole is indicated as a secondary agent in the treatment of Cushing's syndrome. {127} {162}

[Hirsutism (treatment)]1—Ketoconazole is indicated as an alternative (third or fourth line) agent in the treatment of hirsutism {40} {50} {108} {136} {137} {138} {139} ( Evidence rating: III). Ketoconazole has been shown to lower androgen levels and to decrease hair growth with long-term (> 6 months) use in hirsute women. However, some medical experts state that the potential benefits of treating hirsutism with ketoconazole do not outweigh the potential risks (including serious hepatotoxicity) because other less toxic agents are available {143}.

[Histoplasmosis (suppression)]1—Itraconazole is indicated for the suppression of disseminated histoplasmosis caused by Histoplasma capsulatum , in immunocompromised patients. {94}

[Leishmaniasis, cutaneous (treatment) ]1—Itraconazole and ketoconazole are indicated for the treatment of cutaneous leishmaniasis. {165} {166} {167} {168}

[Neutropenia, febrile (prophylaxis) ]1—Fluconazole and itraconazole are indicated for the prophylaxis of febrile neutropenia in patients with hematologic malignancies.{186}{187}{188}{189}{190}{191}{192}{193}{194}{195}{196}{197}{198}.
—In neutropenic patients treated for hematological malignancies with or without autologous stem cell transplantation, fluconazole and itraconazole in low doses result in a similar low frequency of fungal disease{186}{187}{188}{189}{190}{191}{192}{193}{194}{195}{196}{197}{198}..

[Neutropenia, febrile (treatment) ]1—Fluconazole and itraconazole are indicated in the treatment of febrile neutropenia when fungal infections are suspected or proven{186}{187}{188}{189}{190}{191}{192}{193}{194}{195}{196}{197}{198}.

[Paronychia (treatment)]1—Itraconazole and ketoconazole are indicated in the treatment of fungal paronychia. {119} {120} {121} {164}

[Penicillium marneffei infection (treatment)]1—Itraconazole (in adults) and ketoconazole (in children) are indicated in the treatment of P. marneffei infection{199}{200}{201}{202}{203}{204}{205}.
—In certain parts of Southeast Asia and the southern part of China, P. marneffei infection is the third most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients. P. marneffei infection was rare in the past; however, it has increased with the endemic of AIDS in the region. The reservoir of P. marneffei in nature is unknown; however, it seems likely that inhalation may be the route of entry of the organism leading to infection in humans. P. marneffei infection is a treatable disease; however, late diagnosis and treatment may be fatal. Itraconazole and ketoconazole are preferred for mild to moderately severe forms of the disease, whereas parenteral treatment with amphotericin B may be required for seriously ill patients. Recurrence of the disease is common; therefore, maintenance is recommended{199}{200}{201}{202}{203}{204}{205}.

[Pneumonia, fungal (treatment)]1—Fluconazole, itraconazole, and ketoconazole are indicated in the treatment of fungal pneumonia. {118} {119} {162}

[Septicemia, fungal (treatment)]1—Fluconazole, itraconazole, and ketoconazole are indicated in the treatment of fungal septicemia. {118} {119} {162}

[Sporotrichosis, disseminated (treatment)]—Itraconazole and ketoconazole1 are indicated in the treatment of disseminated sporotrichosis. {106} {107} {152} {163}

[Tinea barbae (treatment)] or
[Tinea capitis (treatment)]1—Systemic ketoconazole is indicated, in combination with topical imidazoles, in the treatment of griseofulvin-resistant tinea barbae (ringworm of the beard) and tinea capitis (ringworm of the scalp). {106} {107}

[Tinea manuum (treatment)]1—Fluconazole and itraconazole are indicated in the treatment of tinea manuum (ringworm of the hand). {96} {97} {98} {99}

—Fluconazole is approved for the treatment of systemic candidal infections and is an appropriate, less toxic alternative to amphotericin B. {20} {140} {144} {162}
—Fluconazole has been shown to be efficacious in vivo in the treatment of animals infected with candidiasis, cryptococcosis, histoplasmosis, coccidioidosis, blastomycosis, aspergillosis, and paracoccidioidosis. {02} {36} The in vitro susceptibility testing of fluconazole is affected by composition of the culture medium, pH, inoculum size, incubation temperature, and time. Because of this, published in vitro minimum inhibitory concentration (MIC) data vary widely, and a correlation between this and in vivo clinical efficacy cannot reliably be made. {02} {26} {36} {47} {48}

Unaccepted
Ketoconazole is not effective in the treatment of fungal meningitis because it penetrates poorly into the cerebrospinal fluid (CSF). {106} Also, it is not effective against Aspergillus or Zygomycetes (agents of mucormycosis) or in mycetoma.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

See Table 1 and Table 2.

Table 1. Pharmacology/Pharmacokinetics *



Drug  Route of administration *  Bioavailability (%)  Vol D
CSF/Serum concentrations (%)  Protein binding (%)   Metabolism 
Fluconazole  IV, PO   90 (fasting)   0.7-1 L/kg  54-85
(patients with meningitis) 
11  Hepatic  
Itraconazole  PO, capsules  40-55 (fasting)
90-100 (with food) 
796 L  < 10   99  Hepatic  
IV, PO, oral solution  90-100 (fasting)
55 (with food) 
796 L    99  Hepatic  
Ketoconazole   PO  75 (with food)  0.36
L/kg 
< 10  99  Hepatic 
* IV = intravenous; PO = oral; Vol D = apparent volume of distribution; CSF = cerebrospinal fluid; L/kg = liters per kilogram.
 Fluconazole is primarily excreted by the kidneys; however, a small amount of the drug undergoes hepatic metabolization.
 Itraconazole is extensively metabolized by the liver, with more than 30 identifiable inactive metabolites. The major metabolite, hydroxyitraconazole, has antifungal activity.


Table 2. Pharmacology/Pharmacokinetics



  Half-life (hr)    Peak serum concentration after dose     
Drug  Normal renal function  Impaired renal function  Time to peak serum concentration (hr)  mcg/mL  Dose  Renal excretion (% unchanged)  Biliary excretion 
Fluconazole  30 (adults)
14-20 (children) 
98-125   1-2  4.5-8  100 mg  > 80  Yes; small amount 
Itraconazole
(capsules) 
21
(single dose)  
  3-4  0.132 *  100 mg
(with food) 
0.03  3-18% 
64
(steady state) 
    0.234 *  200 mg
(with food) 
   
Itraconazole
(oral solution) 
39
(steady state) 
  2.5  1.96 *  200 mg
(fasting) 
0.03   
37
(steady state)  
  4.4  1.43 *  200 mg
(with food) 
   
Ketoconazole     1-4  3.5  200 mg
(with food)  
2-4  Yes; primary route of elimination 
* The plasma concentrations reported were measured by high performance liquid chromatography (HPLC), specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those detected by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole.


Physicochemical characteristics:
Molecular weight—
    Fluconazole: 306.28 {08}
    Itraconazole: 705.65 {08}
    Ketoconazole: 531.44 {08}


Chemical class {149}
    Fluconazole: Triazole derivative.
    Itraconazole: Triazole derivative.
    Ketoconazole: Imidazole derivative.

Mechanism of action/Effect:

Fungistatic; may be fungicidal, depending on concentration; azole antifungals interfere with cytochrome P450 enzyme activity, which is necessary for the demethylation of 14-alpha-methylsterols to ergosterol. Ergosterol, the principal sterol in the fungal cell membrane, becomes depleted. This damages the cell membrane, producing alterations in membrane functions and permeability. In Candida albicans , azole antifungals inhibit transformation of blastospores into invasive mycelial form. {02} {09} {10} {11} {51} {52} {61} {109}


Other actions/effects:

High-dose ketoconazole therapy can interfere with the conversion of lanosterol to cholesterol, a major precursor of several hormones. {148} It has been shown to suppress corticosteroid secretion and lower serum testosterone concentrations, which return to baseline values when ketoconazole is discontinued. {103} Adrenocorticotropic hormone (ACTH)-induced serum corticosteroid concentrations and serum testosterone concentrations may be decreased by doses of 800 mg of ketoconazole daily; serum testosterone concentrations are abolished by doses of 1.6 grams of ketoconazole daily, leading to reduced libido and impotence, but return to baseline values when ketoconazole is discontinued. {103} {106} {148}

Compared to ketoconazole, fluconazole and itraconazole have a very weak, noncompetitive inhibitory effect on the liver cytochrome P450 enzyme system, while maintaining a high affinity for fungal cytochrome P450 enzyme activity. {66} {149}

