Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

FLUCONAZOLE AND RELATED AGENTS

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Fluconazole, isavuconazole (the active moiety of isavuconazonium), itraconazole, posaconazole, terconazole, and voriconazole are triazole antifungal agents which inhibit cytochrome P-450 enzymes resulting in impairment of ergosterol synthesis in fungal cell membranes.

Specific Substances

    A) FLUCONAZOLE (synonym)
    1) UK-49858
    2) 2(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-
    3) yl)propan-2-ol
    4) Molecular Formula: C13-H12-F2-N6-O
    5) CAS 86386-73-4
    ISAVUCONAZONIUM (synonym)
    1) Isavuconazonium sulfate
    2) Isavuconazole (synonym)
    ITRACONAZOLE (synonym)
    1) Oriconazole
    2) R-51211
    3) Molecular Formula: C35-H38-Cl2-N8-O4
    4) CAS 84625-61-6
    POSACONAZOLE (synonym)
    1) Posaconazol
    2) Posaconazolum
    3) CAS 171228-49-2
    4) Molecular Formula: C37-H42-F2-N8-O4
    TERCONAZOLE (synonym)
    1) 1-{4-[[2-(2,4-Dichlorophenyl)-r-2--(1H-1,2,4-triazol-
    2) 1-ylmethyl)-1,3-dioxolan--c-4--yl]methoxy]phenyl}-
    3) 4-isopropylpiperazine
    4) Terconazolum
    5) Triaconazole
    6) R-42470
    7) Molecular Formula: C26-H31-Cl2-N5-O3
    8) CAS 67915-31-5
    VORICONAZOLE (synonym)
    1) (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidine- 4-yl)-1-(1,2,4-triazol-1-yl)butan-2-o1
    2) UK-109,496
    3) Voriconazol
    4) Molecular Formula: C16-H14-N5-F3-O
    5) CAS 137234-62-9

    1.2.1) MOLECULAR FORMULA
    1) FLUCONAZOLE: C13H12F2N6O
    2) ISAVUCONAZONIUM SULFATE: C35H35F2N8O5S.HSO4
    3) ITRACONAZOLE: C35H38Cl2N8O4
    4) POSACONAZOLE: C37H42F2N8O4
    5) TERCONAZOLE: C26H31Cl2N5O3
    6) VORICONAZOLE: C16H14F3N5O

Available Forms Sources

    A) FORMS
    1) Fluconazole is available as:
    a) Tablet: 50 mg, 100 mg, 200 mg
    b) Oral solution: 10 mg/mL or 40 mg/mL concentration
    c) Injection: Solution: 100 mL and 200 mL in glass or Viaflex(R) plastic containers
    2) Isavuconazonium is available as (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015):
    a) Capsules: 186 mg (equivalent to 100 mg isavuconazole)
    b) Injection: 372 mg (equivalent to 200 mg isavuconazole) as a sterile lyophilized powder, in a single-dose vial, for intravenous administration.
    3) Itraconazole is available as:
    a) 100 mg capsules and 10 mg/mL oral solution
    4) Posaconazole is available as oral suspension in 4 ounce (123 mL) bottles containing 105 mL of suspension (40 mg/mL). It is also available as 100 mg oral delayed-release tablets and 300 mg/16.7 mL (18 mg/mL) solution for injection (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    5) Noxafil injection: 300 mg per 16.7 mL (18 mg per mL)
    6) Terconazole is available as:
    a) 0.4% and 0.8% cream and 80 mg vaginal suppositories (Prod Info TERAZOL(R) 3 vaginal suppositories, 2014; Prod Info TERAZOL(R) 3 vaginal cream, 2014; Prod Info TERAZOL(R) 7 vaginal cream, 2014)
    7) Voriconazole is available as :
    a) Tablet: 50 mg, 200 mg
    b) Oral suspension: 45 grams of powder in 100 mL bottle; reconstituted to 40 mg/mL (total volume of 75 mL)
    c) Injection: White powder containing 200 mg
    B) USES
    1) Fluconazole is indicated in the treatment of cryptococcal meningitis and oropharyngeal, esophageal, and vaginal candidiasis (Prod Info DIFLUCAN(R) IV injection oral suspension tablets, 2011).
    2) Isavuconazonium, the prodrug for isavuconazole, is indicated in the treatment of invasive aspergillosis and invasive mucormycosis (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    3) Itraconazole capsules are indicated in the treatment of blastomycosis, histoplasmosis, aspergillosis, and onychomycosis (Prod Info SPORANOX(R) oral capsules, 2015), and itraconazole oral solution is indicated in the treatment of oropharyngeal and esophageal candidiasis (Prod Info SPORANOX(R) oral solution, 2015).
    4) Posaconazole is used for the prophylactic treatment of invasive Aspergillus and Candida infections in patients at risk of developing these infections due to being severely immunocompromised (Prod Info NOXAFIL(R) oral suspension, 2012).
    5) Terconazole is used in the local treatment of vulvovaginal candidiasis (Prod Info TERAZOL(R) 3 vaginal suppositories, 2014; Prod Info TERAZOL(R) 3 vaginal cream, 2014; Prod Info TERAZOL(R) 7 vaginal cream, 2014).
    6) Voriconazole is indicated in the treatment of invasive aspergillosis, candidemia and esophageal candidiasis, and fungal infections caused by Scedosporium apiospermum or Fusarium spp. (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Fluconazole is an antifungal medication. It is indicated for the treatment of cryptococcal meningitis and oropharyngeal, esophageal, and vaginal candidiasis. Other azole antifungals include itraconazole, isavuconazonium, posaconazole, terconazole, and voriconazole, which are used to treat a variety of fungal infections including aspergillosis.
    B) PHARMACOLOGY: These agents inhibit cytochrome P-450 enzymes resulting in impairment of ergosterol synthesis in fungal cell membranes.
    C) TOXICOLOGY: Toxicity in overdose is rare and not expected. The majority of toxic effects are related to drug interactions because these agents competitively inhibit CYP3A4.
    D) EPIDEMIOLOGY: Overdose and inadvertent exposures are uncommon and serious toxicity from acute ingestion has not been reported. Adverse drug effects are rare but may be life-threatening.
    E) WITH THERAPEUTIC USE
    1) Adverse effects include nausea, vomiting, diarrhea, abdominal pain, hypokalemia, and visual changes (abnormal vision, color vision changes, photophobia). There are reports of dizziness, hepatotoxicity, congestive heart failure, thrombocytopenia, neutropenia, seizures, and delirium. Azole antifungals have been implicated in case reports to cause toxic epidermal necrolysis and less serious rashes.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Few overdose effects have been reported; however, hallucination and paranoid behavior have been reported with FLUCONAZOLE overdose. Overdose effects would be expected to be similar to adverse effects reported after therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Fluconazole is classified as FDA pregnancy category C when used for vaginal candidiasis (single 150 mg dose), and as FDA category D for all other indications. Isavuconazonium, itraconazole, posaconazole, and terconazole are classified as FDA pregnancy category C, and voriconazole is classified as FDA category D.
    B) Pregnant women administered oral fluconazole 150 to 300 mg from gestational week 7 through 22 had an increased risk of spontaneous abortion compared with women not administered fluconazole or women treated with topical azoles.
    C) Congenital anomalies in infants have been reported following maternal ingestion of fluconazole and itraconazole, but at rates similar to nonexposed women. In animal studies, adverse fetal effects were observed with the administration of isavuconazonium, posaconazole, terconazole, and voriconazole. Fluconazole and itraconazole are excreted in human breast milk while isavuconazonium and posaconazole are excreted in the milk of lactating rats. No impairment of fertility was observed in male or female rats administered with isavuconazonium.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of fluconazole, isavuconazonium, itraconazole, posaconazole, terconazole, or voriconazole.

Laboratory Monitoring

    A) In large overdoses, monitor serum electrolytes, liver enzymes, and complete blood count.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Antiemetic medications and IV fluids can be used for gastrointestinal distress.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after fluconazole (or related agents) overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Most overdoses do not lead to toxicity. Prehospital gastrointestinal decontamination is generally not required.
    2) HOSPITAL: Because most overdoses do not lead to toxicity, activated charcoal is typically not recommended.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) SEIZURE
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    G) ENHANCED ELIMINATION
    1) FLUCONAZOLE: Fluconazole has low protein binding and a small volume of distribution and could be removed by hemodialysis; however, this is not likely to be needed as toxicity is limited.
    2) ITRACONAZOLE AND VORICONAZOLE: Enhanced elimination is NOT LIKELY to be effective for itraconazole or voriconazole because they both have a large volume of distribution.
    3) POSACONAZOLE: Posaconazole is NOT REMOVED by hemodialysis.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: In cases of acute unintentional ingestion, patients may be followed at home if they are asymptomatic.
    2) OBSERVATION CRITERIA: Any patients with deliberate ingestion, very large ingestion, symptoms, or comorbidities should be referred to a health care facility for observation.
    3) ADMISSION CRITERIA: Patients who remain persistently symptomatic despite supportive management should be admitted for further observation and treatment.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity.
    I) PITFALLS
    1) Failure to recognize drug interactions; the majority of toxic effects are due to inhibition of CYP3A4, which is responsible for the metabolism of many drugs.
    J) PHARMACOKINETICS
    1) FLUCONAZOLE: well absorbed after oral administration. Bioavailability: greater than 90%. Tmax: 0.5 to 6 hours. Vd: 0.6 to 0.8 L/kg. Protein binding: 11% to 12%. Excretion: primarily (70% to 80%) excreted unchanged in the urine. Elimination half-life: ranges from 27 to 32 hours (IV); 20 to 50 hours (oral).
    2) ITRACONAZOLE: well absorbed with food. Vd: 10.7 L/kg (IV administration). Protein binding: 99.8%. Oral itraconazole is primarily excreted in the urine (35%) and feces (54%). Elimination half-life: ranges between 17 to 21 hours.
    3) POSACONAZOLE: Tmax: approximately 3 to 5 hours after administration. Protein binding: greater than 98%. Posaconazole is predominantly excreted in feces (71%) with approximately 13% being excreted in urine. Mean elimination half-life: 35 hours.
    4) VORICONAZOLE: Bioavailability: about 96% after oral administration. Tmax: approximately 1 to 2 hours. Vd: 4.6 L/kg. Protein binding: 58%. Voriconazole is primarily excreted in the urine as metabolites (80% to 83%). The terminal half-life is not useful for predicting accumulation or elimination.
    K) DIFFERENTIAL DIAGNOSIS
    1) Consider other xenobiotics that inhibit CYP3A4 and gastrointestinal irritants.

