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KETOCONAZOLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ketoconazole is a broad-spectrum imidazole antifungal agent that interferes with ergosterol synthesis, altering the permeability of the cell membrane of susceptible fungi. Ketoconazole is believed to be fungistatic at therapeutic concentrations.

Specific Substances

    1) Ketoconazolum
    2) R 41400
    3) CAS 65277-42-1
    1.2.1) MOLECULAR FORMULA
    1) C26H28Cl2N4O4

Available Forms Sources

    A) FORMS
    1) Ketoconazole is available as:
    a) 200-mg tablets (Prod Info ketoconazole oral tablets, 2004)
    b) 2% cream (Prod Info ketoconazole cream, 2002)
    c) 1% and 2% shampoo (Prod Info NIZORAL(R) topical application shampoo, 2009)
    d) 2% topical foam (Prod Info EXTINA(R) topical foam, 2007)
    e) 2% topical gel/jelly (Prod Info XOLEGEL(R) topical gel, 2010a)
    B) USES
    1) Ketoconazole tablets are indicated for the treatment of various systemic fungal infections, including candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis (Prod Info ketoconazole oral tablets, 2004).
    2) Ketoconazole 2% cream and shampoo are indicated for tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare) (Prod Info NIZORAL(R) topical application shampoo, 2009; Prod Info ketoconazole cream, 2002).
    3) Ketoconazole 2% cream, gel, and foam are indicated for the treatment of seborrheic dermatitis (Prod Info XOLEGEL(R) topical gel, 2010a; Prod Info EXTINA(R) topical foam, 2007; Prod Info ketoconazole cream, 2002).

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: Ketoconazole tablets are indicated for the treatment of various systemic fungal infections, including candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole 2% cream and shampoo are indicated for tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare). Ketoconazole 2% cream, gel, and foam are indicated for the treatment of seborrheic dermatitis.
    B) PHARMACOLOGY: Ketoconazole is a broad-spectrum imidazole antifungal agent that interferes with ergosterol synthesis, altering the permeability of the cell membrane of susceptible fungi. Ketoconazole is believed to be fungistatic at therapeutic concentrations.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects following therapeutic use have been reported: nausea, vomiting, abdominal pain, diarrhea, hypertension, dizziness, tinnitus, headache, confusion, myopathy, weakness, contact dermatitis, acute generalized exanthematous pustulosis, papilledema, severe hypersensitivity reactions, including anaphylactic reactions, gynecomastia, adrenal suppression, suppression of androgen synthesis, thrombocytopenia, hemolytic anemia, hepatitis, hepatocellular necrosis, and fatal hepatic failure. Ketoconazole is a strong inhibitor of cytochrome P450 3A4.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Headache, fatigue, and tinnitus have occurred following acute overdose.
    0.2.20) REPRODUCTIVE
    A) Ketoconazole is classified as FDA pregnancy category C. Teratogenicity (ie, syndactylia and oligodactylia), embryotoxicity, maternal toxicity, and dystocia have been observed in rats given oral ketoconazole, possibly due to the sensitivity of female rats to the drug. Ketoconazole has been shown to be present in human milk. It is recommended that mothers being treated with oral ketoconazole should not breast-feed. However, it is not known whether topical ketoconazole is systemically absorbed in sufficient quantities to produce detectable levels in breast milk. Ketoconazole impaired the reproductive performance of male and female rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any human carcinogenic potential.

Laboratory Monitoring

    A) Monitor vital signs, liver enzymes, and CBC with platelet count in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

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 vomiting or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors, and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Serious toxicity is not expected after ingestion of ketoconazole alone, and prehospital gastrointestinal decontamination is not routinely required.
    2) HOSPITAL: Significant toxicity is not expected after overdose; gastrointestinal decontamination is generally not necessary.
    D) AIRWAY MANAGEMENTS
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reaction.
    E) ANTIDOTE
    1) None.
    F) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE effects: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids, or epinephrine. SEVERE Effects: Administer oxygen; aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of ketoconazole.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent ingestion, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.
    3) ADMISSION CRITERIA: Hospital admission is rarely necessary. Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) If severe toxicity develops the diagnosis should be reconsidered. When managing a suspected ketoconazole overdose, the possibility of multi-drug involvement should be considered.
    J) PHARMACOKINETICS
    1) Tmax: Oral, 1 to 4 hours; oral bioavailability: 75%; topical: negligible systemic absorption. Protein binding: oral, 91% to 99%. The imidazole and piperazine rings of ketoconazole are oxidized and degraded by hepatic microsomal enzymes. Oxidative O-dealkylation and aromatic hydroxylation also occur. Renal excretion: 13%. Elimination half-life: 2 to 12 hours.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. THERAPEUTIC DOSE: ADULTS: ORAL: 200 to 400 mg once daily. In investigational high-dose studies, up to 1600 mg/day doses were also used. CHILDREN: 2 TO 18 YEARS OF AGE: Single daily dose of 3.3 to 6.6 mg/kg.