Fluconazole and itraconazole have not been reported to have antiandrogenic activity at currently used doses. Itraconazole has not affected cortisol metabolism in patients treated with clinically recommended doses {57} {66}; however, a decrease in cortisol synthesis was observed in a patient receiving high-dose itraconazole therapy (600 mg a day). {60}

Distribution:

Fluconazole—Fluconazole is widely distributed throughout the body, with good penetration into the cerebrospinal fluid (CSF) (ranging from 52 to 85% in patients with fungal meningitis) {02} {03} {04} {18} {19} {24}, the eye {01}, and peritoneal fluid. {12} {23}

Itraconazole—Highly lipophilic; extensively distributed to tissues, concentrating in fatty tissues, the omentum, the liver, and the kidneys. Aqueous fluids, such as the CSF, aqueous humor, and saliva, contain negligible concentrations of itraconazole. Itraconazole also does not distribute into peritoneal dialysate effluent. Exudates, such as pus, may have up to 3.5 times the simultaneous plasma concentration; tissues that are prone to fungal invasion, such as skin, lung tissue, and the female genital tract, have several times the plasma concentration. {51} {61}

Ketoconazole—Well distributed; distributed to inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissues, and testes (small amounts); crosses the placenta; crosses the blood-brain barrier poorly; only negligible amounts reach the CSF. {110} Although concentrations of 2.2 to 3 mcg per mL have been reported in the CSF with corresponding serum concentrations of 9 to 12 mcg per mL, most studies indicate that CSF concentrations > 1 mcg per mL are rare, regardless of dose.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to one azole antifungal agent (fluconazole, itraconazole, ketoconazole) may also be allergic to the other antifungals in this family. {61}

Carcinogenicity/Tumorigenicity

Fluconazole—Studies in rats and mice treated with oral doses of 2.5 to 10 mg per kg of body weight (mg/kg) per day (2 to 7 times the recommended human dose) for 24 months showed no carcinogenic potential. Male rats treated with 5 to 10 mg/kg per day had an increased incidence of hepatocellular adenomas. {39}

Itraconazole—No evidence of carcinogenicity was found in mice given oral doses of up to 80 mg/kg per day, or approximately 10 times the maximum recommended human dose (MRHD), for 23 months. Male rats given 3 times the MRHD had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is caused by chronic itraconazole administration in rats, but did not occur in dogs or humans. Female rats who were given 6.25 times the MRHD had an increased incidence of squamous cell carcinoma in the lung, compared to the untreated group, although the increase in this study was not statistically significant. {61}

Ketoconazole—Long-term feeding studies in Swiss albino mice and in Wistar rats have not shown evidence of oncogenesis. {101} {106}

Mutagenicity

Fluconazole—Mutagenicity tests for fluconazole (with and without metabolic activation) in four strains of Salmonella typhimurium and in the mouse lymphoma L5178Y system were negative. Cytogenetic studies in vivo and in vitro showed no evidence of chromosomal mutations.

Itraconazole—Itraconazole produced no mutagenic effects when assayed in appropriate bacterial, non-mammalian and mammalian test systems. {61}

Ketoconazole—Dominant lethal mutation tests have not shown mutation in any stage of germ cell development in male and female mice given single, oral doses of ketoconazole as high as 80 mg/kg. In addition, the Ames/ Salmonella microsomal activator tests have not shown evidence of mutagenicity. {101} {106}

Pregnancy/Reproduction
Fertility—
Fluconazole: Fertility was not affected in male or female rats treated with oral daily doses of 5 to 20 mg/kg or parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed with oral doses of 20 mg/kg. {19}

Itraconazole: Itraconazole did not affect the fertility of male or female rats treated with oral doses of up to 5 times the MRHD, although parental toxicity was present at this dosage level. {61}

Ketoconazole: Ketoconazole has been shown to decrease or abolish serum testosterone concentrations when used in high doses (e.g., 800 mg to 1.6 grams daily). Ketoconazole has also been shown to cause menstrual irregularities, oligospermia, azoospermia, impotence, and decreased male libido. {104} {105} {107}

Pregnancy—
Fluconazole: Studies in humans have not been done.

Maternal weight gain was impaired in pregnant rabbits administered oral fluconazole at doses ranging from 5 to 75 mg/kg per day. Abortions occurred at 75 mg/kg (20 to 60 times the recommended human dose); no adverse fetal effects were detected. Pregnant rats administered oral fluconazole showed impaired maternal weight gain and increased placental weight at 25 mg/kg. A slight increase in the number of stillborn pups and a decrease in neonatal survival were also seen at these doses. Supernumerary ribs, renal pelvis dilation, and delays in ossification were observed at doses of 25 mg/kg and higher. In rats, death of embryos and fetal abnormalities, including wavy ribs, cleft palate, and abnormal craniofacial ossification, occurred at doses ranging from 80 to 320 mg/kg (approximately 20 to 60 times the recommended human dose). 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; this effect has not been observed in women treated with fluconazole. {19}

FDA Pregnancy Category C.


Itraconazole: Adequate and well-controlled studies in humans have not been done.

Studies in rats found that itraconazole causes a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity, consisting of major skeletal defects, at doses approximately 5 to 20 times the MRHD. Studies in mice also found that itraconazole causes a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity, consisting of encephaloceles and/or macroglossia, at doses approximately 10 times the MRHD. {61}

FDA Pregnancy Category C.


Ketoconazole: Ketoconazole crosses the placenta. Adequate and well-controlled studies in humans have not been done.

Studies in rats given doses of 80 mg/kg per day (10 times the MRHD) have shown ketoconazole to be teratogenic, causing syndactyly and oligodactyly. Ketoconazole has also been shown to be embryotoxic in rats given doses greater than 80 mg/kg during the first trimester. {101} {106}

FDA Pregnancy Category C.


Labor—

Fluconazole: Dystocia and prolongation of parturition were observed in a few pregnant rats given 20 and 40 mg/kg of intravenous fluconazole. {19}

Ketoconazole: Ketoconazole has also been shown to cause dystocia in rats given doses greater than 10 mg/kg (greater than 1.25 times the MRHD) during the third trimester. {101} {106}

Breast-feeding

Fluconazole—Fluconazole is distributed into breast milk at concentrations similar to those in plasma. {141}

Itraconazole—Itraconazole is distributed into breast milk. {61}

Ketoconazole—Ketoconazole is distributed into breast milk. {161}

Pediatrics

Fluconazole—Use of fluconazole in children younger than 6 months of age as well as 6 months of age and older with fungal infections is supported by evidence from adequate and well-controlled studies in adults, with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. {19} {33} {44} {45} {145}{206}

Itraconazole—Appropriate studies on the relationship of age to the effects of itraconazole have not been performed in the pediatric population. Safety and efficacy have not been established. However, a small number of patients from 3 to 16 years of age have been treated with itraconazole capsules, 100 mg per day, for systemic fungal infections, and no serious adverse effects have been reported {61}. Also, a small number of patients from 6 months to 12 years of age have been treated with itraconazole oral solution, 5 mg/kg per day, for systemic fungal infections, and no serious, unexpected adverse events have been reported {178}.

Ketoconazole—Several cases of hepatitis have been reported in children who have taken ketoconazole. Appropriate studies on the relationship of age to the effects of ketoconazole have not been performed in children up to 2 years of age. However, no pediatrics-specific problems have been documented to date in children over 2 years of age. {106} {107}


Geriatrics


No information is available on the relationship of age to the effects of azole antifungals in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment in dosage or dosing interval in patients receiving fluconazole.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» Hepatotoxic medications, other (see Appendix II )    (concurrent use with ketoconazole may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be monitored carefully and should be advised to avoid alcoholic beverages and other hepatotoxins {102} {107})

    (concurrent ingestion of alcohol with ketoconazole has been reported to result in a disulfiram-like reaction, characterized by facial flushing; other symptoms may include difficult breathing, slight fever, and tightness of the chest; these effects subsided spontaneously within 24 hours with no lasting ill effects {123})


» Alprazolam or
» Diazepam or
» Midazolam or
» Triazolam    (concurrent use with itraconazole or ketoconazole elevates the plasma concentration of oral midazolam or triazolam, which may potentiate and prolong their hypnotic and sedative effects; oral midazolam and triazolam should not be used in patients treated with itraconazole or ketoconazole {178} {181} {154}{179}{185}{208})