Range Of Toxicity

    A) TOXICITY: Maximal tolerated dose and minimal lethal human dose have not been determined. ITRACONAZOLE oral capsules have been tolerated up to 3000 mg daily. POSACONAZOLE oral suspension has been tolerated in clinical trials up to 1600 mg/day. One patient inadvertently ingested 1200 mg of posaconazole twice daily for 3 days without related adverse events. VORICONAZOLE: Pediatric patients tolerated doses up to 5 times the recommended IV dose.
    B) THERAPEUTIC DOSES: FLUCONAZOLE: ADULTS: Typical fluconazole doses are 100 mg to 400 mg daily depending on the route and underlying disease. PEDIATRIC: 3 mg to 12 mg/kg depending on age. ITRACONAZOLE: ADULTS: 200 mg to 400 mg daily. POSACONAZOLE: ADULTS: 100 mg to 800 mg daily. PEDIATRIC: 13 TO 18 YEARS OF AGE: 200 mg (5 mL) oral suspension 3 times a day. VORICONAZOLE: ADULTS: ORAL (suspension or tablet): 100 mg to 200 mg every 12 hours. IV: 4 mg/kg to 6 mg/kg every 12 hours. PEDIATRIC: 12 TO 18 YEARS OF AGE: LOADING DOSE: 6 mg/kg IV every 12 hours for 24 hours, then 4 mg/kg IV every 12 hours. MAINTENANCE DOSE: 200 mg orally every 12 hours for patients weighing over 40 kg; 100 mg every 12 hours for patients under 40 kg. The safety and efficacy in patients under 12 years of age have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Fluconazole is an antifungal medication. It is indicated for the treatment of cryptococcal meningitis and oropharyngeal, esophageal, and vaginal candidiasis. Other azole antifungals include itraconazole, isavuconazonium, posaconazole, terconazole, and voriconazole, which are used to treat a variety of fungal infections including aspergillosis.
    B) PHARMACOLOGY: These agents inhibit cytochrome P-450 enzymes resulting in impairment of ergosterol synthesis in fungal cell membranes.
    C) TOXICOLOGY: Toxicity in overdose is rare and not expected. The majority of toxic effects are related to drug interactions because these agents competitively inhibit CYP3A4.
    D) EPIDEMIOLOGY: Overdose and inadvertent exposures are uncommon and serious toxicity from acute ingestion has not been reported. Adverse drug effects are rare but may be life-threatening.
    E) WITH THERAPEUTIC USE
    1) Adverse effects include nausea, vomiting, diarrhea, abdominal pain, hypokalemia, and visual changes (abnormal vision, color vision changes, photophobia). There are reports of dizziness, hepatotoxicity, congestive heart failure, thrombocytopenia, neutropenia, seizures, and delirium. Azole antifungals have been implicated in case reports to cause toxic epidermal necrolysis and less serious rashes.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Few overdose effects have been reported; however, hallucination and paranoid behavior have been reported with FLUCONAZOLE overdose. Overdose effects would be expected to be similar to adverse effects reported after therapeutic use.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) VORICONAZOLE: Abnormal vision, color vision change, and/or photophobia was reported in 21% of patients in voriconazole therapeutic trials (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERICARDIAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 49-year-old woman ingested itraconazole (200 mg twice daily) to treat pulmonary aspergillosis and developed a left-side pleural effusion and pericardial effusion several weeks later. The pleural effusion resolved after being treated by thoracoscopic drainage and the pericardial effusion disappeared after pericardial drainage and a pericardesis. After discontinuation of itraconazole for six weeks, itraconazole therapy was resumed, and two weeks later, chest x-rays showed that the patient had peripheral lung edema and a considerably enlarged heart. The patient recovered following intensified diuresis therapy and discontinuation of itraconazole (Gunther et al, 1993).
    B) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) Congestive heart failure has been reported in patients receiving itraconazole for treatment of fungal nail infections and is contraindicated in patients who have ventricular dysfunction or have a history of congestive heart failure (Prod Info ONMEL(TM) oral tablets, 2012; Prod Info SPORANOX(R) oral solution, 2011).
    2) In a 10-year span, 58 cases of congestive heart failure (CHF) in patients on itraconazole were reported to the FDA's Adverse Event Reporting System. Causality was not established. Potential confounders, such as hypertension, valvular heart disease, and history of CHF, existed in 43 of the patients. Of the 58 cases, there were 28 admissions to the hospital and 13 deaths. Since most patients who died were already very sick, a causal relation with itraconazole was difficult to determine. No CHF cases were reported with other azole antifungals (Ahmad et al, 2001).
    3) CASE REPORT: Two patients with no history of cardiomyopathy developed new-onset congestive heart failure after receiving itraconazole. Following supportive therapy and treatment with diuretics, both patients recovered completely. In the first case, an echocardiogram revealed some residual reduction of pumping function but no underlying structural abnormalities. A challenge with itraconazole resulted in the reoccurrence of the symptoms. In the second case, an echocardiogram revealed mild mitral and tricuspid regurgitations (Ahmad et al, 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) CASE REPORT: A 49-year-old woman ingested itraconazole (200 mg twice daily) to treat pulmonary aspergillosis and developed a left-side pleural effusion and pericardial effusion several weeks later. The pleural effusion resolved after being treated by thoracoscopic drainage and the pericardial effusion disappeared after pericardial drainage and a pericardesis. After discontinuation of itraconazole for six weeks, itraconazole therapy was resumed, and two weeks later, x-rays showed that the patient had peripheral lung edema and a considerably enlarged heart. The patient recovered following intensified diuresis therapy and discontinuation of the itraconazole (Gunther et al, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) CASE REPORT: A 74-year-old man developed delirium when treated with itraconazole 200 mg twice daily for necrotic ulcers and bullae on his hands, secondary to disseminated histoplasmosis. The patient's mental status declined the day after starting itraconazole (score of 25 on the Mini-Mental Status Examination (MMSE)). The only other medication he was taking was docusate sodium. Although the man became combative and his mental status continued to deteriorate (MMSE score of 12 on day 4), treatment with itraconazole was continued because of improvement in his hand lesions and resolution of his low-grade fever. Lowering the dose to 200 mg/day did not stop the mental deterioration. Itraconazole was discontinued when his MMSE score fell to 4 on day 5. After discontinuation, his MMSE score rapidly rose to 26 and he returned to near-baseline cognitive function. However, the hand lesions and fever reappeared. He was again treated with itraconazole, and his MMSE score declined rapidly to 20 (Mittal & Wikaitis, 2003).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) Dizziness has been observed rarely during fluconazole therapy (Budtz-Jorgensen et al, 1988). However, it was unclear if this effect was drug-related.
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) CASE REPORT: A grand mal seizure was reported in a 69-year-old man with acquired immunodeficiency syndrome-related cryptococcal meningitis within 2 hours following a single 100 mg oral dose of fluconazole. The patient had previously received 1.3 grams of amphotericin B (Stern et al, 1988).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) The most common adverse effects of fluconazole include nausea, vomiting, and bloating (Sugar & Saunders, 1988; Anon, 1988).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) Diarrhea may occur with the use of fluconazole (Stern et al, 1988; Budtz-Jorgensen et al, 1988).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) Abdominal discomfort may be noted with therapeutic use. In one study using fluconazole as suppressive therapy of disseminated cryptococcosis, nausea, vomiting, and/or abdominal discomfort were observed in approximately 50% of patients treated (Sugar & Saunders, 1988).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevation of transaminase levels has been observed during fluconazole, itraconazole and voriconazole therapy (Stern et al, 1988; Sugar & Saunders, 1988; Tucker et al, 1988; Cohen, 1989; Gallardo-Quesada et al, 1995).
    1) Approximately 1% of fluconazole-treated patients have serum transaminase elevations of more than 8 times the upper limit of normal.
    2) The incidence of elevated transaminases is greater in patients taking concomitant rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylureas. Rare cases of fatal hepatic reactions have been reported, usually in patients with serious underlying conditions (AIDS, malignancies) on multiple medications (Prod Info Diflucan(R), fluconazole, 1995).
    b) FLUCONAZOLE
    1) In 2 studies utilizing fluconazole for acute treatment and suppressive therapy of cryptococcosis, transaminase elevations occurred in approximately 20% of patients (Stern et al, 1988; Sugar & Saunders, 1988).
    a) CASE REPORT: In a report, one patient developed elevations in SGOT and SGPT levels which resolved upon withdrawal of therapy but recurred after rechallenge; in this patient, liver biopsy demonstrated nonspecific acute and chronic inflammatory changes of the portal triads with mild focal cholangitis (Stern et al, 1988).
    b) CASE SERIES: In 3 patients receiving suppressive therapy, fluconazole was discontinued due to the development of increases in transaminases, then resumed after 7 to 15 days when transaminases either stabilized or returned to normal(Sugar & Saunders, 1988a). All 3 patients continued therapy without incident.
    2) Further studies are required to evaluate the hepatotoxic potential of fluconazole. In comparison, asymptomatic elevation of serum transaminases has been observed in 2% to 5% of patients treated with ketoconazole; progressive hepatitis occurs in 1 in 10,000 patients (Walsh & Pizzo, 1988).
    3) Two patients developed elevated AST levels within 4 weeks of initiating fluconazole therapy(Trujillo et al, 1994). In the second case, the bilirubin levels and the alkaline phosphatase levels were also elevated. Liver biopsy showed no evidence of hepatocyte necrosis. The AST levels returned to normal values spontaneously without discontinuing the fluconazole.
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 46-year-old man with AIDS began fluconazole treatment (200 to 400 mg daily) and subsequently developed elevated liver enzyme levels. A liver biopsy showed a central lobular cholestasis. A dosage reduction of fluconazole (100 mg daily) returned the liver enzyme levels to normal values.
    1) A rechallenge with fluconazole (200 mg daily) resulted in increased liver enzyme levels once again. The patient eventually died after deterioration of his general condition (Wells & Lever, 1992).
    b) CASE REPORT: A 51-year-old woman developed nausea, jaundice, and elevated liver enzyme levels following long-term therapy of itraconazole (116 days). A liver biopsy confirmed a diagnosis of acute hepatitis. The patient's symptoms gradually improved following discontinuation of the itraconazole (Hann et al, 1993).
    C) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) CASE REPORT: A 32-year-old man with AIDS developed progressive fulminant hepatic necrosis within 3 weeks of initiating fluconazole therapy for cryptococcal meningitis. The patient died despite receiving supportive care (Jacobson et al, 1994).
    D) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) The FDA has received and reviewed 24 cases of possible itraconazole-associated liver failure, including 11 deaths. One-half of the liver failure cases received itraconazole for treatment of fungal nail infections or other dermatological infections ((Anon, 2001)).
    2) CASE REPORT: A 61-year-old woman developed acute liver failure that progressed and necessitated liver transplantation 17 days later. The woman's diagnosis came one week after completing a 24-week pulse itraconazole therapy for onychomycosis; no liver enzyme monitoring was done during treatment. Upon admit, AST and ALT values were 3250 and 3330 Units/L, respectively. The woman died a few months later secondary to allograft rejection and cardiovascular failure (Tuccori et al, 2008).
    a) The Naranjo probability scale and Council for the International Organization of Medical Sciences scale rated the relationship of liver failure and itraconazole therapy as "probable".
    E) HYPERPLASIA
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) CASE REPORT: Focal nodular hyperplasia of the liver developed in a 38-year-old woman 2 months after completing a 4 month course of treatment with itraconazole 200 mg/day for a fungal infection of her fingernails (Wolf et al, 2001).
    F) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) CASE REPORT: A 45-year-old woman treated with oral fluconazole 400 mg daily for Cryptococcus neoformans grown from sputum and cerebrospinal fluid developed severe acute hepatic failure evidenced by elevated hepatocellular enzymes, prolonged prothrombin time (PT), hypoglycemia, and hyperammonemia. Anti-fungal therapy also included intravenous amphotericin B 40 mg daily for 2 weeks. The patient took fluconazole for only 5 weeks due to poor compliance. Four weeks after stopping fluconazole therapy, amphotericin B and fluconazole were re-initiated at the same dose as the initial treatment. Renal function began to decline 2 weeks later and the amphotericin B dose was decreased to 35 mg daily. Signs of hepatic failure were evident on day 25 of fluconazole therapy with aspartate transaminase (AST) level of 3202 Units/L, alanine transaminase (ALT) 1281 Units/L, and PT of 21 seconds. The patient was admitted to intensive care and liposomal amphotericin 70 mg daily replaced amphotericin B therapy. Her renal and hepatic function improved over 3 weeks. Concomitant medications included lisinopril, atenolol, and amlodipine, and there was no evidence of alcohol induced hepatitis or cirrhosis. The elimination of fluconazole was impaired in this patient due to renal toxicity caused by amphotericin B (Crerar-Gilbert et al, 1999).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) AMENORRHEA
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) CASE REPORT: Amenorrhea was described in one patient receiving oral fluconazole for coccidioidal meningitis. Menses resumed without intervention after 5 months and it is unclear if fluconazole was the cause of this patient's amenorrhea (Tucker et al, 1988).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) Thrombocytopenia was reported in one patient receiving oral fluconazole 200 mg daily as suppressive therapy of disseminated cryptococcosis; the duration of therapy was unclear. Withdrawal of the drug resulted in normalization of the platelet count (Sugar & Saunders, 1988).
    2) Two patients developed severe thrombocytopenia occurring following therapeutic use of fluconazole. The thrombocytopenia resolved after discontinuation of the fluconazole (Mercurio & Elewski, 1995).
    b) ITRACONAZOLE
    1) CASE REPORT: A 54-year-old man developed thrombocytopenia and leukopenia 6 weeks after beginning itraconazole therapy (200 mg/day) to treat a fungal infection. The patient's platelet count decreased from 98 to 33 cells/nL, the leukocyte count decreased from 9.8 to 3.6 cells/nL, and the neutrophil count decreased from 4.1 to 2.2 cells/nL. After discontinuation of itraconazole, the patient's platelet, leukocyte, and neutrophil counts increased (Horst et al, 1996).
    B) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) CASE REPORT: A 41-year-old woman with a fungal infection was treated with fluconazole and, 18 days later, developed agranulocytosis and thrombocytopenia. The fluconazole was discontinued and the neutrophil and platelet counts returned to normal values 11 days later (Murakami et al, 1992).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) In combined clinical trials and foreign marketing experience prior to US marketing, patients with serious underlying disease (AIDS or malignancy) have rarely developed exfoliative skin disorders. Fatal Stevens-Johnson Syndrome has been reported (Prod Info DIFLUCAN(R) oral tablets, IV injection, oral suspension, 2008).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rashes and itching have been observed during fluconazole, itraconazole and voriconazole therapy (Stern et al, 1988; Cohen, 1989; Morgan & Carmichael, 1994; Kramer et al, 1997; Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).
    b) ITRACONAZOLE
    1) CASE REPORT: A 65-year-old man developed angioedema and urticaria within 3 days of beginning a regimen of oral itraconazole 100 mg twice a day for prevention of candidiasis. He had tolerated the drug well 2 years previously. His symptoms responded to parenteral steroids. A skin prick test with itraconazole 10 mg/mL was negative. Oral challenge with itraconazole caused eruption of a maculopapular rash and angioedema within 2 hours. Double-blind oral challenge with other agents showed normal tolerance to fluconazole 100 mg and ketoconazole 200 mg. After withdrawal of itraconazole, there were no further episodes of urticaria (Martinez-Alonso et al, 2003).
    2) CASE REPORT: Two cases of acute generalized exanthematous pustulosis were reported following itraconazole therapy. Edema of the face and legs, hypoalbuminemia, and hypocalcemia occurred in one patient, and both patients developed fevers and leukocytosis. The pustulosis resolved after corticosteroid treatment and discontinuation of itraconazole (Heymann & Manders, 1995; Park et al, 1997).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) CASE REPORT: A 33-year-old man, with HIV infection, developed malaise, pruritus, fever, and exfoliating erythematous rash seven days after initiating fluconazole therapy, 50 mg every 12 hours, to treat severe and recurrent oral thrush. A skin biopsy revealed toxic epidermal necrolysis. The necrolysis resolved following supportive care and after discontinuation of the fluconazole (Azon-Masoliver & Vilaplana, 1993).
    D) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) Alopecia was reported in patients receiving high doses of fluconazole (200 to 400 mg daily) for extended periods of time (2 months or longer). The alopecia was reversible upon discontinuation of the fluconazole (Weinroth & Tuazon, 1993; Pappas et al, 1995).
    E) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) Two cases of peripheral edema occurred following itraconazole therapy (100 mg twice daily) to treat fungal infections. The edema resolved within days after drug cessation (Rosen, 1994).
    2) Peripheral edema was also associated with the concurrent administration of felodipine and itraconazole (Neuvonen & Suhonen, 1995).
    F) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) ITRACONAZOLE
    1) CASE REPORT: Approximately 3 days after beginning itraconazole therapy to treat a fungal nail infection, a 53-year-old woman developed a serum sickness-like reaction, consisting of malaise, arthralgias, and erythema multiforme. The patient recovered following withdrawal of itraconazole therapy and administration of corticosteroids (Park et al, 1998).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HORMONE LEVEL - FINDING
    1) WITH THERAPEUTIC USE
    a) FLUCONAZOLE
    1) TESTOSTERONE EFFECTS: One study evaluated the effect of fluconazole 25 or 50 mg daily for 28 days on serum testosterone levels in healthy volunteers(Hanger et al, 1988a). No significant effect of the drug on circulating testosterone levels was observed.
    a) In this study, the ability of fluconazole to influence biosynthesis of testosterone by rat Leydig cells in vitro was also assessed. In concentrations of up 10 mcg/mL, fluconazole produced only weak inhibition of testosterone production.
    b) In contrast, ketoconazole was shown to produce greater than 50% inhibition at concentrations of 0.1 mcg/mL. The authors suggested that at these doses, fluconazole would be unlikely to cause the endocrinologic adverse effects observed with ketoconazole. However, effects on testosterone need to be evaluated utilizing doses of fluconazole greater than 50 mg daily.
    B) LACK OF EFFECT
    1) As compared to ketoconazole, fluconazole has greater selectivity for fungal as opposed to human P450 enzymes.
    2) Despite fluconazole's ability to markedly inhibit fungal ergosterol synthesis in vitro, only minimal effects on human steroid synthesis have been observed (Tucker et al, 1988; Hanger et al, 1988; Stevens, 1988).
    3) Available data suggest that fluconazole does not produce significant interference with the synthesis of testosterone and cortisol (Tucker et al, 1988; Stevens, 1988; Devenport et al, 1989).
    4) No endocrinologic adverse effects have been observed; however, studies employing larger numbers of patients are required to more fully evaluate the potential endocrine toxicity of fluconazole.