Clinical Effects

Summary Of Exposure

    A) USES: Ketoconazole tablets are indicated for the treatment of various systemic fungal infections, including candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole 2% cream and shampoo are indicated for tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare). Ketoconazole 2% cream, gel, and foam are indicated for the treatment of seborrheic dermatitis.
    B) PHARMACOLOGY: Ketoconazole is a broad-spectrum imidazole antifungal agent that interferes with ergosterol synthesis, altering the permeability of the cell membrane of susceptible fungi. Ketoconazole is believed to be fungistatic at therapeutic concentrations.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects following therapeutic use have been reported: nausea, vomiting, abdominal pain, diarrhea, hypertension, dizziness, tinnitus, headache, confusion, myopathy, weakness, contact dermatitis, acute generalized exanthematous pustulosis, papilledema, severe hypersensitivity reactions, including anaphylactic reactions, gynecomastia, adrenal suppression, suppression of androgen synthesis, thrombocytopenia, hemolytic anemia, hepatitis, hepatocellular necrosis, and fatal hepatic failure. Ketoconazole is a strong inhibitor of cytochrome P450 3A4.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Headache, fatigue, and tinnitus have occurred following acute overdose.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) PAPILLEDEMA: A 29-year-old woman was given ketoconazole, 800 mg per day, to treat hirsutism. Four months later, she developed papilledema. The ketoconazole was discontinued and the papilledema resolved after 3 months. Six months later, 600 mg per day of ketoconazole therapy was resumed. The papilledema recurred after 2 months of therapy. Again, the ketoconazole was discontinued and the papilledema completely resolved in 3 months (Or et al, 1993).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension may occur, especially with high doses (Aabo & De Coster, 1987).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in less than 1% of patients (Prod Info ketoconazole oral tablets, 2004).
    B) TINNITUS
    1) WITH THERAPEUTIC USE
    a) Tinnitus has been reported (Graybill et al, 1980; Borelli, 1980; Welsh et al, 1980; Welsh & Rodriguez, 1980).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Tinnitus was reported in a 36-year-old man who ingested a "handful" of ketoconazole and zidovudine tablets. Spontaneous emesis occurred; at 24 hours postingestion, the tinnitus resolved (Gorman et al, 1995; Gorman et al, 1992).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported as an adverse effect in less than 1% of patients (Prod Info ketoconazole oral tablets, 2004).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Headache was reported in a 36-year-old man who ingested a "handful" of ketoconazole and zidovudine tablets. Spontaneous emesis occurred; at 24 hours postingestion, the headache resolved (Gorman et al, 1995; Gorman et al, 1992).
    D) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Mental confusion has been reported in a patient receiving 1200 mg/day (Personal Communication, 1989).
    E) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Fatigue was reported in a 36-year-old man who ingested a "handful" of ketoconazole and zidovudine tablets. Spontaneous emesis occurred; at 24 hours postingestion, the patient remained fatigued (Gorman et al, 1995; Gorman et al, 1992).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are the most frequent adverse reactions to ketoconazole, and have been reported in 3% of patients receiving the drug (Prod Info ketoconazole oral tablets, 2004).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been noted in less than 1% of patients (Prod Info ketoconazole oral tablets, 2004).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been noted in 1.2% of patients treated with ketoconazole (Prod Info ketoconazole oral tablets, 2004).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Hepatotoxic effects have been observed with therapeutic use (Svedhem, 1984; Tkach & Rinaldi, 1982; Petersen et al, 1980) .
    b) The hepatotoxic potential of ketoconazole is well documented. The toxicity is usually hepatocellular but may be cholestatic or both, and is usually reversible upon discontinuation of the drug (Gasior-Chrzan et al, 1991; Tabor, 1985).
    c) CASE REPORT: A 45-year-old woman developed fulminant hepatitis after 2 months of ketoconazole therapy, 200 mg per day, to treat candidal onychomycosis. Liver failure ensued during the third week of illness and the patient underwent liver transplantation (Knight et al, 1991).
    d) CASE REPORT: An article reported a case of a patient who developed hepatotoxicity after taking ketoconazole 200 mg per day for a month. The hepatotoxicity lasted for several months and continued to worsen, indicating a possible need for a liver transplant (Brusko & Marten, 1991).
    1) It is important to note that the patient described by Brusko and Marten (1991) had also been taking acetaminophen when she was admitted to the hospital. It is possible that the acetaminophen contributed to the progression of the hepatotoxicity.
    B) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Five cases of hepatic damage associated with chronic therapeutic administration of ketoconazole, 400 mg/day have been reported. Cholestasis was the primary finding in 4 of the 5 patients. Two of the 5 patients died, 1 who developed massive necrosis with fulminant liver failure and the other who developed submassive necrosis. Both patients had continued taking ketoconazole despite the onset of hepatic symptoms (Findor et al, 1998).
    C) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 14-year-old girl with Cushing syndrome, who had taken ketoconazole 200 mg twice daily (for 7 weeks) prior to a transsphenoidal resection, developed jaundice, elevated liver transaminases and bilirubin, generalized pruritus, fever, anorexia, nausea, and vomiting approximately 1 month after restarting ketoconazole therapy following surgery. Ketoconazole therapy was discontinued; however, the patient developed hepatorenal failure with disseminated intravascular coagulation 6 days later, and subsequently died despite supportive therapy (Zollner et al, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported in less than 1% of patients taking the drug (Prod Info ketoconazole oral tablets, 2004).