» Antacids or
» Anticholinergics/antispasmodics or
» Histamine H 2-receptor antagonists or
» Omeprazole or
» Sucralfate    (these medications increase gastrointestinal pH; this may result in a marked reduction in absorption of itraconazole and ketoconazole; ketoconazole depends on stomach acid for dissolution and subsequent absorption; patients should be advised to take these medications at least 2 hours after taking itraconazole or ketoconazole {61} {106} {113} {114} {148} {170} {171})


» Antidiabetic agents, oral    (concurrent use of fluconazole or itraconazole with tolbutamide, chlorpropamide, glyburide, or glipizide has increased the plasma concentrations of these sulfonylurea agents; hypoglycemia has been noted; blood glucose concentrations should be monitored, and the dose of the oral hypoglycemic agent may need to be reduced {26} {27} {36} {150})


» Astemizole or
» Terfenadine    (concurrent use of these medications with itraconazole or ketoconazole is contraindicated; concurrent use of these antihistamines with itraconazole or ketoconazole may result in elevated plasma concentrations of astemizole or terfenadine by inhibiting the cytochrome P450 enzyme metabolic pathways; this has led to cardiac arrhythmias, including QT prolongation, ventricular tachycardia, torsades de pointes, and death; in a small study, fluconazole was given with terfenadine and a small pharmacokinetic interaction was found; although no change in cardiac repolarization or accumulation of parent terfenadine was found, concurrent use of terfenadine with fluconazole at doses of 400 mg or greater per day is contraindicated {61} {62} {125} {129} {130} {145} {151} {160} {172}{179}{180})


» Atorvastatin or
» Cerivastatin or
» Lovastatin or
» Simvastatin    (concurrent use of itraconazole, capsules and injection, with atorvastatin, cerivastatin, lovastatin or simvastatin is contraindicated . Itraconazole inhibits the metabolism of atorvastatin, cerivastatin, lovastatin and simvastatin resulting in significantly elevated plasma concentrations of lovastatin or lovastatic acid, which have been associated with rhabdomyolysis; use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are metabolized by the cytochrome P450 enzyme system, such as atorvastatin, cerivastatin, lovastatin and simvastatin, should be temporarily discontinued during itraconazole therapy{178}{179}{185}{208})


» Busulfan or
» Docetaxel or
» Vinca Alkaloids    (itraconazole may inhibit the metabolism of these drugs)

{208}
Calcium channel blockers, including
» Felodipine or
» Nifedipine or
» Verapamil    (concurrent use may result in edema, and dosage adjustment may be needed. caution should be used as itraconazole may inhibit the metabolism of calcium channel blockers, and calcium channel blockers can have a negative inotropic effect and may be additive to those of itraconazole)

{208}
» Carbamazepine or
» Phenobarbital or{208}
» Phenytoin{208}    (concurrent use may decrease itraconazole plasma concentrations, leading to treatment failure or clinical relapse {110}{208})

    (concurrent use with any azole antifungal may decrease the metabolism of phenytoin, resulting in increased plasma phenytoin concentrations; a 75% increase in the AUC of phenytoin was found in volunteers given 200 mg of fluconazole per day; concurrent use has also been reported to decrease the plasma concentration of azole antifungals, which may lead to treatment failure or relapse of the fungal infection; response to both medications should be monitored closely {05} {19} {31} {32} {51} {61} {65} {107})


» Cisapride    (concurrent use of cisapride with itraconazole or oral ketoconazole is contraindicated; concurrent use of cisapride with these antifungals may inhibit the cytochrome P450 enzyme metabolic pathways, resulting in elevated plasma concentrations of cisapride; this has led to ventricular arrhythmias, including torsades de pointes and QT prolongation (with itraconazole), in patients taking cisapride and oral ketoconazole or itraconazole{177}{179}{185})


» Cyclosporine or
» Tacrolimus{208}    (itraconazole, ketoconazole, and high doses of fluconazole have been reported to inhibit the metabolism of cyclosporine and tacrolimus; this may increase the plasma concentration of cyclosporine or tacrolimus to potentially toxic levels; a few studies have not found a significant interaction between fluconazole and cyclosporine; however, plasma cyclosporine concentrations should be monitored carefully in patients receiving any of the azole antifungals; the dose of cyclosporine may need to be reduced; it is currently recommended that the dose of cyclosporine be reduced by 50% when itraconazole is started {06} {07} {19} {27} {28} {29} {30} {46} {51} {54} {55} {56} {61} {107} {131}{208})


» Didanosine (ddI)    (didanosine contains a buffer that increases gastrointestinal pH in order to increase its absorption; itraconazole and ketoconazole require an acidic environment for their optimal absorption; concurrent administration may result in a marked reduction in absorption of any of these medications; itraconazole and ketoconazole should be administered at least 2 hours before or 2 hours after didanosine is given {93} {126} {128})


» Digoxin    (itraconazole and ketoconazole may increase serum digoxin concentrations, leading to toxicity; digoxin concentrations should be monitored {61} {63} {64} {69} {181})


» Dofetilide or
» Quinidine    (concurrent use of itraconazole with dofetilide or quinidine is contraindicated; coadministration with itraconazole may increase plasma concentrations of dofetilide or quinidine possibly resulting in serious cardiovascular events{208})


Hydrochlorothiazide    (concurrent use of fluconazole with hydrochlorothiazide 50 mg for 10 days in volunteers resulted in a 41% increase in peak plasma concentration, and a 43% increase in the area under the plasma concentration–time curve [AUC] of fluconazole; this is thought to be due to a mean decrease of approximately 20% in the renal clearance of fluconazole {141})


» Indinavir or
» Ritonavir or
» Saquinavir    (concurrent use of ketoconazole with indinavir increases the AUC for indinavir by 68 ± 48% {184}; a dose reduction of indinavir to 600 mg every 8 hours is recommended {184}{208})


» Isoniazid or
» Rifampin    (concurrent use of rifampin may increase the metabolism of fluconazole, itraconazole, and ketoconazole, lowering their plasma concentrations; this may lead to clinical failure or relapse; concurrent use of isoniazid with ketoconazole has also been reported to decrease serum concentrations of ketoconazole; isoniazid or rifampin in not recommended to be given concurrently with azole antifungals {26} {27} {38} {51} {59} {61} {65} {106} {111})


Macrolide antibiotics, including
» Clarithromycin or
» Erythromycin    (clarithromycin and erythromycin are known inhibitors of CYP34A and may increase plasma concentrations of itraconazole{208})


Nevirapine    (concomitant administration is not recommended as there is the possibility of a significant reduction in bioavailability of itraconazole. studies have not been done with nevirapine and itraconazole, but studies done with ketoconazole have demonstrated that nevirapine induces the metabolism of ketoconazole , greatly reducing the bioavailability of ketoconazole.)

{208}
» Pimozide    (concurrent use of pimozide with itraconazole is contraindicated ; concurrent use of pimozide with itraconazole may inhibit the cytochrome P450 enzyme metabolic pathways, resulting in elevated plasma concentrations of pimozide; cardiac arrhythmias, including QT prolongation, ventricular tachycardia, torsades de pointes, and death{179}{185})


Rifabutin    (pharmacokinetic studies with fluconazole and rifabutin show that fluconazole appears to increase the serum concentration of rifabutin; however, this is not thought to have clinical significance, and rifabutin dosing does not need to be modified in patients receiving fluconazole{169} )


Theophylline    (fluconazole has been found to increase serum theophylline concentrations by approximately 13%, which may lead to toxicity; theophylline concentrations should be monitored {174})


» Warfarin    (anticoagulant effects may be increased when warfarin is used concurrently with any azole antifungal, resulting in an increase in prothrombin time [PT]; PT must be monitored carefully in patients receiving warfarin and azole antifungals {26} {27} {37} {53} {61} {106} {107} {112})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
» Alanine aminotransferase (ALT [SGPT]) and
» Alkaline phosphatase and
» Aspartate aminotransferase (AST [SGOT]) and
» Bilirubin    (serum values may be elevated {19} {51} {58} {106} {107})


» Potassium, serum    (hypokalemia has occurred in approximately 2 to 6% of patients treated with oral itraconazole, and has resulted in ventricular fibrillation, especially at higher doses {58} {60} {100} {156} {162})


» Corticosteroid concentrations, serum, adrenocorticotropic hormone (ACTH)–induced and
» Testosterone concentrations, serum    (ACTH-induced serum corticosteroid concentrations and serum testosterone concentrations may be decreased by doses of 800 mg of ketoconazole daily; serum testosterone concentrations are abolished by doses of 1.6 grams of ketoconazole daily, but return to baseline values when ketoconazole is discontinued {103} {106})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Congestive heart failure (CHF) or
» Ventricular dysfunction    (itraconazole capsules should not be used in patients with a evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF due to negative inotropic effects)