Reproductive

    3.20.1) SUMMARY
    A) Fluconazole is classified as FDA pregnancy category C when used for vaginal candidiasis (single 150 mg dose), and as FDA category D for all other indications. Isavuconazonium, itraconazole, posaconazole, and terconazole are classified as FDA pregnancy category C, and voriconazole is classified as FDA category D.
    B) Pregnant women administered oral fluconazole 150 to 300 mg from gestational week 7 through 22 had an increased risk of spontaneous abortion compared with women not administered fluconazole or women treated with topical azoles.
    C) Congenital anomalies in infants have been reported following maternal ingestion of fluconazole and itraconazole, but at rates similar to nonexposed women. In animal studies, adverse fetal effects were observed with the administration of isavuconazonium, posaconazole, terconazole, and voriconazole. Fluconazole and itraconazole are excreted in human breast milk while isavuconazonium and posaconazole are excreted in the milk of lactating rats. No impairment of fertility was observed in male or female rats administered with isavuconazonium.
    3.20.2) TERATOGENICITY
    A) SPONTANEOUS ABORTION
    1) FLUCONAZOLE
    a) Pregnant women administered oral fluconazole 150 to 300 mg from gestational week 7 through 22 experienced a 48% significant increased risk of spontaneous abortion compared with women not administered fluconazole (Molgaard-Nielsen et al, 2016).
    b) Pregnant women administered oral fluconazole from gestational week 7 through 22 experienced a 62% significant increased risk of spontaneous abortion compared with women exposed to topical azoles (Molgaard-Nielsen et al, 2016).
    B) CONGENITAL ANOMALY
    1) FLUCONAZOLE
    a) No adequate and well-controlled studies have been conducted with fluconazole in pregnant women, but epidemiologic studies suggest there is no increased risk of congenital anomalies with single maternal doses of 150 mg for vaginal candidiasis. Case reports of rare birth defects have been reported when infants were exposed to 400 to 800 mg/day during most or all of the first trimester. The distinctive pattern of birth defects included brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease (Prod Info DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, 2011).
    b) A population-based retrospective cohort study showed no difference in adjusted overall rates of congenital malformations among live births and stillbirths occurring after the 20th week of gestation in 1079 pregnant women who received fluconazole (total dose range of 150 mg to 600 mg) during the first trimester compared with a reference group of 170,453 pregnant women who did not. Overall, congenital malformations were reported in 4.1% of births in the fluconazole group compared with 3.6% in the reference group. There was also no increased risk of low birth weight, preterm birth, or stillbirth reported in the fluconazole-treated group compared to the reference group (Norgaard et al, 2008).
    c) A study evaluating the outcomes of pregnant women who received fluconazole (n=234), topical azoles (miconazole, ketoconazole, or econazole) (n=492), or oral itraconazole (n=88) during the first trimester of pregnancy demonstrated that such exposure does not increase the risk of congenital disorders in infants when compared with an unexposed control group (n=1629). The relative risks for fluconazole, oral itraconazole, and topical azoles in the first trimester of pregnancy compared with those who were unexposed were 1.1 (95% confidence interval [CI], 0.4 to 3.3), 2.1 (95% CI, 0.7 to 6.8), and 0.6 (95% CI, 0.2 to 1.6), respectively. The congenital anomalies were: fluconazole group: polydactyly-syndactyly (n=1), heart defect (n=1), spina bifida (n=1); topical azole group: polydactyly-syndactyly (n=1), other limb disorders (n=1), cleft lip or palate (n=1); oral itraconazole group: heart defect (n=1), other limb disorders (n=1); unexposed group: polydactyly-syndactyly (n=5), other limb disorders (n=3), cleft palate (n=3), heart defects (n=5), genitourinary disorders (n=3), spina bifida (n=2) (Jick & S, 1999).
    d) Congenital anomalies, primarily craniofacial, skeletal, and cardiac, occurred in 3 infants following maternal ingestion of fluconazole during the first and second trimesters of pregnancy. Two of the three infants died. One case report describes a 25-year-old woman, treated with fluconazole throughout her pregnancy, who delivered a male child with several gestational anomalies. Delivered by cesarean section at 38 weeks gestation, the 1878-g infant was cyanotic and with poor tone. His joints had limited range of motion, and when one leg was straightened to measure the length, his femur fractured. Numerous craniofacial abnormalities were noted on physical examination, including a flattened occiput, brachycephaly, trigonocephaly, and supraorbital ridge hypoplasia. Radiographs showed bowed femurs, diffuse osteopenia, thin ribs and clavicles, and long bones, with metacarpals and phalanges that appeared disproportionately long (Pursley et al, 1996).
    2) ITRACONAZOLE
    a) A prospective cohort study of women exposed to itraconazole during the first trimester of pregnancy (n=206) matched with control subjects not exposed to any known teratogens (n=207) found no significant difference in major congenital malformations (1.8% (n=3/163) vs 2.1% (n=4/190), respectively). The study enrolled women who contacted the Italian teratology information services and, using a structured questionnaire, data were collected 1 month following delivery. Women exposed to itraconazole received daily doses ranging from 119.65 mg to 244.81 mg (mean, 182.33 +/- 62.58 mg), with a mean duration of therapy between 0.5 and 13.3 days (mean, 6.9 +/- 6.4 days) for vaginal mycosis. The congenital malformations in the exposed did not follow a specific pattern and included one atrial septal defect, one unilateral hydronephrosis, and one cerebral calcification and hepatomegaly; one case also had chromosome 17 inversion. Notably, the rates of therapeutic abortion, spontaneous abortion, and live births were statistically significantly different between the drug-exposed group (9.2%, 11.2%, and 79.1%, respectively) and the control group (3.4%, 4.8%, and 91.8%, respectively) (p less than 0.05 for all). The between-group difference in live birth was maintained (87% and 95%, respectively; p less than 0.02) after excluding cases of therapeutic abortion (De Santis et al, 2009).
    b) In a prospective cohort study of women exposed to oral itraconazole during the first trimester of pregnancy, no difference in the rate of major malformations was observed in the itraconazole-exposed pregnancies. One hundred and eighty-nine women used the drug during the first trimester of pregnancy, with total doses that ranged from 200 mg to 18,600 mg (median of 800 mg). The mean duration of therapy was 8.5 days. Mean birth weight was significantly lower in the drug-exposed group, but this was not clinically significant. The rates of therapeutic abortion, spontaneous abortion, fetal death, and live birth were significantly different between the two groups; however, this could not be conclusively linked to itraconazole (Bar-Oz et al, 2000).
    c) A series of observational cohort studies suggested that itraconazole does not cause an increased rate of congenital anomalies when used during pregnancy. Of 337 pregnant women who took the drug, 286 discontinued the drug before the last menstrual period; 41 were exposed during the first trimester, and 6 during the second or third trimester; exposure for 6 was unknown. Of the 41 exposed during the first trimester, there were 30 births without congenital anomalies, 1 ectopic pregnancy, 2 spontaneous abortions, and 6 pregnancies intentionally terminated. The outcome of 2 pregnancies was unknown (Wilton et al, 1998).
    C) ANIMAL STUDIES
    1) ISAVUCONAZONIUM
    a) Dose-related increases in incidences of zygomatic arch fusion and supernumerary ribs/rudimentary supernumerary ribs were observed in rats following isavuconazonium doses 30 mg/kg and greater (one-fifth the clinical dose based on AUC) (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    b) Dose-related increases in incidences of rudimentary cervical ribs were observed in rats given isavuconazonium dose of 30 mg/kg (one-fifth the clinical dose based on AUC) and rabbits given isavuconazonium dose of 45 mg/kg (one-tenth the clinical dose based on AUC) (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015)
    2) POSACONAZOLE
    a) Studies in rats showed skeletal malformations in the fetus at doses resulting in an exposure greater than or equal to 1.4 times that achieved by a 400 mg twice-daily regimen in healthy humans. The no-effect dose for malformations was 9 mg/kg (0.7 times the exposure with the 400 mg twice-daily regimen). While no malformations were noted in rabbits at doses achieving an exposure up to 5.2 times that achieved by a 400 mg twice-daily regimen, increased incidence of resorption was seen at doses of 40 mg/kg and 80 mg/kg (2.9 and 5.2 times the exposure achieved by a 400 mg twice-daily regimen, respectively). Additionally, reductions in litter size and body weight gain of females were noted at doses of 80 mg/kg (Prod Info NOXAFIL(R) oral suspension, 2009).
    3) VORICONAZOLE
    a) Voriconazole has been shown to be teratogenic in pregnant rats at doses from 10 mg/kg (0.3 times the recommended maintenance dose [RMD] on a mg/m(2) basis) and embryotoxic in pregnant rabbits at doses of 100 mg/kg (6 times the RMD). Effects in rats included cleft palates, hydronephrosis/hydroureter, increased gestational length and dystocia (associated with increased perinatal pup mortality), reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, sternebrae anomalies, ureter/renal pelvis dilatation, and reduced plasma estradiol levels. Effects in rabbits included reduced fetal weights, increased embryomortality, and increased incidence of skeletal variations, cervical ribs, and extrasternebral ossification sites (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The following drugs have been classified as FDA pregnancy category C:
    a) Fluconazole, when used for vaginal candidiasis (single 150 mg dose) (Prod Info DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, 2011)