    B) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia has been reported in less than 1% of oral ketoconazole recipients (Prod Info ketoconazole oral tablets, 2004).
    b) CASE REPORT: Immune hemolytic anemia was described in a 42-year-old man following approximately 20 days of therapy with ketoconazole 200 mg orally daily for an unidentified skin rash. The last dose of the drug was administered 6 days prior to hospital admission and 3 days prior to onset of symptoms of weakness, jaundice, and lightheadedness. The patient gradually recovered following corticosteroid therapy. However, from the data presented, it is unclear if the immune hemolysis in this patient was definitely related to ketoconazole therapy (Umstead et al, 1987).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Various skin reactions have occurred as adverse effects (Graybill & Drutz, 1980).
    b) CASE REPORT: A 32-year-old woman developed a fixed drug eruption which resolved with topical corticosteroids and systemic antihistamines. She developed the same symptoms upon subsequent rechallenge (Bharija & Belhaj, 1988).
    B) ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS
    1) WITH THERAPEUTIC USE
    a) A case report described the occurrence of acute generalized exanthematous pustulosis in a 12-year-old girl following ketoconazole therapy for prophylaxis of oral candidiasis. The girl presented with sudden onset of high fever and a 5-day history of a widespread erythematous rash, with small pustules developing on her trunk and extremities. She had a 1-year history of dermatomyositis, which was being treated with methylprednisolone. Oral ketoconazole 100 mg/day had been initiated 1 day prior to development of fever and rash. Laboratory tests revealed leukocytosis and neutrophilia; liver and renal function, and serum electrolytes were normal. Microbiologic studies of pustules, viral serology, and C-reactive protein were negative. A large subcorneal pustule, along with moderate acanthosis, an edematous papillary dermis with mixed perivascular inflammatory cell infiltrates and leukocytoclastic vasculitis, was evident on histologic examination. Ketoconazole therapy was stopped and methylprednisolone was continued, accompanied by symptomatic treatment with topical hydrocortisone 0.1% cream and levocetirizine 5 mg daily (Miteva et al, 2010).
    C) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A case of phototoxic photodermatitis was reported in a 36-year-old woman (Mohamed, 1988); however, the relationship between the rash and the drug was not clearly established.
    D) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) There are several case reports of contact dermatitis occurring after using ketoconazole topically. Each patient experienced a positive reaction from patch tests that were administered using ketoconazole (Valsecchi et al, 1993; Santucci et al, 1992; Verschueren & Bruynzlel, 1992) .
    E) ABNORMAL HAIR TEXTURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One article reported a case of trichoptilosis (the splitting of hairs at their ends) following the misuse of ketoconazole 2% shampoo. The patient used approximately 120 mL of shampoo during 10 applications. However, it is not certain that the ketoconazole is the sole causative agent because there are also other ingredients in the shampoo that may have caused the trichoptilosis (Aljabre, 1993).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) DRUG-INDUCED MYOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 17-year-old boy was treated with ketoconazole 200 mg per day for oral candidiasis. Within a week, the patient experienced significant weakness and diffuse myalgias. The serum CPK increased to 5200 units/L (normal range, 20 to 200 units/L). Ketoconazole was discontinued 8 days after initiating therapy and the weakness and myalgias slowly resolved. Three weeks later, the serum CPK decreased to 96 units/L (Garty et al, 1991).
    B) PARALYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 77-year-old man developed weakness of the extremities, leading to paralysis of the legs, hand and foot tremors, dysarthria, and dyspnea within 1 hour of taking ketoconazole 200 mg for oral thrush. He was hospitalized and all symptoms resolved within 24 hours without treatment. He was discharged with a diagnosis of transient ischemic attack. A few days later, he took another 200- mg dose of ketoconazole and began to experience dysarthria, tremors, and tetraplegia within 1 hour. The symptoms resolved within hours (Bulkowstein et al, 2003).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) Gynecomastia has been reported (DeFelice et al, 1981).
    B) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) Suppression of androgen synthesis is common, especially at high doses (eg, 400 mg every 8 hours) (Amery et al, 1986; Pont et al, 1982; Schurmeyer & Neischlag, 1982).
    C) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) Decreased serum cortisol levels have been reported at high doses (Tucker et al, 1985; Pont et al, 1983) ; this appears due to a direct effect on cortisol synthesis as well as a diminished response of the adrenal glands to adrenocorticotrophic hormone (Graybill, 1983; Pont et al, 1983) .
    b) CASE REPORT: A 77-year-old man presented with nausea and vomiting, abdominal pain, weakness, mental status changes, hypotension, tachycardia, and abnormal electrolyte levels (sodium 122 mmol/L, potassium 6 mmol/L) 9 days after beginning ketoconazole therapy, 200 mg orally 4 times daily, for testosterone suppression. The patient became alert and verbally responsive, with a normalization of his blood pressure, 1 hour after corticosteroid administration.