{208}{209}{208}{209}
» Hypersensitivity to azole antifungals
Risk-benefit should be considered when the following medical problems exist
» Achlorhydria or
» Hypochlorhydria    (may cause marked reduction in absorption of itraconazole and ketoconazole; patients with acquired immunodeficiency syndrome [AIDS] may have reduced itraconazole and ketoconazole absorption due to hypochlorhydria {66} {68} {106} {107} {124})


» Alcoholism, active or in remission or
» Hepatic function impairment    (azole antifungals are metabolized in the liver and may, infrequently, be hepatotoxic; azole antifungals, especially ketoconazole, should be used with caution in patients with pre-existing liver function impairment, those who have experienced liver toxicity with other medications, or a history of alcoholism {25} {61} {106} {107}{179}{185})

    (ketoconazole has also been reported to cause a disulfiram-like reaction to alcohol, characterized by flushing, rash, peripheral edema, nausea, and headache; symptoms resolved within a few hours {158} {164})


» Renal function impairment {19}{185}    (because fluconazole is excreted through the kidneys, a reduction in dosage, or increase in dosing interval, is recommended in patients with renal function impairment)

    (Intravenous itraconazole contains the vehicle hydroxypropyl-beta-cyclodextrin, and elimination of the vehicle will be prolonged in patients with renal impairment )



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood urea nitrogen or
Creatinine concentration, serum    (blood urea nitrogen or serum creatinine concentrations should be monitored as clinically indicated in patients taking fluconazole since patients with renal function impairment will require an adjustment in dosage {19})


» Hepatic function determinations    (liver function tests are recommended prior to treatment, monthly for 3 to 4 months after treatment is started, and periodically thereafter during treatment in patients receiving ketoconazole and itraconazole; elevated serum enzyme values may occur without clinical hepatitis; however, ketoconazole or itraconazole should be discontinued if even minor abnormalities in enzyme values persist or worsen, or if they are accompanied by symptoms of hepatotoxicity; mild, transient increase in transaminases may occur with fluconazole and itraconazole therapy, and may, on rare occasion, progress to hepatotoxicity; liver function tests should be monitored periodically during treatment in all patients receiving continuous treatment for more than 1 month or any time a patient develops signs or symptoms suggestive of liver dysfunction; fluconazole and itraconazole should be discontinued if abnormal enzyme values persist or worsen, or if they are accompanied by symptoms of hepatotoxicity {02} {03} {04} {13} {14} {61} {102} {104} {107}{179}{185})


» Potassium, serum    (hypokalemia has occurred in patients treated with itraconazole, and has been associated with ventricular fibrillation {58} {60} {100} {156})




Side/Adverse Effects

Note: In patients taking ketoconazole, hepatotoxicity, consisting primarily of hepatocellular damage or mixed hepatocellular and cholestatic changes, has been reported in approximately 1 in 10,000 exposed patients. It is usually, but not always, reversible upon discontinuation of ketoconazole, and fatalities have been reported rarely. It is considered to be an idiosyncratic reaction and can occur at any time during therapy. Females and patients over the age of 40 may be predisposed to hepatotoxicity. Several cases of hepatitis have also been reported in children. {102} {103} {106} {132} {133} {134}
High-dose ketoconazole therapy has also been shown to suppress corticosteroid secretion. In addition, ketoconazole has been shown to lower serum testosterone concentrations at doses of 800 mg per day, and abolish concentrations at 1600 mg per day; these concentrations return to baseline values when ketoconazole is discontinued. {103}
The overall incidence of side effects with fluconazole has been reported to be higher in human immunodeficiency virus (HIV)–infected patients (21%) than in those being treated with fluconazole who were not infected with HIV (13%); however, many patients in these studies were also receiving other medications known to be hepatotoxic or associated with exfoliative skin disorders, making a direct causal association with fluconazole difficult. {19}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention {04} {19} {26} {43} {58} {61} {106} {107} {147}
Incidence less frequent
    
Hypersensitivity (fever and chills; skin rash or itching)

Incidence rare
    
Agranulocytosis (fever and sore throat)—for fluconazole
    
exfoliative skin disorders, including Stevens-Johnson syndrome (reddening, blistering, peeling, or loosening of skin and mucous membranes)—for fluconazole
    
hepatotoxicity (dark or amber urine; loss of appetite; pale stools; stomach pain; unusual tiredness or weakness; yellow eyes or skin)
    
thrombocytopenia (unusual bleeding or bruising)—for fluconazole



Those indicating need for medical attention only if they continue or are bothersome {02} {04} {13} {14} {51} {106} {107}
Incidence less frequent
    
Central nervous system (CNS) effects (dizziness; drowsiness; headache)
    
gastrointestinal disturbances (abdominal pain; constipation; diarrhea; loss of appetite; nausea; vomiting)

Incidence rare
—for ketoconazole    
Gynecomastia (enlargement of the breasts in males)
    
impotence (decreased sexual ability in males)
    
menstrual irregularities
    
photophobia (increased sensitivity of the eyes to light)
Note: Gynecomastia and impotence are due to inhibition of testosterone and adrenal steroid synthesis.







Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antifungals, Azole (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to azole antifungals



Fertility—
High doses of ketoconazole have been shown to cause menstrual irregularities, oligospermia, azoospermia, and impotence

Pregnancy—High doses of azole antifungals may cause maternal toxicity, embryotoxicity, and teratogenicity in animals



Contraindicated medications
Astemizole (with itraconazole or ketoconazole), atorvastatin, cerivastatincisapride (with itraconazole or oral ketoconazole), dofetilide, lovastatin,pimozide (with itraconazole), quinidine (with itraconazole), simvastatin,and terfenadine (with fluconazole ³ 400 mg per day, itraconazole, or ketoconazole).
Other medications, especially alcohol, alprazolam, antacids, anticholinergics/antispasmodics, oral antidiabetic agents, busulfan, carbamazepine, clarithromycin, cyclosporine, diazepam didanosine, digoxin, dihydropyridine calcium channel blockers, docetaxel, erythromycin, hepatotoxic medications, histamine H 2-receptor antagonists, indinavir, isoniazid, lovastatin, midazolam, nevirapine, omeprazole, phenobarbital, phenytoin, rifampin, ritonavir, saquinavir, simvastatin, sucralfate, tacrolimus, triazolam, verapamil, vinca alkaloids,or warfarin
Other medical problems, especially achlorhydria, alcoholism, CHF, hepatic function impairment, hypochlorhydria, renal function impairment or ventricular dysfunction

Proper use of this medication
» Taking itraconazole capsules with a full mealand ketoconazole with food to increase absorption

» Taking itraconazole oral solution on an empty stomach to increase absorption

Proper administration technique for oral liquids

Proper administration technique in achlorhydria

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days

» Not taking oral ketoconazole with terfenadine, cisapride, or astemizole, not taking itraconazole with astemizole, cisapride,dofetilide, pimozide, or quinidine, and not taking ³ 400 mg per day of fluconazole with terfenadine; concurrent use may cause cardiac arrhythmias

» Avoiding intake of alcoholic beverages or other alcohol-containing preparations while taking ketoconazole because of increased risk of hepatotoxicity

» Avoiding use of antacids and other medications that increase gastrointestinal pH while taking itraconazole or ketoconazole; concurrent use may decrease the absorption of itraconazole or ketoconazole

Possible photophobic reactions when taking ketoconazole; wearing sunglasses and avoiding bright light to minimize potential eye discomfort


Side/adverse effects
Agranulocytosis, exfoliative skin disorders, hepatotoxicity, and thrombocytopenia

FLUCONAZOLE

Summary of Differences


Indications:
Also indicated for the treatment of vulvovaginal candidiasis.



Pharmacology/pharmacokinetics:
Good penetration into the cerebrospinal fluid; 80% of an administered dose is eliminated as unchanged drug in the urine.



Precautions:
Medical considerations/contraindications—Dose may need to be adjusted in patients with renal function impairment.

Drug interactions and/or related problems—Use with oral antidiabetic agents has increased the plasma concentration of these sulfonylurea agents, leading to hypoglycemia.


At fluconazole doses of 400 mg per day or greater, concurrent use with terfenadine is contraindicated and may increase the risk of cardiac arrhythmias, including torsades de pointes.