    b) Isavuconazonium (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015)
    c) Itraconazole (Prod Info SPORANOX(R) oral capsules, 2009)
    d) Posaconazole (Prod Info NOXAFIL(R) oral suspension, 2009)
    e) Terconazole (Prod Info terconazole vaginal suppositories, 2004)
    2) The following drugs have been classified as FDA pregnancy category D: .
    a) Fluconazole, for all indications other than vaginal candidiasis (Prod Info DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, 2011)
    b) Voriconazole (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008)
    3) Exercise caution when administering fluconazole to a pregnant woman (Prod Info DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, 2011). Advise pregnant women that develop a yeast infection to discuss possible alternative treatment options to oral fluconazole (US Food and Drug Administration, 2016).
    B) LACK OF EFFECT
    1) FLUCONAZOLE
    a) Use of oral fluconazole at doses of 150 or 300 mg did not increase the overall risk of birth defects among 7352 exposed infants, or 14 of 15 birth defects previously attributed to azole antifungal use. There were no cases of craniofacial defects, middle-ear defects, or pulmonary-artery hypoplasia; however, there was a significantly increased risk of tetralogy of Fallot with fluconazole exposure during pregnancy (Molgaard-Nielsen et al, 2013).
    b) No adequate and well-controlled studies have been conducted with fluconazole in pregnant women, but epidemiologic studies suggest there is no increased risk of congenital anomalies with single maternal doses of 150 mg for vaginal candidiasis (Prod Info DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, 2011).
    c) A population-based follow-up study demonstrated that the prevalence of malformed infants among 121 women with first-trimester exposure to fluconazole was not significantly elevated. The authors concluded that using fluconazole during pregnancy did not indicate any teratogenic risk, but that complete safety (nonteratogenicity) was very difficult to prove (Sorensen et al, 1999).
    d) A cohort study of 226 women who had known exposure to fluconazole (total dose range 100 mg to 2100 mg) revealed no increase in congenital anomalies as compared to a similar reference group of 452 women without exposure. These findings do not exclude the teratogenic potential of fluconazole, especially at the prolonged higher doses used in systemic and life-threatening conditions. They do suggest that this type of exposure is not a medical indication for pregnancy termination (Mastroiacovo et al, 1996).
    e) In a case report, a 24-year-old pregnant woman (gestation week 16) with Candida albicans sepsis and endophthalmitis tolerated high-dose fluconazole therapy and delivered a healthy female infant at week 39 of gestation. The patient received 400 mg fluconazole (10 mg/kg) per day administered intravenously for 16 days, then orally at the same dosage for another 34 days. The woman was discharged on day 40 of therapy and completed the fluconazole therapy without adverse events on an outpatient basis. A healthy female infant (2834 grams) was vaginally delivered at week 39 of gestation, with subsequent normal growth and mental development through age 2 years (Wiesinger et al, 1996).
    2) TERCONAZOLE
    a) Terconazole suppositories and cream were administered to 1946 pregnant and nonpregnant patients in 16 separate controlled clinical studies in Europe. There were no reports of adverse effects to the offspring of the pregnant patients (Hirsch, 1989).
    C) ANIMAL STUDIES
    1) ISAVUCONAZONIUM
    a) In animal studies, perinatal mortality was significantly increased in the offspring of pregnant rats given isavuconazonium 90 mg/kg/day orally (less than half the human maintenance dose based on AUC) from pregnancy to weaning (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    2) POSACONAZOLE
    a) Studies in rats showed skeletal malformations in the fetus at doses resulting in an exposure greater than or equal to 1.4 times that achieved by a 400-mg twice-daily regimen in healthy humans. The no-effect dose for malformations was 9 mg/kg (0.7 times the exposure with the 400-mg twice-daily regimen). While no malformations were noted in rabbits at doses achieving an exposure up to 5.2 times that achieved by a 400-mg twice-daily regimen, increased incidence of resorption was seen at doses of 40 mg/kg and 80 mg/kg (2.9 and 5.2 times the exposure achieved by a 400-mg twice-daily regimen, respectively). Additionally, reductions in litter size and body weight gain of females were noted at doses of 80 mg/kg (Prod Info NOXAFIL(R) oral suspension, 2006).
    3) TERCONAZOLE
    a) Embryotoxicity, but not teratogenicity, was found with the administration of terconazole oral doses up to 40 mg/kg/day (25 times the recommended intravaginal human dose of the suppository formulation) or subQ doses of 20 mg/kg/day in rats and rabbits, respectively. Embryotoxicity in rats resulted in decreased litter size and viable young, reduced fetal weight, delayed ossification, and increase in skeletal variants. In rats, doses up to 10 mg/kg/day did not result in embryotoxicity, but delayed ossification was noted with the 10 mg/kg/day dose (17 times the recommended intravaginal human dose of the suppository formulation) (Prod Info terconazole vaginal suppositories, 2004; Prod Info terconazole vaginal cream, 2004; Prod Info terconazole vaginal cream, 0.8%, 2003).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) ISAVUCONAZONIUM
    a) Since isavuconazonium is excreted in the milk of lactating rats, it is recommended that mothers who are taking isavuconazonium should not breast feed (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    2) POSACONAZOLE
    a) Studies have not been conducted to determine whether posaconazole is excreted into human breast milk (Prod Info NOXAFIL(R) oral suspension, 2009).
    3) VORICONAZOLE
    a) It is not known whether voriconazole is excreted into human breast milk (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008).
    B) BREAST MILK
    1) FLUCONAZOLE
    a) Fluconazole is excreted into human breast milk at concentrations similar to maternal plasma concentrations (Prod Info DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, 2011).
    b) A significant amount of fluconazole (85% of the plasma concentration) appeared in the breast milk at 5, 24, and 48 hours after a 150-mg dose of fluconazole in a breastfeeding woman. The mother's plasma concentrations were 6.42, 2.79, 2.52, and 1.19 mcg/mL, and the corresponding breast milk concentrations were 2.93, 2.66, 1.76, and 0.98 mcg/mL at 2, 5, 24, and 48 hours after a single dose (Force, 1995).
    2) ITRACONAZOLE
    a) Itraconazole is excreted into human breast milk (Prod Info SPORANOX(R) oral capsules, 2009).
    C) ANIMAL STUDIES
    1) ISAVUCONAZONIUM
    a) Isavuconazonium is secreted in the milk of lactating rats (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    2) POSACONAZOLE
    a) Posaconazole is secreted in the milk of lactating rats (Prod Info NOXAFIL(R) oral suspension, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) ISAVUCONAZONIUM
    a) No impairment of fertility was observed in male or female rats administered isavuconazonium 90 mg/kg/day (less than half the human maintenance dose based on AUC) (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of fluconazole, isavuconazonium, itraconazole, posaconazole, terconazole, or voriconazole.
    3.21.4) ANIMAL STUDIES
    A) FLUCONAZOLE
    1) RATS: An increased incidence of hepatocellular adenomas was observed in male rats administered oral fluconazole 5 and 10 mg/kg/day for 24 months (Prod Info DIFLUCAN(R) oral tablets, IV injection, oral suspension, 2008).
    B) ITRACONAZOLE
    1) RATS: The administration of oral itraconazole 25 mg/kg/day (3.1 times the maximum recommended human dose (MRHD)) in male rats resulted in a slightly increased incidence of soft tissue sarcoma, which may be attributable to hypercholesterolemia due to chronic itraconazole administration. This response has only been observed in rats, not in humans or dogs. A statistically nonsignificant increase in squamous cell carcinoma of the lung was reported in female rats administered oral itraconazole 50 mg/kg/day (approximately 6.25 times the MRHD) compared with untreated rats (Prod Info SPORANOX(R) oral solution, 2004; Prod Info SPORANOX(R) oral capsules, 2009; Prod Info SPORANOX(R) IV infusion, 2009).
    C) VORICONAZOLE
    1) MICE AND RATS: In 2-year carcinogenicity studies, hepatocellular adenomas were observed in mice administered oral voriconazole doses of 100 mg/kg (1.4 times the recommended maintenance dose (RMD) on a mg/m(2) basis) and in female rats administered 50 mg/kg (1.6 times the RMD on a mg/m(2) basis). Hepatocellular carcinomas were also reported in male rats administered oral voriconazole at doses of 6 and 50 mg/kg (0.2 and 1.6 times the RMD on a mg/m(2) basis) and male mice with doses of 100 mg/kg (1.4 times the RMD on a mg/m(2) basis) (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008).
    D) LACK OF EFFECT
    1) FLUCONAZOLE
    a) MICE AND RATS: Studies in rats and mice administered oral fluconazole 2.5, 5, or 10 mg/kg/day (approximately 2 to 7 times the recommended human dose) for 24 months produced no evidence of carcinogenic potential (Prod Info DIFLUCAN(R) oral tablets, IV injection, oral suspension, 2008).
    2) ITRACONAZOLE
    a) MICE: Studies in mice administered oral itraconazole at doses up to 80 mg/kg/day (approximately 10 times the recommended human dose) for 23 months produced no evidence of carcinogenic potential (Prod Info SPORANOX(R) oral solution, 2004; Prod Info SPORANOX(R) oral capsules, 2009; Prod Info SPORANOX(R) IV infusion, 2009).
    3) POSACONAZOLE
    a) MICE AND RATS: No evidence of drug-related neoplasms were observed in mice administered oral posaconazole at doses up to 60 mg/kg/day (4.8 times the human exposure with a 400-mg twice-daily regimen) or in male and female rats at doses up to 30 mg/kg and 20 mg/kg (3.5 and 3.9 times the human exposure with a 400-mg twice-daily regimen), respectively, over 2 years (Prod Info NOXAFIL(R) oral suspension, 2009).