    1) It was suggested that adrenal insufficiency related to high-dose ketoconazole therapy was the cause of the patient's symptoms; however, a serum cortisol level was not obtained prior to corticosteroid treatment and an adrenocorticotrophic hormone stimulation test performed 2 days later, and after discontinuation of ketoconazole therapy, did not show any evidence of underlying adrenal insufficiency (Sarver et al, 1997).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) There have been reports of severe hypersensitivity reactions, including anaphylactic reactions, during postmarketing use of ketoconazole shampoo (Prod Info NIZORAL(R) topical application shampoo, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Ketoconazole is classified as FDA pregnancy category C. Teratogenicity (ie, syndactylia and oligodactylia), embryotoxicity, maternal toxicity, and dystocia have been observed in rats given oral ketoconazole, possibly due to the sensitivity of female rats to the drug. Ketoconazole has been shown to be present in human milk. It is recommended that mothers being treated with oral ketoconazole should not breast-feed. However, it is not known whether topical ketoconazole is systemically absorbed in sufficient quantities to produce detectable levels in breast milk. Ketoconazole impaired the reproductive performance of male and female rats.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) A case report described the birth of a healthy infant to a 26-year-old who had first trimester exposure to ketoconazole. While awaiting pituitary surgery for Cushing's disease, she received ketoconazole 200 mg twice daily and losartan 50 mg/day. Despite the use of contraception, a diagnosis of pregnancy was made 9 weeks later; ketoconazole was stopped immediately and losartan was switched to alpha-methyldopa 250 mg three times daily. Subsequently, an ultrasound revealed a healthy 15-week fetus. Following a right pituitary adenoma resection at week 16 of pregnancy, metyrapone was initiated at week 20 due to persistently elevated plasma cortisol; she also received labetalol to improve hypertensive control. A healthy male child was born at 34 weeks, with no neonatal complications (Boronat et al, 2011).
    B) ANIMAL STUDIES
    1) RATS: Syndactylia and oligodactylia were reported in rats given ketoconazole 80 mg/kg/day (10 times the maximum recommended human dose) in the diet. These effects may be related to maternal toxicity which was also observed at this and higher ketoconazole doses (Prod Info ketoconazole oral tablets, 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans.
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified ketoconazole as FDA pregnancy category C (Prod Info XOLEGEL(R) topical gel, 2010; Prod Info NIZORAL(R) topical application shampoo, 2009; Prod Info EXTINA(R) topical foam, 2007; Prod Info ketoconazole oral tablets, 2004; Prod Info ketoconazole topical cream, 2002).
    C) ANIMAL STUDIES
    1) RATS: Maternal toxicity and embryotoxicity were observed in rats given ketoconazole 80 mg/kg/day (10 times the maximum recommended human dose) and higher doses in the diet. Dystocia was reported at ketoconazole doses higher than 10 mg/kg (higher than 1.25 times the maximum human dose). It is postulated that these adverse events in female rats may be due to the particular sensitivity of the female rat to ketoconazole. The oral LD(50) of ketoconazole given by gavage to the female rat is 166 mg/kg compared to 287 mg/kg in the male rat (Prod Info ketoconazole oral tablets, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) TOPICAL: It is not known whether topical ketoconazole is systemically absorbed in sufficient quantities to produce detectable levels in breast milk (Prod Info XOLEGEL(R) topical gel, 2010; Prod Info NIZORAL(R) topical application shampoo, 2009; Prod Info EXTINA(R) topical foam, 2007; Prod Info ketoconazole topical cream, 2002).
    B) BREAST MILK
    1) ORAL: Ketoconazole has been shown to be present in human milk. It is recommended that mothers being treated with oral ketoconazole should not breast-feed (Prod Info ketoconazole oral tablets, 2004). However, it is not known whether topical ketoconazole is systemically absorbed in sufficient quantities to produce detectable levels in breast milk (Prod Info XOLEGEL(R) topical gel, 2010; Prod Info NIZORAL(R) topical application shampoo, 2009; Prod Info EXTINA(R) topical foam, 2007; Prod Info ketoconazole topical cream, 2002)
    2) Based on data from one woman, ketoconazole milk to plasma ratio was estimated at 0.38, and the calculated dose available to the nursing infant was 1.4% of the weight-adjusted maternal dose (Moretti et al, 1995).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no human data were available to assess the potential effects on fertility from exposure to this agent.
    B) ANIMAL STUDIES
    1) In rat fertility studies, the administration of oral ketoconazole at doses of 75 to 80 mg/kg/day (71 to 76 times the recommended human dose) resulted in decreased pregnancy and implantation rates (in females) and increased abnormal sperm and decreased sperm motility (in males) (Prod Info XOLEGEL(R) topical gel, 2010).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any human carcinogenic potential.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) In a 2-year dermal carcinogenicity study, no evidence of dermal or systemic tumorigenic effects were observed in CD-1 mice administered topical ketoconazole gel at doses up to 80 mg/kg/day (76 times the human dose) (Prod Info XOLEGEL(R) topical gel, 2012).
    2) In a long-term feeding study, no evidence of oncogenic activity was noted in Swiss Albino mice and Wistar rats administered ketoconazole (Prod Info XOLEGEL(R) topical gel, 2012; Prod Info NIZORAL(R) topical application shampoo, 2009; Prod Info ketoconazole oral tablets, 2004; Prod Info ketoconazole topical cream, 2002).
    3) No evidence of photocarcinogenic potential was reported when hairless mice were exposed to topical ketoconazole gel at doses up to 5 mg/kg/dose for 5 days/week for 40 weeks (Prod Info XOLEGEL(R) topical gel, 2012).
    4) Oral ketoconazole was not carcinogenic in studies of mice and rats administered doses of 5, 20, and 80 mg/kg/day for 18 months and 24 months, respectively. The highest dose (80 mg/kg/day) was approximately 2.4 to 4.8 times the expected human topical dose based on a mg/m(2) comparison (Prod Info EXTINA(R) topical foam, 2007).