Side/adverse effects:
Increased risk of exfoliative skin disorders, including Stevens-Johnson syndrome, agranulocytosis, and thrombocytopenia.



Additional Dosing Information
Because oral fluconazole is almost completely bioavailable, the daily oral dose is the same as the intravenous dose.

Intravenous fluconazole should be administered at a maximum rate of approximately 200 mg per hour by continuous infusion. {174}

The dose of fluconazole and the length of treatment should be based on the site of infection and the individual response to therapy. Treatment should be continued until clinical parameters and laboratory tests indicate that active fungal infection has subsided. Acquired immunodeficiency syndrome (AIDS) patients with cryptococcal meningitis or recurrent oropharyngeal candidiasis require maintenance therapy to prevent relapse.

Patients undergoing bone marrow transplantation in whom severe granulocytopenia is anticipated should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue treatment for seven days after the neutrophil count rises above 1000 cells per mm 3. {174}

Adults with impaired renal function require an adjustment in dose as follows: {02} {12} {17} {21}



Creatinine clearance
(mL/min)/(mL/sec) 
Percent of recommended dose 
> 50/0.83  100 
11–50/0.18–0.83  50 
Hemodialysis patients   100 after each dialysis  


On dialysis days, the dose of fluconazole should be administered after hemodialysis has been performed since a single 3-hour dialysis period will reduce plasma fluconazole concentrations by approximately 50%. {01} {19}


Oral Dosage Forms

FLUCONAZOLE CAPSULES

Usual adult dose
Candidiasis, vulvovaginal
Oral, 150 mg as a single dose {183}.


Usual pediatric dose
Safety and efficacy have not been established for children up to 18 years of age {183}.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


150 mg (Rx) [Diflucan-150 (lactose)]{183}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F).


FLUCONAZOLE FOR ORAL SUSPENSION

Usual adult and adolescent dose
Candidiasis (prophylaxis)
Oral, 400 mg once a day {174}.

Candidiasis, disseminated
Oral, 400 mg on the first day, then 200 mg once a day for at least four weeks and for at least two weeks following the resolution of symptoms {174}.

Candidiasis, esophageal
Oral, 200 mg on the first day, then 100 mg once a day for at least three weeks and for at least two weeks following the resolution of symptoms. Doses of up to 400 mg once a day may be used depending on clinical response {174}.

Candidiasis, oropharyngeal
Oral, 200 mg on the first day, then 100 mg once a day for at least two weeks {174}.

Candidiasis, vulvovaginal
Oral, 150 mg as a single dose. {142} {148} {176}.

Meningitis, cryptococcal (treatment)
Oral, 400 mg once a day until a clear clinical response is seen, then 200 to 400 mg once a day for at least ten to twelve weeks after the cerebrospinal fluid becomes culture-negative. {21} {22}

Note: Some clinicians prefer a loading dose of 400 mg two times a day for two days, then 400 mg a day for at least ten to twelve weeks after the cerebrospinal fluid becomes culture-negative. {42}


Meningitis, cryptococcal (suppressive therapy)
Oral, 200 mg once a day.

[Neutropenia, febrile (prophylaxis and treatment)]1
Oral, 50 mg two times a day until neutrophil levels had recovered to at least 1000/mcL for 7 days.

Note: Antifungal prophylaxis could be given continuously for up to 90 days for patients receiving multiple course of cytotoxic chemotherapy within this period. Clinical trials have demonstrated that high-dose and low-dose fluconazole are equally effective; however high-dose fluconazole was not superior to low-dose fluconazole{186}{187}{188}{189}{190}{191}{192}{193}{194}{195}{196}{197}{198}.



Usual pediatric dose
[Candidiasis, disseminated]1
Neonates: Oral, 6 mg per kg of body weight (mg/kg) once a day. The dose may be reduced to 3 mg/kg once a day for neonates with reduced renal function.{206}

Candidiasis, esophageal
Infants and children 6 months of age and older: Oral, 3 mg per kg of body weight once a day for at least three weeks, and for at least two weeks following resolution of symptoms {145}.

Infants up to 6 months of age: Dosage has not been established {145}.

Candidiasis, oropharyngeal
Infants and children 6 months of age and older: Oral, 3 mg per kg of body weight once a day for at least two weeks {145}.

Infants up to 6 months of age: Dosage has not been established {145}.

Meningitis, cryptococcal (treatment)
Infants and children 6 months of age and older: Oral, 6 to 12 mg per kg of body weight once a day for at least ten to twelve weeks after the cerebrospinal fluid becomes culture-negative {145}.

Infants up to 6 months of age: Dosage has not been established {145}.

Meningitis, cryptococcal (suppressive therapy)
Infants and children 6 months of age and older: Oral, 6 mg per kg of body weight once a day {145}.

Infants up to 6 months of age: Dosage has not been established {145}.


Note: Patients with acute infections should be given a loading dose equal to twice the daily dose, not to exceed 12 mg per kg of body weight, on the first day of treatment {145}.

[Neutropenia, febrile (prophylaxis and treatment)]1
Studies have not been performed in persons younger than 18 years of age.


Usual pediatric prescribing limits
600 mg per day {145}.

Strength(s) usually available
U.S.—


10 mg per mL (when reconstituted according to manufacturers instructions) (Rx) [Diflucan (sodium benzoate) ( sucrose)]{155}


40 mg per mL (when reconstituted according to manufacturers instructions) (Rx) [Diflucan (sodium benzoate) ( sucrose)]{155}

Canada—


10 mg per mL (when reconstituted according to manufacturers instructions) (Rx) [Diflucan (sodium benzoate) ( sucrose)]{182}


40 mg per mL (when reconstituted according to manufacturers instructions) (Rx) [Diflucan (sodium benzoate) ( sucrose)]{182}

Packaging and storage:
Store between 5 and 30 °C (41 and 86 °F) in a well-closed container. Protect from freezing.

Stability:
After reconstitution, suspensions retain their potency for 14 days. {174}

Auxiliary labeling:
   • Shake well.
   • Continue medicine for full time of treatment.
   • Beyond-use date.

Note: When dispensing, include a calibrated liquid-measuring device.



FLUCONAZOLE TABLETS

Usual adult and adolescent dose
See Fluconazole for Oral Suspension .

Usual pediatric dose
See Fluconazole for Oral Suspension .

Strength(s) usually available
U.S.—


50 mg (Rx) [Diflucan]{155}


100 mg (Rx) [Diflucan]{155}


150 mg (Rx) [Diflucan]{155}


200 mg (Rx) [Diflucan]{155}

Canada—


50 mg (Rx) [Diflucan]{182}


100 mg (Rx) [Diflucan]{182}


200 mg (Rx) [Diflucan]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container.

Auxiliary labeling:
   • Continue for full time of treatment.



Parenteral Dosage Forms

FLUCONAZOLE INJECTION

Usual adult and adolescent dose
Candidiasis (prophylaxis)
Intravenous, 400 mg once a day {174}.

Candidiasis, disseminated
Intravenous, 400 mg on the first day, then 200 mg once a day for at least four weeks and for at least two weeks following the resolution of symptoms {174}.

Candidiasis, esophageal
Intravenous, 200 mg on the first day, then 100 mg once a day for at least three weeks and for at least two weeks following the resolution of symptoms. Doses of up to 400 mg once a day may be used depending on clinical response. {174}

Candidiasis, oropharyngeal
Intravenous, 200 mg on the first day, then 100 mg once a day for at least two weeks {174}.

Meningitis, cryptococcal (treatment)
Intravenous, 400 mg once a day until a clear clinical response is seen, then 200 to 400 mg once a day for at least ten to twelve weeks after the cerebrospinal fluid becomes culture-negative. The patient should be switched to fluconazole tablets when oral therapy can be administered. {21} {22}

Note: Some clinicians prefer a loading dose of 400 mg two times a day for two days, then 400 mg a day for at least ten to twelve weeks after the cerebrospinal fluid becomes culture-negative. {42}


Meningitis, cryptococcal (suppressive therapy)
Intravenous, 200 mg once a day {174}.


Usual pediatric dose
[Candidiasis, disseminated]1
Neonates: Intravenous, 6 mg/kg once a day. The dose may be reduced to 3 mg/kg once a day for neonates with reduced renal function.{206}

Note: USP experts recommend that amphotericin B as the first line agent for systemic candidiasis with fluconazole as an adjunct unless amphotericin B is contraindicated. Although oral fluconazole has been used in the treatment of systemic candidiasis, intravenous fluconazole may be the preferred dosage form, especially during initial treatment.{207}


Candidiasis, esophageal
Infants and children 6 months of age and older: Intravenous, 3 mg per kg of body weight once a day for at least three weeks, and for at least two weeks following resolution of symptoms {145}.