Genotoxicity

    A) FLUCONAZOLE
    1) No evidence of chromosomal mutations were found in in vitro and in vivo cytogenetic studies with fluconazole. Mutagenicity was also negative in tests (mouse lymphoma, S. typhimurium) with fluconazole, with or without metabolic activation (Prod Info DIFLUCAN(R) oral tablets, IV injection, oral suspension, 2008).
    B) ISAVUCONAZONIUM
    1) Based on in vitro bacterial reverse mutation assay and in vivo bone marrow micronucleus assay in rats, isavuconazonium was not mutagenic or clastogenic (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    C) ITRACONAZOLE
    1) No mutagenic effects were reported with itraconazole in the following tests: DNA repair (unscheduled DNA synthesis) in primary rat hepatocytes; Ames (Salmonella typhimurium, Escherichia coli); mouse lymphoma gene mutation; sex-linked recessive lethal mutation (Drosophila melanogaster); chromosome aberration in human lymphocytes; cell transformation with mouse embryo fibroblasts cells; dominant lethal mutation in male and female mice; and micronucleus in mice and rats (Prod Info SPORANOX(R) oral solution, 2004; Prod Info SPORANOX(R) oral capsules, 2009; Prod Info SPORANOX(R) IV infusion, 2009).
    D) POSACONAZOLE
    1) The following tests produced no evidence of genotoxicity or clastogenicity with posaconazole: Ames, mouse bone marrow micronucleus, chromosome aberration in human peripheral blood lymphocytes, and Chinese hamster ovary cell mutagenicity (Prod Info NOXAFIL(R) oral suspension, 2009).
    E) TERCONAZOLE
    1) No mutagenic effects were noted with in vitro (for microbial point mutation (Ames test) or cellular transformation induction) or in vivo (for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ cells) testing of terconazole (Prod Info terconazole vaginal suppositories, 2004; Prod Info terconazole vaginal cream, 2004; Prod Info terconazole vaginal cream, 0.8%, 2003).
    F) VORICONAZOLE
    1) In vitro tests in human lymphocyte cultures showed clastogenic activity (primarily chromosome breaks) with voriconazole. No genotoxic effects were noted with voriconazole in the Ames, Chinese hamster ovary, or mouse micronucleus assays, or in the DNA repair test (unscheduled DNA synthesis) (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) In large overdoses, monitor serum electrolytes, liver enzymes, and complete blood count.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) LIVER ENZYMES: Elevation of serum transaminases has been observed during fluconazole therapy (Stern et al, 1988; Sugar & Saunders, 1988; Tucker et al, 1988; Cohen, 1989).
    a) When elevations of hepatic function tests are observed during fluconazole therapy, close monitoring is recommended to detect the development of more serious hepatic injury. Fluconazole should be discontinued in patients who develop signs and symptoms consistent with liver disease.
    2) POTASSIUM: It is suggested that serum potassium levels be monitored closely in patients with acute myeloid leukemia during oral fluconazole therapy (Kidd et al, 1989).
    B) HEMATOLOGIC
    1) A complete blood count should be monitored for possible thrombocytopenia and agranulocytosis.
    4.1.4) OTHER
    A) OTHER
    1) DERMAL
    a) Immunocompromised patients who develop skin rashes while on fluconazole should be monitored closely and the drug discontinued if the lesions progress.

Methods

    A) CHROMATOGRAPHY
    1) A high performance liquid chromatographic (HPLC) method for determining fluconazole in plasma and urine has been described (Wood & Tarbit, 1986; Debruyne et al, 1988; Ng et al, 1996).
    2) Liquid to liquid and solid phase extraction procedures followed by high performance liquid chromatographic methods were used for determining itraconazole in plasma and esophageal tissue (Poirier et al, 1994; Brandsteterova et al, 1995; Darouiche et al, 1995; Rifai et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain persistently symptomatic despite supportive management should be admitted for further observation and treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) In cases of acute unintentional ingestion, patients may be followed at home if they are asymptomatic.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patients with deliberate ingestion, very large ingestion, symptoms, or comorbidities should be referred to a health care facility for observation.

Monitoring

    A) In large overdoses, monitor serum electrolytes, liver enzymes, and complete blood count.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Most overdoses do not lead to toxicity. Prehospital gastrointestinal decontamination is generally not required.
    6.5.2) PREVENTION OF ABSORPTION
    A) Because most overdoses do not lead to toxicity, activated charcoal is typically not recommended.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Antiemetic medications and IV fluids can be used for gastrointestinal distress. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Severe toxicity is not expected after fluconazole (or related agents) overdose. There is no specific antidote.
    B) MONITORING OF PATIENT
    1) In large overdoses, monitor serum electrolytes, liver enzymes, and complete blood count.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) FLUCONAZOLE: Fluconazole has low protein binding and a small volume of distribution and could be removed by hemodialysis; however, this is not likely to be needed as toxicity is limited. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50% (Prod Info DIFLUCAN(R) IV injection oral suspension tablets, 2011).
    2) ITRACONAZOLE AND VORICONAZOLE: Hemodialysis is NOT LIKELY to be effective for itraconazole (Prod Info SPORANOX(R) oral solution, 2011; Prod Info ONMEL(TM) oral tablets, 2012) or voriconazole because they both have a large volume of distribution. However, in cases of overdose, hemodialysis may provide some assistance in the removal of VORICONAZOLE from the body. VORICONAZOLE is hemodialyzed with clearance of 121 mL/min while the IV vehicle, sulfobutyl ether beta-cyclodextrin sodium (SBECD), is hemodialyzed with clearance of 55 mL/min (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).
    3) POSACONAZOLE: Posaconazole is NOT REMOVED by hemodialysis (Prod Info NOXAFIL(R) oral suspension, 2012).