Genotoxicity

    A) There was no evidence of mutagenicity with the Ames salmonella microsomal activator assay. In addition, ketoconazole single oral doses as high as 80 mg/kg were not mutagenic to germ cells (dominant lethal test in male and female mice) (Prod Info XOLEGEL(R) topical gel, 2012; Prod Info NIZORAL(R) topical application shampoo, 2009; Prod Info ketoconazole oral tablets, 2004; Prod Info ketoconazole topical cream, 2002). Ketoconazole was also not genotoxic based on the in vivo sister chromatid exchange assay (humans) and dominant lethal and micronucleus tests (mice) (Prod Info EXTINA(R) topical foam, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, liver enzymes, and CBC with platelet count in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) A blood level of 1 mcg/mL (approximately a 200-mg dose) is necessary for therapeutic effect (Borelli et al, 1979).

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) Hospital admission is rarely necessary. Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent ingestion, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) Monitor vital signs, liver enzymes, and CBC with platelet count in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Serious toxicity is not expected after ingestion of ketoconazole alone, and prehospital gastrointestinal decontamination is not routinely required.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Significant toxicity is not expected after overdose; gastrointestinal decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs, liver enzymes, and CBC with platelet count in symptomatic patients.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) ANTACID
    1) Antacids have been shown to reduce the absorption of ketoconazole (Van Der Meer et al, 1980), possibly by reducing tablet dissolution.
    2) Early administration of antacid after overdose may delay or reduce absorption (Prod Info, 1987).
    C) HYPERSENSITIVITY REACTION
    1) In patients with acute allergic reaction to ketoconazole, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors, and epinephrine may be required.
    2) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    3) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    4) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    5) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    6) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    7) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    8) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    9) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    10) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    11) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    12) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    13) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of ketoconazole.
    2) Not dialyzable to any significant extent (Brass et al, 1980).

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) A 22-year-old woman developed QT prolongation with torsades de pointes following the ingestion of ketoconazole (200 mg per day) and terfenadine (120 mg per day) for 5 days. The QT intervals slowly returned to normal following discontinuation of the medications (Zimmerman et al, 1992).
    B) ADULT
    1) Following the ingestion of a "handful" of ketoconazole and zidovudine tablets, a 36-year-old man experienced headache, fatigue, and tinnitus. Spontaneous emesis occurred. At 24 hours postingestion, headache and tinnitus resolved, but the patient remained fatigued (Gorman et al, 1992).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. THERAPEUTIC DOSE: ADULTS: ORAL: 200 to 400 mg once daily. In investigational high-dose studies, up to 1600 mg/day doses were also used. CHILDREN: 2 TO 18 YEARS OF AGE: Single daily dose of 3.3 to 6.6 mg/kg.