Infants up to 6 months of age: Dosage has not been established {145}.

Candidiasis, oropharyngeal
Infants and children 6 months of age and older: Intravenous, 3 mg per kg of body weight once a day for at least two weeks {145}.

Infants up to 6 months of age: Dosage has not been established {145}.

Meningitis, cryptococcal (treatment)
Infants and children 6 months of age and older: Intravenous, 6 to 12 mg per kg of body weight once a day for at least ten to twelve weeks after the cerebrospinal fluid becomes culture-negative {145}.

Infants up to 6 months of age: Dosage has not been established {145}.

Meningitis, cryptococcal (suppressive therapy)
Infants and children 6 months of age and older: Intravenous, 6 mg per kg of body weight once a day {145}.

Infants up to 6 months of age: Dosage has not been established {145}.


Note: Patients with acute infections should be given a loading dose equal to twice the daily dose, not to exceed 12 mg per kg of body weight, on the first day of treatment {145}.


Usual pediatric prescribing limits
600 mg per day {145}.

Strength(s) usually available
U.S.—


200 mg in 100 mL (Rx) [Diflucan (56 mg dextrose per mL)]{155}


200 mg in 100 mL (Rx) [Diflucan (9 mg sodium chloride per mL )]{155}


400 mg in 200 mL (Rx) [Diflucan (56 mg dextrose per mL)]{155}


400 mg in 200 mL (Rx) [Diflucan (9 mg sodium chloride per mL )]{155}

Canada—


200 mg in 100 mL (Rx) [Diflucan (9 mg sodium chloride per mL ){182}]


400 mg in 200 mL (Rx) [Diflucan (9 mg sodium chloride per mL ){182}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Protect from freezing.

Incompatibilities:
Intravenous admixtures of fluconazole and other medications are not recommended.


ITRACONAZOLE

Summary of Differences


Precautions:


Drug interactions and/or related problems—
Antacids, anticholinergics/antispasmodics, histamine H 2-receptor antagonists, omeprazole, or sucralfate will increase the pH of the stomach and decrease the absorption of itraconazole.

Use with astemizole, cisapride, dofetilide, pimozide, quinidine, or terfenadine is contraindicated and may increase the risk of cardiac arrhythmias, including QT prolongation, ventricular tachycardia,torsades de pointes, and death.

Didanosine contains a buffer to increase its absorption; this will decrease the absorption of itraconazole since itraconazole needs an acidic environment.

Use with oral antidiabetic agents has increased the plasma concentration of these sulfonylurea agents, leading to hypoglycemia.

Use with carbamazepine, phenobarbital and phenytoin may decrease itraconazole plasma concentrations, leading to treatment failure or relapse.

Itraconazole may increase digoxin concentrations, leading to digoxin toxicity.

Use with atovastatin, cerivastatin, lovastatin or simvastatin may increase the plasma concentrations of these cholesterol-lowering agents and may increase the risk of rhabdomyolysis.

Use with alprazolam, diazepam, midazolam or triazolam may potentiate the hypnotic and sedative effects of these benzodiazepines.

Use with nifedipine, felodipine, or verapamil may cause additive negative inotropic effects.

Use with macrolide antibiotics such as clarithromycin and erythromycin may cause increased plasma concentrations of itraconazole.



Medical considerations/contraindications—
Achlorhydria or hypochlorhydria will decrease the absorption of itraconazole.




Additional Dosing Information
Itraconazole capsules and itraconazole oral solution are not bioequivalent; the two dosage forms should not be used interchangeably {178} {179}.

The dose of itraconazole and the length of treatment should be based on the site of infection and the individual response to therapy. Treatment may be continued for weeks or months until clinical parameters and laboratory tests indicate that active fungal infection has subsided. {61}

Because patients with acquired immunodeficiency syndrome (AIDS) may have reduced absorption of itraconazole due to hypochlorhydria, they may require higher doses to achieve a clinical response. {68} {87}

Although studies did not provide for a loading dose, in life-threatening situations, a loading dose of 200 mg three times a day (600 mg per day) for the first 3 days is recommended, based on pharmacokinetic data. {61}

Doses above 200 mg per day should be given in two divided doses. {61}

Diet/Nutrition
Itraconazole capsules should be taken with a full meal to ensure maximal absorption of the medication.{208}

Itraconazole oral solution should be taken on an empty stomach to increase absorption of the medication.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in Us. product labeling.

ITRACONAZOLE CAPSULES

Usual adult and adolescent dose
Aspergillosis
Oral, 200 mg one or two times a day with meals for at least three months. {75} {76} {77} {78} {173}

Blastomycosis or
Histoplasmosis (treatment)
Oral, 200 mg once a day with meals. The dose may be increased by 100 mg, up to a maximum of 400 mg a day, if there is no obvious improvement or if there is evidence of progressive fungal disease.

[Candidiasis, esophageal ] or
[Candidiasis, oropharyngeal]
Oral, 100 to 200 mg once a day with a meal for fourteen days {74} {87} {88}; the dose for AIDS and neutropenic patients is increased to 200 mg for four weeks. {163}

[Candidiasis, vulvovaginal]1
Oral, 200 mg once a day with a meal for three days. {91} {92} {157}

[Chromomycosis]
Oral, 100 to 200 mg once a day with a meal for three to six months. {163}

[Coccidioidomycosis ]1
Oral, 200 mg two times a day with meals for six weeks. {70} {71} {72}

[Cryptococcosis (treatment)]1 or
[Meningitis, cryptococcal (suppression)]1
Oral, 200 mg two times a day with meals. {74} {77} {79} {80} {81} {82}

[Histoplasmosis (suppression)]1
Oral, 200 mg two times a day with meals. {94}

[Neutropenia, febrile (prophylaxis and treatment)]1
Oral, 100 mg two times a day until neutrophil levels had recovered to at least 1000/mcL for 7 days{186}{187}{188}{189}{190}{191}{192}{193}{194}{195}{196}{197}{198}.

Onychomycosis1
Fingernails only: Oral, 200 mg two times a day with meals for one week; this treatment is suspended for three weeks, then resumed for one week {83} {84} {85} {179}.

Toenails with or without fingernail involvement: Oral, 200 mg once a day with meals for twelve consecutive weeks {83} {84} {85} {179}.

[Paracoccidioidomycosis ]
Oral, 100 mg once a day with a meal for six months. {163}

[ Penicillium Marneffei infection (treatment)]1
Oral, 400 mg two times a day for two months followed by 100 mg once a day for another month.

Note: Itraconazole has been shown to be effective in the initial treatment of Penicillium Marneffei infection; however, relapse after treatment is common and long-term suppressive treatment is recommended{199}{200}{201}{202}{203}{204}.


[Sporotrichosis]
Oral, 100 mg once a day with a meal for three months. {163}

[Tinea corporis]or
[Tinea cruris]
Oral, 100 mg once a day with a meal for fifteen days. {96} {98} {99}

[Tinea manuum ]1 or
[Tinea pedis]
Oral, 100 mg once a day with a meal for thirty days. {96} {97} {98}


Usual pediatric dose
Safety and efficacy have not been established. However, a small number of patients 3 to 16 years of age have been treated with itraconazole capsules, 100 mg per day, for systemic fungal infections, and no serious adverse effects have been reported. {61}

Strength(s) usually available
U.S.—


100 mg (Rx) [Sporanox (sucrose)]{179}

Canada—


100 mg (Rx) [Sporanox (sugar spheres NF)]{180}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container.

Auxiliary labeling:
   • Take with food.
   • Continue medicine for full time of treatment.


ITRACONAZOLE ORAL SOLUTION

Usual adult and adolescent dose
Candidiasis, esophageal
Oral, 100 mg once a day for a minimum of three weeks {178}; treatment should continue for two weeks after resolution of symptoms {178}.

Candidiasis, oropharyngeal
Oral, 200 mg once a day for seven to fourteen days {178}.

Note: For patients unresponsive or refractory to treatment with fluconazole, 100 mg two times a day for two to four weeks {178}.



Usual pediatric dose
Safety and efficacy have not been established. However, a small number of patients 6 months to 12 years of age have been treated with itraconazole oral solution, 5 mg per kg per day, for systemic fungal infections, and no unexpected serious adverse effects have been reported {178}.