Range Of Toxicity

Summary

    A) TOXICITY: Maximal tolerated dose and minimal lethal human dose have not been determined. ITRACONAZOLE oral capsules have been tolerated up to 3000 mg daily. POSACONAZOLE oral suspension has been tolerated in clinical trials up to 1600 mg/day. One patient inadvertently ingested 1200 mg of posaconazole twice daily for 3 days without related adverse events. VORICONAZOLE: Pediatric patients tolerated doses up to 5 times the recommended IV dose.
    B) THERAPEUTIC DOSES: FLUCONAZOLE: ADULTS: Typical fluconazole doses are 100 mg to 400 mg daily depending on the route and underlying disease. PEDIATRIC: 3 mg to 12 mg/kg depending on age. ITRACONAZOLE: ADULTS: 200 mg to 400 mg daily. POSACONAZOLE: ADULTS: 100 mg to 800 mg daily. PEDIATRIC: 13 TO 18 YEARS OF AGE: 200 mg (5 mL) oral suspension 3 times a day. VORICONAZOLE: ADULTS: ORAL (suspension or tablet): 100 mg to 200 mg every 12 hours. IV: 4 mg/kg to 6 mg/kg every 12 hours. PEDIATRIC: 12 TO 18 YEARS OF AGE: LOADING DOSE: 6 mg/kg IV every 12 hours for 24 hours, then 4 mg/kg IV every 12 hours. MAINTENANCE DOSE: 200 mg orally every 12 hours for patients weighing over 40 kg; 100 mg every 12 hours for patients under 40 kg. The safety and efficacy in patients under 12 years of age have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) FLUCONAZOLE
    a) ORAL and INTRAVENOUS: The recommended dose is 50 to 400 mg/day. MAXIMUM DOSE: 400 mg/day (Prod Info DIFLUCAN(R) IV injection oral suspension tablets, 2011).
    2) ISAVUCONAZONIUM
    a) ORAL and INTRAVENOUS: The recommended initial loading dose is 372 mg every 8 hours for 48 hours (a total of 6 doses), and the recommended maintenance dose is 372 mg once daily, starting 12 to 24 hours after the last loading dose (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    3) ITRACONAZOLE
    a) INTRAVENOUS: The recommended dose is 200 mg twice daily for 4 doses, then once daily (administered over 1 hour) (Prod Info SPORANOX(R) IV infusion, 2009).
    b) ORAL CAPSULE: The recommended dose is 200 mg to 400 mg/day. MAXIMUM DOSE: 400 mg/day (Prod Info SPORANOX(R) oral capsules, 2015).
    c) ORAL SOLUTION: The recommended dose is 100 to 200 mg (10 to 20 mL) once daily. MAXIMUM DOSE: 200 mg (20 mL) once daily (Prod Info SPORANOX(R) oral solution, 2015).
    d) ORAL TABLETS: The recommended dose is 200 mg once daily for 12 weeks (Prod Info ONMEL(TM) oral tablets, 2012).
    4) POSACONAZOLE
    a) DELAYED-RELEASE TABLETS
    1) The recommended loading dose is 300 mg twice daily with food on the first day of treatment. The recommended maintenance dose is 300 mg once daily with food. Delayed-release tablets should not be divided, crushed, or chewed (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    b) INJECTION
    1) The recommended loading dose is 300 mg IV twice daily on the first day of treatment. The recommended maintenance dose is 300 mg IV once daily thereafter (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    c) ORAL SUSPENSION
    1) ORAL SUSPENSION: The recommended dose is 100 mg to 800 mg (2.5 to 20 mL) daily with a full meal or acidic carbonated beverage to aid absorption. The 600 mg and 800 mg daily dosages should be administered in divided doses (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    5) TERCONAZOLE
    a) CREAM, 0.4% or 0.8%; SUPPOSITORY: The recommended dose is 20 to 80 mg at bedtime (Prod Info TERAZOL(R) 7 vaginal cream, 2014; Prod Info TERAZOL(R) 3 vaginal cream, 2014; Prod Info TERAZOL(R) 3 vaginal suppositories, 2014).
    6) VORICONAZOLE
    a) INTRAVENOUS: Recommended dose: Loading dose: 6 mg/kg every 12 hours for 24 hours. Maintenance dose: 4 mg/kg every 12 hours for a minimum of 14 days (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).
    b) ORAL SUSPENSION or TABLET: Recommended dose: Maintenance Dose: 200 mg every 12 hours for patients weighing 40 kg or more; 100 mg every 12 hours for patients under 40 kg (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) FLUCONAZOLE
    a) PREMATURE NEWBORNS (GESTATIONAL AGE 26 TO 29 WEEKS): The recommended dose is 3 to 12 mg/kg ORALLY or IV every 72 hours. After 2 weeks, administer dose once daily (Prod Info DIFLUCAN(R) IV injection oral suspension tablets, 2011).
    b) 6 MONTHS TO 18 YEARS OF AGE: The recommended dose is 3 to 12 mg/kg/day ORALLY or IV. MAXIMUM DOSE: 12 mg/kg/day (400 mg/day)(Prod Info DIFLUCAN(R) IV injection oral suspension tablets, 2011).
    c) Doses up to 600 mg/day to 800 mg/day have been used in pediatric patients with severe fungal infections (Perfect et al, 2010; Centers for Disease Control and Prevention et al, 2009)
    2) ISAVUCONAZONIUM
    a) Safety and efficacy in pediatric patients have not been established (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    3) ITRACONAZOLE
    a) Safety and efficacy in pediatric patients have not been established (Prod Info SPORANOX(R) oral capsules, 2015; Prod Info SPORANOX(R) oral solution, 2015; Prod Info ONMEL(TM) oral tablets, 2012; Prod Info SPORANOX(R) IV infusion, 2009).
    4) POSACONAZOLE
    a) LESS THAN 13 YEARS OF AGE: The safety and efficacy in patients under 13 years of age have not been established (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    b) DELAYED-RELEASE TABLETS
    1) 13 to 17 YEARS OF AGE: The recommended loading dose is 300 mg twice daily with food on the first day of treatment. The recommended maintenance dose is 300 mg once daily with food (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    c) INJECTION
    1) Safety and efficacy in pediatric patients have not been established (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    d) ORAL SUSPENSION
    1) The recommended dose is 100 mg to 800 mg (2.5 to 20 mL) daily with a full meal or acidic carbonated beverage to aid absorption. The 600 mg and 800 mg daily dosages should be administered in divided doses (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014).
    5) TERCONAZOLE
    a) Safety and efficacy in pediatric patients have not been established (Prod Info TERAZOL(R) 7 vaginal cream, 2014; Prod Info TERAZOL(R) 3 vaginal cream, 2014; Prod Info TERAZOL(R) 3 vaginal suppositories, 2014).
    6) VORICONAZOLE
    a) LESS THAN 12 YEARS OF AGE: The safety and efficacy in patients under 12 years of age have not been established (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).
    b) 12 TO 18 YEARS OF AGE: LOADING DOSE: 6 mg/kg IV every 12 hours for 24 hours, then 4 mg/kg IV every 12 hours. MAINTENANCE DOSE: 200 mg orally every 12 hours for patients weighing over 40 kg; 100 mg every 12 hours for patients under 40 kg (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).

Minimum Lethal Exposure

    A) The minimum lethal exposure has not been defined.

Maximum Tolerated Exposure

    A) The maximum tolerated dose has not been defined.
    B) ITRACONAZOLE: Itraconazole capsules have been tolerated up to 3000 mg daily (Prod Info SPORANOX(R) IV infusion, 2009).
    C) POSACONAZOLE: In clinical studies, patients tolerated doses of posaconazole oral suspension up to 1600 mg/day without experiencing adverse reactions differing from those at lower doses. One patient inadvertently ingested 1200 mg of posaconazole twice daily for 3 days without related adverse events (Prod Info NOXAFIL(R) oral suspension, 2012).
    D) VORICONAZOLE: During clinical studies involving 3 pediatric cases, patients tolerated doses of voriconazole up to 5 times the recommended IV dose. One event of photophobia lasting 10 minutes was reported (Prod Info VFEND(R) oral tablets, oral suspension, intravenous injection, 2011).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) THERAPEUTIC SERUM LEVELS have not been established.
    2) FLUCONAZOLE: In one study, clinical and microbiological response was observed in patients with cryptococcal meningitis and extraneural infection with serum levels ranging from 6.5 to 15.1 mcg/mL following at least one week of treatment with 100 mg daily. Corresponding cerebrospinal fluid levels ranged from 2.6 to 10.5 mcg/mL (Stern et al, 1988).
    3) FLUCONAZOLE: The minimum inhibitory concentration for Cryptococcus neoformans has ranged from 3 to 6.25 mcg/mL in some reports (Perfect et al, 1986), and similar levels of fluconazole are generally maintained in serum with daily oral doses of 100 mg after a loading dose of 200 mg (van ''t Wout et al, 1988). Further investigations are necessary to determine optimal therapeutic levels in cerebrospinal fluid and serum.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) This group of drugs are triazole antifungal agents which are related to the imidazole ketoconazole (Saag & Dismukes, 1988). These drugs are water soluble (Dudley, 1990) and are effective orally and intravenously for a variety of fungal infections, especially cryptococcosis in acquired immunodeficiency syndrome patients (Walsh & Pizzo, 1988; Stevens, 1988; Sugar & Saunders, 1988).
    B) The mechanism of action of these drugs is similar to that of other imidazole and triazole antifungal agents, specifically, inhibition of cytochrome P-450-dependent ergosterol synthesis, mediated via 14-alpha-sterol demethylase (Stevens, 1988; Dudley, 1990).
    1) These agents appear to have greater selectivity for fungal as compared to human P-450 enzymes, and produces less blockade of human steroid synthesis than ketoconazole (Tucker et al, 1988; Stevens, 1988).

Physicochemical

Physical Characteristics

    A) FLUCONAZOLE: White crystalline solid that is slightly soluble in saline and water (Prod Info DIFLUCAN(R) oral tablets, intravenous injection, oral suspension, 2013).
    B) ISAVUCONAZONIUM SULFATE: White to yellowish-white powder that is soluble in water (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015).
    C) ITRACONAZOLE: White to slightly yellowish powder that is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane (Prod Info ONMEL(TM) oral tablets, 2012).
    D) POSACONAZOLE: White powder that is insoluble in water (Prod Info NOXAFIL(R) oral suspension, 2013).
    E) TERCONAZOLE: White to almost white powder that is soluble in butanol, sparingly soluble in ethanol, and insoluble in water (Prod Info TERAZOL(R) 3 vaginal suppositories, 2013).
    F) VORICONAZOLE: White to light-colored powder (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008).