Therapeutic Dose

    7.2.1) ADULT
    A) ANTIFUNGAL
    1) ORAL TABLETS
    a) 200 mg (1 tablet) orally once daily until infection has resolved (usually about 6 months); may be increased to 400 mg (2 tablets) orally once daily (Prod Info NIZORAL(R) oral tablets, 2014)
    b) INVESTIGATIONAL HIGH-DOSE PROTOCOLS:
    1) ADVANCED PROSTATIC CARCINOMA: 1200 to 1600 mg/day (400 mg every 6 to 8 hours) (Vanuytsel et al, 1987).
    2) CUSHING SYNDROME: 400 to 1000 mg/day (Loli et al, 1986; Sonino, 1988).
    2) TOPICAL CREAM
    a) CANDIDAL INFECTIONS, TINEA CRURIS, AND TINEA VERSICOLOR: Apply topically once daily for 2 weeks (Prod Info ketoconazole 2% topical cream, 2011)
    b) TINEA PEDIS: Apply topically once daily for 6 weeks (Prod Info ketoconazole 2% topical cream, 2011)
    3) TOPICAL SHAMPOO
    a) Apply topically, leave in place for 5 minutes, and then rinse off with water; one application should be sufficient (Prod Info NIZORAL(R) topical shampoo, 2013).
    B) SEBORRHEIC DERMATITIS
    1) TOPICAL CREAM, FOAM, AND GEL
    a) Apply topically twice daily for up to 4 weeks (Prod Info ketoconazole 2% topical cream, 2011; Prod Info EXTINA(R) topical foam, 2014; Prod Info XOLEGEL(R) topical gel, 2012)
    7.2.2) PEDIATRIC
    A) ANTIFUNGAL
    1) ORAL TABLET
    a) 2 TO 18 YEARS OF AGE: 3.3 to 6.6 mg/kg orally once daily (Prod Info NIZORAL(R) oral tablets, 2014)
    b) LESS THAN 2 YEARS OF AGE: Safety and efficacy data have not been established (Prod Info NIZORAL(R) oral tablets, 2014)
    2) TOPICAL CREAM AND SHAMPOO
    a) Safety and efficacy have not been established in pediatric patients (Prod Info ketoconazole 2% topical cream, 2011; Prod Info NIZORAL(R) topical shampoo, 2013).
    B) SEBORRHEIC DERMATITIS
    1) TOPICAL FOAM
    a) UNDER 12 YEARS: Safety and efficacy have not been established (Prod Info EXTINA(R) topical foam, 2014).
    b) 12 YEARS AND OLDER: Apply topically twice daily for 4 weeks (Prod Info EXTINA(R) topical foam, 2014)
    2) TOPICAL GEL
    a) UNDER 12 YEARS: Safety and efficacy have not been established (Prod Info XOLEGEL(R) topical gel, 2012).
    b) 12 YEARS AND OLDER: Apply topically once daily for 2 weeks (Prod Info XOLEGEL(R) topical gel, 2012)

Maximum Tolerated Exposure

    A) In investigational high-dose studies, up to 1600 mg/day doses were used (Sonino, 1988; Vanuytsel et al, 1987; Loli et al, 1986).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 618 mg/kg ((RTECS, 2000))
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) greater than 4 g/kg ((RTECS, 2000))
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 1474 mg/kg ((RTECS, 2000))
    4) LD50- (ORAL)RAT:
    a) 166 mg/kg ((RTECS, 2000))
    5) LD50- (SUBCUTANEOUS)RAT:
    a) greater than 2400 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ketoconazole is a synthetic, broad-spectrum, imidazole antifungal agent that inhibits the CYP450 dependant enzyme lanosterol 14 alpha-demethylase which is responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. Depletion of ergosterol in the fungal cell membrane results in a weakening of its structure and function (Prod Info NIZORAL(R) oral tablets, 2013; Prod Info NIZORAL(R) topical shampoo, 2012). The mechanism of action for topical treatment of seborrheic dermatitis is unknown (Prod Info XOLEGEL(R) topical gel, 2012; Prod Info EXTINA(R) topical foam, 2007)

Physicochemical

Physical Characteristics

    A) White or almost white, odorless powder that is soluble in acids (Prod Info ketoconazole oral tablets, 2004) and practically insoluble in water at a pH of greater than 3 (4 mg/100 mL) (Daneshmend & Warnock, 1988)

Molecular Weight

    A) 531.43 (Prod Info XOLEGEL(R) topical gel, 2010; Prod Info EXTINA(R) topical foam, 2007; Prod Info ketoconazole oral tablets, 2004)