Strength(s) usually available
U.S.—


100 mg per 10 mL (Rx) [Sporanox (hydroxypropyl-beta-cyclodextrin [400 mg per mL]) (sodium saccharin)]{178}

Canada—
Not commercially available.

Packaging and storage:
Store at or below 25 °C (77 °F). Protect from freezing.

Preparation of dosage form:
Proper use of dosage form—Itraconazole oral solution should be vigorously swished in the mouth, 10 mL at a time, for several seconds and swallowed {178}.

Auxiliary labeling:
   • Take on an empty stomach.




Parenteral Dosage Forms

ITRACONAZOLE INJECTION

Usual adult dose
Aspergillosis or
Blastomycosis or
Histoplasmosis (treatment)
Intravenous, 200 mg twice a day for four doses followed by 200 mg once a day. Switch to oral itraconazole as soon as possible.
{185}
Note: Each intravenous dose should be infused over 1 hour.



Usual pediatric dose
Safety and efficacy have not been established. {185}

Strength(s) usually available
U.S.—


200 mg in 50 mL (Rx) [Sporanox]{185}

Packaging and storage:
Store at or below 25 °C (77 °F). Protect from light and freezing.

Incompatibilities:
Intravenous admixtures of itraconazole and other medications are not recommended.


KETOCONAZOLE

Summary of Differences


Pharmacology/pharmacokinetics:
Ketoconazole has been shown to suppress corticosteroid secretion and lower serum testosterone concentrations.

Ketoconazole penetrates poorly into the cerebrospinal fluid.



Precautions:


Pregnancy/reproduction—
Ketoconazole may cause menstrual irregularities, oligospermia, azoospermia, impotence, and decreased male libido.



Drug interactions and/or related problems—
Alcohol and hepatotoxic medications may increase the risk of hepatotoxicity.

Antacids, anticholinergics/antispasmodics, histamine H 2-receptor antagonists, omeprazole, or sucralfate will increase the pH of the stomach and decrease the absorption of ketoconazole.

Use with astemizole, cisapride, or terfenadine is contraindicated and may increase the risk of cardiac arrhythmias, including torsades de pointes.

Didanosine contains a buffer to increase its absorption, which will decrease the absorption of ketoconazole.

Ketoconazole may increase digoxin concentrations, leading to digoxin toxicity.

Ketoconazole may increase plasma concentrations of indinavir; a dose reduction of indinavir is recommended.

Use with midazolam or triazolam may potentiate the hypnotic and sedative effects of these benzodiazepines.



Medical considerations/contraindications—
Achlorhydria or hypochlorhydria will decrease the absorption of ketoconazole.




Side/adverse effects:
Increased risk of hepatotoxicity and of side effects due to inhibition of testosterone and corticosteroid synthesis, such as menstrual irregularities, oligospermia, azoospermia, impotence, and decreased male libido.



Additional Dosing Information
In patients with achlorhydria or hypochlorhydria, higher serum concentrations may be achieved by taking the medication with an acidic drink. Ketoconazole may be dissolved in cola or seltzer water and swallowed, or the medication may be taken with a glass of cola or seltzer water. {173} An alternative is to dissolve each tablet in 4 mL of 0.2 N hydrochloric acid. Patients may further dilute the resulting mixture in a small amount of water and should be instructed to drink it through a plastic or glass straw to avoid contact with the teeth. This should be followed by one-half glass (120 mL) of water, which is swished around in the mouth and swallowed. {106}

Therapy should be continued for at least l to 2 weeks in candidiasis {107} (3 to 5 days in vaginal candidiasis) {115}; for 1 to 8 weeks in dermatomycoses caused by yeasts or dermatophytes, and mycoses of hair and scalp {115}; for 3 months to l year in paracoccidioidomycosis; and for 6 months or longer in other systemic mycoses. Chronic mucocutaneous candidiasis following a remission usually requires indefinite maintenance treatment to prevent relapse. {106}

Diet/Nutrition
Ketoconazole may be taken with a meal or snack to minimize nausea or vomiting and to promote absorption.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

KETOCONAZOLE ORAL SUSPENSION

Usual adult and adolescent dose
[Candidiasis, vulvovaginal]1
Oral, 200 to 400 mg once a day for five days. {104} {119} {120} {121}

[Carcinoma, prostatic]1
Oral, 400 mg three times a day. {116} {122} {159}

[Cushing's syndrome]1
Oral, 600 mg to 1.2 grams a day. {117}

[Paronychia ]1
Oral, 200 to 400 mg once a day. {119} {120} {121}

Pityriasis versicolor
Oral, 200 mg once a day for five to ten days. {106} {135}

[Pneumonia, fungal]1 or
[Septicemia, fungal]1
Oral, 400 mg to 1 gram once a day. {118} {119}

For all other antifungal indications
Oral, 200 to 400 mg once a day. {106} {107}


Usual adult prescribing limits
Antifungal
1 gram a day.

[Antiadrenal; antineoplastic]1
1.2 grams a day


Usual pediatric dose
[Candidiasis, vulvovaginal]1
Children 2 years of age and older: Oral, 5 to 10 mg per kg of body weight once a day for five days. {104} {118} {119}

Infants and children up to 2 years of age: Dosage has not been established. {106} {107}

[Paronychia ]1 or
[Penicillium Marneffei infection]1 or
[Pneumonia, fungal]1 or
[Septicemia, fungal]1
Children 2 years of age and older: Oral, 5 to 10 mg per kg of body weight once a day. {104} {118} {119}{199}{204}

Infants and children up to 2 years of age: Dosage has not been established. {106} {107}

Note: It is estimated that 6000–7200 human immunodeficiency virus (HIV)-infected children are born in Thailand every year. Many of these children will develop systemic P. Marneffei infection. Early diagnosis and prompt administration of antifungal treatment are crucial for improved outcome. Therefore, histologically or culture-proved P. Marneffei infection in HIV-infected children may be treated with ketoconazole{199}{204}.


For all other antifungal indications
Children 2 years of age and older: Oral, 3.3 to 6.6 mg per kg of body weight once a day. {106}

Infants and children up to 2 years of age: Dosage has not been established. {106} {107}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


100 mg per 5 mL (Rx) [Nizoral (sodium [< 0.55 mg per mL] ) (sodium benzoate) ( sucrose)]{146}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container. Protect from freezing.

Auxiliary labeling:
   • Shake well.
   • Take with food.
   • Avoid alcoholic beverages.
   • May cause dizziness or drowsiness.
   • Continue medicine for full time of treatment (antifungal only).


KETOCONAZOLE TABLETS USP

Usual adult and adolescent dose
See Ketoconazole Oral Suspension.

Usual adult prescribing limits
See Ketoconazole Oral Suspension.

Usual pediatric dose
See Ketoconazole Oral Suspension.

Strength(s) usually available
U.S.—


200 mg (Rx) [Nizoral (scored) (lactose )]{154}

Canada—


200 mg (Rx) [Nizoral (scored) (lactose )]{146}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a well-closed container.

Auxiliary labeling:
   • Take with food.
   • Avoid alcoholic beverages.
   • May cause dizziness or drowsiness.
   • Continue medicine for full time of treatment (antifungal only).