Ph

    A) FLUCONAZOLE: 3.5 to 6.5 (injection, dextrose diluent); 4 to 8 (injection, sodium chloride diluent) (Prod Info DIFLUCAN(R) oral tablets, intravenous injection, oral suspension, 2013)
    B) ITRACONAZOLE: 4.5 (injection) (Prod Info SPORANOX(R) IV infusion, 2009)
    C) POSACONAZOLE: 2.6 (injection) (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014)

Molecular Weight

    A) FLUCONAZOLE: 306.3 (Prod Info DIFLUCAN(R) oral tablets, intravenous injection, oral suspension, 2013)
    B) ISAVUCONAZONIUM SULFATE: 814.84 (Prod Info CRESEMBA(R) oral capsules, intravenous injection, 2015)
    C) ITRACONAZOLE: 705.64 (Prod Info ONMEL(TM) oral tablets, 2012)
    D) POSACONAZOLE: 700.8 (Prod Info Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, 2014)
    E) TERCONAZOLE: 532.47 (Prod Info TERAZOL(R) 3 vaginal suppositories, 2013)
    F) VORICONAZOLE: 349.3 (Prod Info VFEND(R) IV injection, oral tablets, suspension, 2008)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Ahmad SR, Singer SJ, & Leissa BG: Congestive heart failure associated with itraconazole (letter). Lancet 2001; 357:1766-1767.
    3) Alderman CP & Allcroft PD: Digoxin-itraconazole interaction: possible mechanisms. Ann Pharmacother 1997; 31:438-440.
    4) Anon: FDA Talk Paper: FDA issues health advisory regarding the safety of Sporanox(R) products and Lamisil(R) tablets to treat fungal nail infections. U.S. Food and Drug Administration. Rockville, MD, USA. 2001. Available from URL: http://www.fda.gov/bbs/topics/answers/2001/ans01083.html. As accessed Accessed May 9, 2001.
    5) Anon: Multicentre Study Group. Treatment of vaginal candidiasis with a single oral dose of fluconazole. Eur J Clin Microbiol Infect Dis 1988; 7:364-367.
    6) Arndt CA, Walsh TJ, & McCully C: Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis 1988; 157:178-180.
    7) Azon-Masoliver A & Vilaplana J: Fluconazole-induced toxic epidermal necrolysis in a patient with human immunodeficiency virus infection. Dermatol 1993; 187:268-269.
    8) Bar-Oz B, Moretti ME, Bishai R, et al: Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol 2000; 183:617-620.
    9) Bohme A, Ganser A, & Hoelzer D: Aggravation of vincristine-induced neurotoxicity by itraconazole in the treatment of adult ALL. Ann Hematol 1995; 71:311-312.
    10) Brandsteterova E, Kubalec P, & Rady A: Determination of itraconazole and its metabolite in plasma using SPE-HPLC. Pharmazie 1995; 50:597-599.
    11) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    12) Budtz-Jorgensen E, Holmstrup P, & Krogh P: Fluconazole in the treatment of Candida-associated denture stomatitis. Antimicrob Agents Chemother 1988; 32:1859-1863.
    13) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    14) Cadle RM, Zenon GJ, & Rodriguez-Barradas MC: Fluconazole-induced symptomatic phenytoin toxicity. Ann Pharmacother 1994; 28:191-195.
    15) Capone D, Gentile A, & Imperatore P: Effects of itraconazole on tacrolimus blood concentrations in a renal transplant recipient (letter). Ann Pharmacother 1999; 33:1124-1125.
    16) Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America, et al: Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children. Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep 2009; 58(RR11):1-166.
    17) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    18) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    19) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    20) Cleveland KO & Campbell JW: Hallucinations associated with itraconazole therapy (letter). CID 1995; 21:456.
    21) Cohen J: Treatment of systemic yeast infection with fluconazole. J Antimicrob Chemother 1989; 23:294-295.
    22) Collignan P, Hurley B, & Mitchell D: Interaction of fluconazole with cyclosporin. Lancet 1989; 1:1262.
    23) Courtney R, Wexler D, Radwanski E, et al: Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2003; 57(2):218-222.
    24) Crane JK & Shih HT: Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine. Amer J Med 1993; 95:445-446.
    25) Crerar-Gilbert A, Boots R, Fraenkel D, et al: Survival following fulminant hepatic failure from fluconazole induced hepatitis. Anaesth Intensive Care 1999; 27:650-652.
    26) Darouiche RO, Setoodeh A, & Anaissie EJ: Potential use of a simplified method for determination of itraconazole levels in plasma and esophageal tissue by using high-performance liquid chromatography. Antimicrob Agents and Chemother 1995; 39:757-759.
    27) De Santis M, Di Gianantonio E, Cesari E, et al: First-trimester itraconazole exposure and pregnancy outcome: a prospective cohort study of women contacting teratology information services in Italy. Drug Saf 2009; 32(3):239-244.
    28) Debruyne D, Ryckelynck JP, & Bigot MC: Determination of fluconazole in biological fluids by capillary column gas chromatography with a nitrogen detector. J Pharm Sci 1988; 77:534-535.
    29) Devenport MH, Crook D, & Wynn V: Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives. Br J Clin Pharmacol 1989; 27:851-859.
    30) Drayton J, Dickinson G, & Rinaldi MG: Coadministration of rifampin and itraconazole leads to undetectable levels of serum itraconazole. CID 1994; 18:266.
    31) Drew RH, Perfect JR, & Gallis HA: Use of fluconazole in a patient with documented malabsorption of ketoconazole. Clin Pharm 1988; 7:622-623.
    32) Ducharme MP, Slaughter RL, & Warbasse LH: Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin. Clin Pharmacol Ther 1995; 58:617-624.
    33) Dudley MN: Clinical pharmacology of fluconazole. Pharmacotherapy 1990; 10:141S-145S.
    34) Ebden P, Neill P, & Farrow PR: Sputum levels of fluconazole in humans. Antimicrob Agents Chemother 1989; 33:963-964.
    35) Eiden C , Palenzuela G , Hillaire-Buys D , et al: Posaconazole-increased vincristine neurotoxicity in a child: a case report. J Pediatr Hematol Oncol 2009; 31(4):292-295.
    36) Feola D & Rapp RP: Effect of food intake on the bioavailability of itraconazole (letter). CID 1997; 25:344-345.
    37) Force WR: Fluconazole concentrations in breast milk. Pediatr Infect Dis J 1995; 14(3):235-236.
    38) Foulds G, Brennan DR, & Wajszczuk C: Fluconazole penetration into cerebrospinal fluid in humans. J Clin Pharmacol 1988; 28:363-366.
    39) Foulds G, Wajszczuk C, & Weidler DJ: Steady state parenteral kinetics of fluconazole in man. Ann N Y Acad Sci 1988a; 544:427-430.
    40) Gallardo-Quesada S, Luelmo-Aquilar J, & Guanyabens-Calvet C: Hepatotoxicity associated with itraconazole (letter). Intl J Dermatol 1995; 34:589.
    41) Gannon RH: Fluconazole-nortriptyline drug interaction (letter). Ann Pharmacother 1992; 26:1456-1457.
    42) Gillies J, Hung KA, & Fitzsimons E: Severe vincristine toxicity in combination with itraconazole. Clin Lab Haem 1998; 20:123-124.
    43) Gunther J, Lode H, & Raffenberg M: Development of pleural and pericardial effusions during itraconazole therapy of pulmonary aspergillosis. Eur J Clin Microbiol Infect Dis 1993; 12:723-724.
    44) Hanger DP, Jevons S, & Shaw JTB: Fluconazole and testosterone: in vivo and in vitro studies. Antimicrob Agents Chemother 1988a; 32:646-648.
    45) Hanger DP, Jevons S, & Shaw JTB: Fluconazole and testosterone: in vivo and in vitro studies. Antimicrob Agents Chemother 1988; 32(5):646-648.
    46) Hann SK, Kim JB, & IM S: Itraconazole-induced acute hepatitis (letter). Br J Dermatol 1993; 129:500-501.
    47) Haria M, Bryson HM, & Goa KL: Itraconazole: a reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections. Drugs 1996; 51:585-620.
    48) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    49) Heymann WR & Manders SM: Itraconazole-induced acute generalized exanthemic pustulosis. J Amer Acad Dermatol 1995; 33:130-131.
    50) Hirsch HA: Clinical evaluation of terconazole: European experience. J Reprod Med 1989; 34(Suppl):593-596.
    51) Horst HA, Parwaresch R, & Loffler H: Thrombocytopenia and leukopenia associated with itraconazole (letter). Ann Int Med 1996; 125:156-157.
    52) Humphrey MJ, Jevons S, & Tarbit MH: Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal agent, in animals and humans. Antimicrob Agents Chemother 1985; 28:648-653.
    53) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    54) Jacobson MA, Hanks DK, & Ferrell LD: Fatal acute hepatic necrosis due to fluconazole. Am J Med 1994; 96:188-190.
    55) Jalava KM, Partanen J, & Neuvonen PJ: Itraconazole decreases renal clearance of digoxin. Ther Drug Monitor 1997; 19:609-613.
    56) Jick & S: Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy 1999; 19(2):221-222.
    57) Kaukonen KM, Olkkola KT, & Neuvonen PJ: Itraconazole increases plasma concentrations of quinidine. Clin Pharmacol Ther 1997; 62:510-517.
    58) Kidd D, Ranaghan EA, & Morris TCM: Hypokalemia in patients with acute myeloid leukemia after treatment with fluconazole (letter). Lancet 1989; 1:1017.
    59) Kivisto KT, Lamberg TS, & Kantola T: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. Clin Pharmacol Ther 1997; 62:348-354.
    60) Kowalsky SF: Drug interactions with fluconazole. Pharmacotherapy 1990; 10:170S-173S.
    61) Kramer KE, Yaar M, & Andersen W: Purpuric drug eruption secondary to itraconazole. J Amer Acad Dermatol 1997; 37:994-995.
    62) Lees RS & Lees AM: Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole (letter). N Eng J Med 1995; 333:664-665.
    63) Lefort A, Launay O, & Carbon C: Uveitis associated with rifabutin prophylaxis and itraconazole therapy (letter). Ann Int Med 1996; 125:939-940.
    64) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    65) Lopez-Gil JA: Fluconazole-cyclosporine interaction: a dose-dependent effect?. Ann Pharmacother 1993; 27:427-430.
    66) Lukkari E, Juhakoski A, & Aranko K: Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite. Eur J Clin Pharmacol 1997; 52:403-406.
    67) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    68) Martinez-Alonso JC, Dominguez-Ortega FJ, & Fuentes-Gonzalo MJ: Urticaria and angioedema due to itraconazole. Allergy 2003; 58(12):1317-1318.
    69) Mastroiacovo P, Mazzone T, Botto LD, et al: Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 1996; 175(6):1645-1650.
    70) Mercurio MG & Elewski BE: Thrombocytopenia caused by fluconazole therapy. J Am Acad Dermatol 1995; 32:525-526.
    71) Meyboom RH, van Puijenbroek EP, & Vinks MH: Disturbance of withdrawal bleeding during concomitant use of itraconazole and oral contraceptives. N Zeal Med J 1997; 110:300.
    72) Mitchell AS & Holland JT: Fluconazole and phenytoin: a predictable interaction. Br Med J 1989; 298:1315.
    73) Mittal D & Wikaitis J: Itraconazole-induced delirium (letter). Psychosomatics 2003; 44(3):260-261.
    74) Molgaard-Nielsen D, Pasternak B, & Hviid A: Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med 2013; 369(9):830-839.
    75) Molgaard-Nielsen D, Svanstrom H, Melbye M, et al: Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA 2016; 315(1):58-67.
    76) Morgan JM & Carmichael AJ: Fixed drug eruption with fluconazole (letter). Br Med J 1994; 308:454.