References

General Bibliography

    1) Aabo K & De Coster R: Hypertension during high-dose ketoconazole treatment: a probable mineralocorticoid effect. Lancet 1987; 2:637-638.
    2) Aljabre SHM: Trichoptilosis caused by misuse of ketoconazole 2% shampoo (letter). Intl J Dermatol 1993; 32:150-151.
    3) Amery WK, De Coster R, & Caers I: Ketoconazole: from an antimycotic to a drug for prostate cancer. Drug Devel Res 1986; 8:299-307.
    4) Baciewicz AM & Baciewicz FA: Ketoconazole and fluconazole drug interactions. Arch Intern Med 1993; 153:1970-1976.
    5) Bharija SC & Belhaj MS: Ketoconazole-induced fixed drug eruption. Int J Dermatol 1988; 27:278-279.
    6) Borelli D, Fuentes J, & Leiderman E: Ketoconazole, an oral antifungal: laboratory and clinical assessment of imidazole drugs. Postgrad Med J 1979; 55:657-661.
    7) Borelli D: Treatment of pityriasis versicolor with ketoconazole. Rev Infect Dis 1980; 2:592-595.
    8) Borgers M: Mechanism of action of antifungal drugs with special reference to the imidazole derivatives. Rev Infect Dis 1980; 2:520-531.
    9) Boronat M, Marrero D, Lopez-Plasencia Y, et al: Successful outcome of pregnancy in a patient with Cushing's disease under treatment with ketoconazole during the first trimester of gestation. Gynecol Endocrinol 2011; 27(9):675-677.
    10) Brass C, Galgiani JN, & Campbell SC: Therapy of disseminated or pulmonary coccidioidomycosis with ketoconazole. Rev Infect Dis 1980; 2:656-660.
    11) Brusko CS & Marten JT: Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis. DICP Ann Pharmacother 1991; 25:1321-1325.
    12) Bulkowstein M, Mordish Y, Zimmerman DR, et al: Ketoconazole-induced neurologic sequelae. Vet Hum Toxicol 2003; 45(5):239-240.
    13) Carver PL, Berardi RR, & Knapp MJ: In vivo interaction of ketoconazole and sucralfate in healthy volunteers. Antimicrob Agents Chemother 1994; 38:326-329.
    14) Daneshmend TK & Warnock DW: Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet 1988; 14:13-34.
    15) DeFelice R, Johnson DG, & Galgian JN: Gynecomastia with ketoconazole. Antimicrob Agents Chemother 1981; 19:1073-1074.
    16) Findor JA, Sorda JA, & Igartua EB: Ketoconazole-induced liver damage. Medicina (Buenos Aires) 1998; 58:277-281.
    17) First MR, Schroeder TJ, & Michael A: Cyclosporine-ketoconazole interaction. Transplantation 1993; 55:1000-1004.
    18) Garty BZ, Kauli R, & Livni E: Myopathy associated with ketoconazole treatment (letter). AJDC 1991; 145:970-971.
    19) Gasior-Chrzan B, Stenvold SE, & Falk ES: Juvenile tinea capitis caused by Trichophyton violaceum: hepatic reactions during ketoconazole treatment. Acta Derm Venereol (Stockh) 1991; 71:57-58.
    20) Gorman SE, Dela Cruz F, & Paloucek F: Ketoconazole and zidovudine overdose (letter). Am J Emerg Med 1995; 13:115-116.
    21) Gorman SE, Dela Cruz F, & Paloucek F: Ketoconazole and zidovudine (AZT) overdose: case report and review (abstract). Vet Hum Toxicol 1992; 34:332.
    22) Graybill JR & Drutz DJ: Ketoconazole: a major innovation for treatment of fungal disease. Ann Intern Med 1980; 93:921-923.
    23) Graybill JR, Lundberg D, Donovan W, et al: Treatment of coccidioidomycosis with ketoconazole: clinical and laboratory studies of 18 patients. Rev Infect Dis 1980; 2:661-674.
    24) Graybill JR: Summary: potential and problems with ketoconazole. Am J Med 1983; 74:86-90.
    25) Knight TE, Shikuma CY, & Knight J: Ketoconazole-induced fulminant hepatitis necessitating liver transplantation. J Amer Acad Dermatol 1991; 25:398-400.
    26) Koch H: Ketoconazole. Pharmacy International 1983; 4:151-152.
    27) Krishnaiah YSR, Satyanarayana S, & Visweswaram D: Interaction between tolbutamide and ketoconazole in healthy subjects. Br J Clin Pharmacol 1994; 37:205-207.
    28) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    29) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    30) Loli P, Berselli ME, & Tagliaferri M: Use of ketoconazole in the treatment of Cushing's syndrome. J Clin Endocrinol Metab 1986; 63:1365-1371.
    31) Magnasco AJ & Magnasco LD: Interaction of ketoconazole and ethanol. Clin Pharm 1986; 5:522-523.
    32) Miteva L, Kadurina M, & Schwartz RA: Childhood acute generalized exanthematous pustulosis induced by oral ketoconazole. Acta Dermatovenerol Croat 2010; 18(4):267-270.