Developed: 11/14/1994
Revised: 06/27/2001



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  1. Goodless DR, Ramos-Caro FA, Flowers FP. Ketoconazole in the treatment of pityriasis versicolor: international review of clinical trials. DICP 1991; 25: 395-8.
  1. Conget JI, Halperin I, Ferrer J, et al. Evaluation of clinical and hormonal effects in hirsute women treated with ketoconazole. J Endocrinol Invest 1990; 13: 867-70.
  1. Sonino N, Scaroni C, Biason A, et al. Low-dose ketoconazole treatment in hirsute women. J Endocrinol Invest 1990; 13: 35-40.
  1. Martikainen H, Heikkinen J, Ruokonen A, et al. Hormonal and clinical effects of ketoconazole in hirsute women. J Clin Endocrinol Metab 1988; 66: 987-91.
  1. Venturoli S, Fabbri R, Dal Prato L, et al. Ketoconazole therapy for women with acne and/or hirsutism. J Clin Endocrinol Metab 1990; 71: 335-9.
  1. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia: Candidemia Study Group and the National Institute. N Engl J Med 1994; 331(20): 1325-30.
  1. Fluconazole package insert (Diflucan, Pfizer—US), Rev 6/92, Rec 9/92.
  1. Debruyne D, Ryckelynck J-P. Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet 1993; 24(1): 10-27.
  1. Reviewers' consensus on monograph revision of 5/98.
  1. Panel comment, 6/98.
  1. Fluconazole package insert (Diflucan, Pfizer—US), Rev 2/97, Rec 8/97.
  1. Ketoconazole (Nizoral, Janssen-Ortho). In: CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association; 1997. p. 1050-1.
  1. Murakami H, Katahira H, Matsushima T, et al. Agranulocytosis during treatment with fluconazole. J Int Med Res 1992; 20: 492-4.
  1. Bodey GP. Azole antifungal agents. Clin Infect Dis 1992; 14 Suppl 1: S161-S169.
  1. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol 1993; 28(5 Part 1): S28-S34.
  1. Itraconazole package insert (Sporonax, Janssen—US), Rev 2/93, Rec 6/93.
  1. Crane JK, Shih H-T. Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine. Am J Med 1993; 95: 445-6.
  1. Sharkey-Mathis PK, Kauffman CA, Graybill JR, et al. Treatment of sporotrichosis with itraconazole. Am J Med 1993; 95: 279-85.
  1. Korting HC, Schafer-Korting M, Zienicke H, et al. Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole. Antimicrob Agents Chemother 1993; 37(10): 2064-8.
  1. Ketoconazole package insert (Nizoral, Janssen—US), Rev 6/96, Rec 8/97.
  1. Fluconazole (Diflucan, Pfizer). In: PDR Physicians' desk reference. 51st ed. 1997. Montvale, NJ: Medical Economics Company; 1997. p. 2003-7.
  1. Nelson MR, Smith D, Erskine D, et al. Ventricular fibrillation secondary to itraconazole induced hypokalemia. J Infect Dis 1993; 26(3): 348.
  1. Gorlero F, Larosa E, Cauwenbergh G, et al. Itraconazole plasma and vaginal mucosal levels in patients with chronic vaginal candidosis treated with itraconazole 200 mg once daily for 3 consecutive days. Drug Invest 1993; 6(1): 22-4.
  1. Ketoconazole package insert (Nizoral, Janssen—US), Rev 10/92, Rec 6/93.
  1. Percy LA. Ketoconazole in advanced prostate cancer. Ann Pharmacother 1992; 26: 1527-9.
  1. Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction. JAMA 1993; 269(12): 1513-8.
  1. Panel comment, 7/93.
  1. Reviewers' responses to monograph revision of 1/94.
  1. Panel comment, 2/94.
  1. Panel comment, 2/94.
  1. Viallet J, MacLean JD, Robson H. Response to ketoconazole in two cases of longstanding cutaneous leishmaniasis. Am J Trop Med Hyg 1986; 35(3): 491-5.
  1. Saenz RE, Paz H, Berman JD. Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Am J Med 1990; 89: 147-55.
  1. Al-Fouzan AS, Al Saleh QA, Najem NM, et al. Cutaneous leishmaniasis in Kuwait. Int J Dermatol 1991; 30: 519-24.
  1. Navin TR, Arana BA, Arana FE, et al. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 1992; 165: 528-34.
  1. Panel comment, 6/93.
  1. Hoeschele JD, Roy AK, Pecoraro VL, et al. In vitro analysis of the interaction between sucralfate and ketoconazole. Antimicrob Agents Chemother 1994; 38(2): 319-25.
  1. Carver PL, Berardi RR, Knapp MJ, et al. In vivo interaction of ketoconazole and sucralfate in healthy volunteers. Antimicrob Agents Chemother 1994; 38(2): 326-9.
  1. Honig PK, Wortham DC, Zamani K, et al. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993; 53: 630-6.
  1. Personal communication, Michelle Ratzell, Jannsen Pharmaceuticals, 4/20/94.
  1. Fluconazole package insert (Diflucan, Pfizer—US), Rev 1/94, Rec 4/94.
  1. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326(13): 845-51.
  1. Fluconazole package insert (Diflucan, Pfizer—US), Rev 7/94, Rec 10/94.
  1. Propulsid package insert (Janssen—US), Rev 1/95, Rec 2/95.
  1. Itraconazole oral solution package insert (Sporanox, Janssen—US), Rev 2/97, Rec 5/97.
  1. Product Information: Sporanox (R) itraconazole capsules. Janssen Pharmaceutica Inc., Titusville, NJ, (PI revised 11/1999) reviewed 3/2000.
  1. Itraconazole (Sporanox, Janssen-Ortho). In: CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association; 1997. p. 1490-2.
  1. Ketoconazole (Nizoral, Pfizer). In: PDR Physicians' desk reference. 51st ed. 1997. Montvale, NJ: Medical Economics Company; 1997. p. 1345-6.
  1. Fluconazole (Diflucan, Pfizer). In: CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association; 1997. p. 453-6.
  1. Fluconazole (Diflucan-150, Pfizer). In: CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association; 1997. p. 456-7.
  1. Indinavir package insert (Crixivan, Merck—US), New 3/97, Rec 7/97.
  1. Product information Sporanox (R) itraconazole injection. OrthoBiotech, Raritan, NJ,(PI revised 1/2000) reviewed 3/2000.
  1. Panel consensus, 6/2000.
  1. Nucci M, Biasoli I, Akiti T, et al. A Double-Blind, Randomized, Placebo-Controlled Trial of Itraconazole Capsules as Antifungal Prophylaxis for Neutropenic Patients. Clin Infect Dis 2000; 30: 300-5.
  1. Morgenstern GR, Prentice AG, Prentice HG, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. The U.K. Multicentre Antifungal Prophylaxis Study Group. Br J Haematol 1999; 105(4): 901-11.
  1. Huijgens PC, Simoons-Smit AM, van Loenen AC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999; 52(5): 376-80.
  1. Menichetti F, Del Favero A, Martino P, et al. Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: A randomized placebo-controlled, double-blind, multicenter trial. Clin Infect Dis 1999; 28: 250-5.
  1. Glasmacher A, Hahn C, Leutner C, et al. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses 1999; 42(7-8): 443-51.
  1. Annaloro C, Oriani A, Tagaliaferri E, et al. Efficacy of different antifungal regimens in bone marrow transplantation. Hematologica 1995; 80: 512-7.
  1. Panel consensus, 7/2000.
  1. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefits based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999; 28: 331-40.
  1. Takatsuka H, Takemoto Y, Okamoto T, et al Fluconazole versus amphotericin B for the prevention of fungal infection in neutropenic patients with hematologic malignancy. Drugs Exp Clin Res 1999; 25(4): 193-200.
  1. Malik IA, Morid I, Aziz Z, et al. A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged ever and neutropenia. Am J Med 1998; 105: 478-83.
  1. Yamac K, Senol E, Haznedar R. Prophylactic use of fluconazole in neutropenic cancer patients. Postgrad Med J 1995; 71(835): 284-6.
  1. Menichetti F, Del Favero A, Martino P, et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. The GIMEMA Infection Program. Ann Intern Med 1994; 120(11): 913-8.
  1. Panel consensus, 7/2000
  1. Sirisanthana T, Supparatpinyo K, Perriens J, et al. Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficency virus-infected patients. Clin Infect Dis 1998; 26: 1107-10.
  1. Supparatpinyo K, Perriens J, Nelson KE, et al. A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the human immunodeficency virus. N Engl J Med 1998; 339: 1739-43.
  1. Julander I, Petrini B. Penicillium marneffei infection in a Swedish HIV-infected immunodeficient narcotic addict. Scand J Infect Dis 1997; 29(3): 320-2.
  1. Supparatpinyo K, Chiewchanvit S, Hirunsri P, et al. An efficacy study of itraconazole in the treatment of Penicillium marneffei infection. J Med Assoc Thai 1992; 75(12): 688-91.
  1. Sirisanthana V, Sirisanthana T. Disseminated Penicillium marneffei infection in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1995; 14(11): 935-40.
  1. Cooper CR Jr, McGinnis MR. Pathology of Penicillium marneffei: an emerging acquired immunodeficiency syndrome-related pathogen. Arch Pathol Lab Med 1997; 121(8): 798-804.
  1. Consensus on review of evidence table, 08/2000.
  1. Panel comment, 01/2001.
  1. Product Information: Sporanox®, itraconazole. Janssen Pharmaceutica Products, Titusville, New Jersey. PI revised 04/2001 (PI reviewed 05/2001)
  1. FDA Talk Paper: FDA Issues Health Advisory regarding the safety of Sporanox® Products and Lamisil® Tablets to Treat Fungal Nail Infection. Issued 05/09/2001 (reviewed 5/2001)
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