    77) Murakami H, Katahira H, & Matsushima T: Agranulocytosis during treatment with fluconazole. J Intl Med Res 1992; 20:492-494.
    78) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    79) Negroni R & Arechavala AI: Itraconazole: pharmacokinetics and indications. Arch Med Res 1993; 24:387-393.
    80) Neuvonen PJ & Jalava KM: Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60:54-61.
    81) Neuvonen PJ & Suhonen R: Itraconazole interacts with felodipine. J Amer Acad Dermatol 1995; 33:134-135.
    82) Ng TKC, Chan RCY, & Adeyemi-Doro FAB: Rapid high performance liquid chromatographic assay for antifungal agents in human sera. J Antimicrob Chemother 1996; 37:465-472.
    83) Norgaard M, Pedersen L, Gislum M, et al: Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother 2008; 62(1):172-176.
    84) Olkkola KT, Ahonen J, & Neuvonen PJ: The effect of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996; 82:511-516.
    85) Olkkola KT, Backman JT, & Neuvonen PJ: Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55:481-485.
    86) Pappas PG, Kauffman CA, & Perfect J: Alopecia associated with fluconazole therapy. Ann Int Med 1995; 123:354-357.
    87) Park H, Knowles S, & Shear NH: Serum sickness-like reaction to itraconazole (letter). Ann Pharmacother 1998; 32:1249-1250.
    88) Park YM, Kim JW, & Kim CW: Acute generalized exanthemous pustulosis induced by itraconazole. J Amer Acad Dermatol 1997; 36:794-796.
    89) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    90) Perfect JR, Dismukes WE, Dromer F, et al: Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50(3):291-322.
    91) Perfect JR, Savani DV, & Durack DT: Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother 1986; 29:579-583.
    92) Pillans PI & Sparrow MJ: Pregnancy associated with a combined oral contraceptive and itraconazole. N Zeal Med J 1993; 106:436.
    93) Poirier JM, Lebot M, & Descamps P: Determination of itraconazole and its active metabolite in plasma by column liquid chromatography. Ther Drug Monitor 1994; 16:596-601.
    94) Product Information: CRESEMBA(R) oral capsules, intravenous injection, isavuconazonium sulfate oral capsules, intravenous injection. Astellas Pharma US (per FDA), Northbrook, IL, 2015.
    95) Product Information: DIFLUCAN(R) IV injection oral suspension tablets, fluconazole IV injection oral suspension tablets. Roerig (per FDA), New York, NY, 2011.
    96) Product Information: DIFLUCAN(R) oral tablets, IV injection, oral suspension, fluconazole oral tablets, IV injection, oral suspension. Pfizer Inc, New York, NY, 2008.
    97) Product Information: DIFLUCAN(R) oral tablets, intravenous infusion, oral suspension, fluconazole oral tablets, intravenous infusion, oral suspension. Roerig (per FDA), New York, New York, 2011.
    98) Product Information: DIFLUCAN(R) oral tablets, intravenous injection, oral suspension, fluconazole oral tablets, intravenous injection, oral suspension. Roerig (per FDA), New York, NY, 2013.
    99) Product Information: Diflucan(R), fluconazole. Roerig Division Pfizer Inc, New York, NY, 1995.
    100) Product Information: NOXAFIL(R) oral suspension, posaconazole oral suspension. Schering Corporation, Kenilworth, NJ, 2006.
    101) Product Information: NOXAFIL(R) oral suspension, posaconazole oral suspension. Merck Sharp & Dohme Corp. (per manufacturer), Whitehouse Station, NJ, 2013.
    102) Product Information: NOXAFIL(R) oral suspension, posaconazole oral suspension. Schering Corporation (per FDA), Whitehouse Station, NJ, 2012.
    103) Product Information: NOXAFIL(R) oral suspension, posaconazole oral suspension. Schering Plough, Kenilworth, NJ, 2009.
    104) Product Information: Noxafil(R) oral delayed-release tablets, oral suspension , posaconazole oral delayed-release tablets, oral suspension. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013.
    105) Product Information: Noxafil(R) oral delayed-release tablets, oral suspension, intravenous injection, posaconazole oral delayed-release tablets, oral suspension, intravenous injection. Merck Sharp & Dohme Corp. (per manufacturer), Whitehouse Station, NJ, 2014.
    106) Product Information: ONMEL(TM) oral tablets, itraconazole oral tablets. Stiefel Laboratories, Inc. (per DailyMed), Research Triangle Park, NC, 2012.
    107) Product Information: SPORANOX(R) IV infusion, itraconazole IV infusion. Ortho Biotech Products, LP, Raritan, NJ, 2009.
    108) Product Information: SPORANOX(R) oral capsules, itraconazole oral capsules. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2015.
    109) Product Information: SPORANOX(R) oral capsules, itraconazole oral capsules. PriCara, Raritan, NJ, 2009.
    110) Product Information: SPORANOX(R) oral solution, itraconazole oral solution. Ortho Biotech Products,LP, Raritan, NJ, 2004.
    111) Product Information: SPORANOX(R) oral solution, itraconazole oral solution. Centocor Ortho Biotech Products, L.P. (per DailyMed), Raritan, NJ, 2011.
    112) Product Information: SPORANOX(R) oral solution, itraconazole oral solution. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2015.
    113) Product Information: TERAZOL(R) 3 vaginal cream, terconazole 0.8% vaginal cream. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2014.
    114) Product Information: TERAZOL(R) 3 vaginal suppositories, terconazole vaginal suppositories. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2013.
    115) Product Information: TERAZOL(R) 3 vaginal suppositories, terconazole vaginal suppositories. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2014.
    116) Product Information: TERAZOL(R) 7 vaginal cream, terconazole 0.4% vaginal cream. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2014.
    117) Product Information: VFEND(R) IV injection, oral tablets, oral suspension, voriconazole IV injection, oral tablets, oral suspension. Pfizer,Inc, New York, NY, 2008.
    118) Product Information: VFEND(R) IV injection, oral tablets, suspension, voriconazole IV injection, oral tablets, solution. Roerig, New York, NY, 2008.
    119) Product Information: VFEND(R) oral tablets, oral suspension, intravenous injection, voriconazole oral tablets, oral suspension, intravenous injection. Roerig(per FDA), New York, NY, 2011.
    120) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    121) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    122) Product Information: terconazole vaginal cream, 0.8%, terconazole vaginal cream, 0.8%. E Fougera & Co, Melville, NY, 2003.
    123) Product Information: terconazole vaginal cream, terconazole vaginal cream. Taro Pharmaceuticals, Hawthorne, NY, 2004.
    124) Product Information: terconazole vaginal suppositories, terconazole vaginal suppositories. Clay-Park Labs,Inc, Bronx, NY, 2004.
    125) Pursley T, Blomquist I, Abraham J, et al: Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996; 22:336-340.
    126) Rifai N, Sakamoto M, & Platt O: A high-performance liquid chromatographic assay for the determination of itraconazole concentration using solid-phase extraction and small sample volume. Ther Drug Monitor 1995; 17:522-525.
    127) Rosen T: Debilitating edema associated with itraconazole therapy. Arch Dermatol 1994; 130:260-261.
    128) Saag M & Dismukes WE: Azole antifungal agents: emphasis on new triazoles. Antimicrob Agents Chemother 1988; 32:1-8.
    129) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    130) Segaert MF, De Soete C, & Vandewiele I: Drug-interaction-induced rhabdomyolysis. Nephrol Dial Transplant 1996; 11:1846-1847.
    131) Sintonen SP, Viitasalo M, & Toivonen L: Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993; 45:191-193.
    132) Sorensen HT, Nielsen GL, Olesen C, et al: Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 1999; 48(2):234-238.
    133) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    134) Stern JJ, Hartman BJ, & Sharkey P: Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med 1988; 85:477-480.
    135) Stern JJ, Hartman BJ, Sharkey P, et al: Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients.. Am J Med 1988a; 85:477-480.
    136) Stevens DA: The new generation of antifungal drugs (editorial). Eur J Clin Microbiol Infect Dis 1988; 7:732-735.
    137) Sugar AM & Saunders C: Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med 1988; 85:481-489.
    138) Sugar AM & Saunders C: Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome.. Am J Med 1988a; 85:481-488.
    139) Tailor SAN, Gupta AK, & Walker SE: Peripheral edema due to nifedipine- itraconazole interaction: a case report. Arch Dermatol 1996; 132:350-352.
    140) Trujillo MA, Galgiani JN, & Sampliner RE: Evaluation of hepatic injury arising during fluconazole therapy. Arch Intern Med 1994; 154:102-104.
    141) Tuccori M, Bresci F, Guidi B, et al: Fatal hepatitis after long-term pulse itraconazole treatment for onychomycosis. Ann Pharmacother 2008; 42(7):1112-1117.
    142) Tucker RM, Williams PL & Levine BE et al: Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis (abstract 777). Proc of 27th Intersci Conf on Antimicrob Agents Chemother, 1987.
    143) Tucker RM, Williams PL, & Arathoon EG: Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother 1988; 32:369-373.
    144) Tucker RM, Williams PL, Arathoon EG, et al: Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother 1988a; 32:369-373.
    145) US Food and Drug Administration: FDA Drug Safety Communication: FDA to review study examining use of oral fluconazole (Diflucan) in pregnancy. US Food and Drug Administration. Silver Spring, MD. 2016. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm497482.htm. As accessed 2016-04-26.
    146) Varhe A, Olkkola KT, & Neuvonen PJ: Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 56:601-607.
    147) Walsh TJ & Pizzo A: Treatment of systemic fungal infections: Recent progress and current problems. Eur J Clin Microbiol Infect Dis 1988; 7:460-475.
    148) Weinroth SE & Tuazon CU: Alopecia associated with fluconazole treatment (letter). Ann Int Med 1993; 119:637.
    149) Wells C & Lever AML: Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenge (letter). J Infection 1992; 24:111-112.
    150) Wiesinger EC, Mayerhofer S, Wenisch C, et al: Fluconazole in Candida albicans sepsis during pregnancy: case report and review of the literature. Infection 1996; 24(3):263-266.
    151) Wilton LV, Pearce GL, Martin RM, et al: The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998; 105:882-889.
    152) Wolf R, Wolf D, & Kuperman S: Focal nodular hyperplasia of the liver after intraconazole treatment. J Clin Gastroenterol 2001; 33:418-420.
    153) Wood PR & Tarbit MH: Gas chromatographic method of the determination of fluconazole, a novel antifungal agent, in human plasma and urine. J Chromatogr 1986; 383:179-186.
    154) van ''t Wout JW, de Graeff-Meeder ER, & Paul LC: Treatment of two cases of cryptococcal meningitis with fluconazole. Scand J Infect Dis 1988; 20:193-198.