    33) Mohamed KN: Severe photodermatitis during ketoconazole therapy. Clin Exp Dermatol 1988; 13:54.
    34) Mok NS, Lo YK, Tsui PT, et al: Ketoconazole induced torsades de pointes without concomitant use of QT interval-prolonging drug. J Cardiovasc Electrophysiol 2005; 16(12):1375-1377.
    35) Moretti ME, Ito S, & Koren G: Disposition of maternal ketoconazole in breast milk. Am J Obstet Gynecol 1995; 173:1625-6.
    36) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    37) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    38) 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.
    39) Or M, Akbatur H, & Hasanerisoglu B: Ketoconazole-induced papilledema. Acta Ophthalmologica 1993; 71:270-272.
    40) Personal Communication: Personal Communication: Irene White. Medical Affairs, Janssen Pharmaceutica, 1989.
    41) Petersen EA, Alling DW, & Kirkpatrick CH: Treatment of chronic mucocutaneous candidiasis with ketoconazole. Ann Intern Med 1980; 93:791-795.
    42) Piscitelli SC, Goss TF, & Wilton JH: Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother 1991; 35:1765-1771.
    43) Piscitelli SC, Goss TF, Wilton JH, et al: Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother 1991a; 35:1765-1771.
    44) Pont A, Graybill JR, & Craven PL: Effect of high-dose ketoconazole on adrenal and testicular function. Clin Res 1983; 31:91A.
    45) Pont A, Williams PL, & Azhar S: Ketoconazole blocks testosterone synthesis. Arch Intern Med 1982; 142:2137-2140.
    46) Product Information: EXTINA(R) topical foam, ketoconazole topical foam. Stiefel Laboratories,Inc, Coral Gables, FL, 2007.
    47) Product Information: EXTINA(R) topical foam, ketoconazole 2% topical foam. Prestium Pharma, Inc. (per DailyMed), Newtown, PA, 2014.
    48) Product Information: NIZORAL(R) oral tablets, ketoconazole oral tablets. Janssen Pharmaceuticals (per FDA), Titusville, NJ, 2013.
    49) Product Information: NIZORAL(R) oral tablets, ketoconazole oral tablets. Janssen Pharmaceuticals, Inc (per FDA), Titusville, NJ, 2014.
    50) Product Information: NIZORAL(R) topical application shampoo, ketoconazole 2% topical application shampoo. PriCara, Raritan, NJ, 2009.
    51) Product Information: NIZORAL(R) topical shampoo, ketoconazole 2% topical shampoo. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2012.
    52) Product Information: NIZORAL(R) topical shampoo, ketoconazole 2% topical shampoo. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2013.
    53) Product Information: Nizoral(R) tablets, ketoconazole. Janssen Pharmaceutica, Inc, Titusville, NJ, 1998.
    54) Product Information: XOLEGEL(R) topical gel, ketoconazole 2% topical gel. Stiefel Laboratories, Inc, Research Triangle Park, NC, 2010a.
    55) Product Information: XOLEGEL(R) topical gel, ketoconazole topical gel. Aqua Pharmaceuticals, LLC (per FDA), San Antonio, TX, 2012.
    56) Product Information: XOLEGEL(R) topical gel, ketoconazole topical gel. Stiefel Laboratories Inc, Coral Gables, FL, 2010.
    57) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    58) Product Information: ketoconazole 2% topical cream, ketoconazole 2% topical cream. E. Fougera & Co. (per DailyMed), Melville, NY, 2011.
    59) Product Information: ketoconazole cream, ketoconazole cream. Taro Pharmaceuticals, Brampton, Ontario, 2002.
    60) Product Information: ketoconazole oral tablets, ketoconazole oral tablets. Apotex,Corp, Weston, FL, 2004.
    61) Product Information: ketoconazole topical cream, ketoconazole topical cream. Taro Pharmaceuticals Inc, Brampton, ON, Canada, 2002.
    62) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    63) S Sweetman : Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    64) Santucci B, Cannistraci C, & Cristaudo A: Contact dermatitis from ketoconazole cream. Contact Dermatitis 1992; 27:274-275.
    65) Sarver RG, Dalkin BL, & Ahmann FR: Ketoconazole-induced adrenal crisis in a patient with metastatic prostatic adenocarcinoma: case report and review of the literature. Urology 1997; 49:781-785.
    66) Schurmeyer T & Neischlag E: Ketoconazole-induced drop in serum and saliva testosterone. Lancet 1982; 2:1098.
    67) Shepard JH, Canafax DM, & Simmons RL: Cyclosporine-ketoconazole: a potentially dangerous interaction. Clin Pharm 1986; 5:468.
    68) Sonino N: Current trends in the endocrine use of ketoconazole. J Endocrinol Invest 1988; 11:741-74.
    69) Svedhem A: Toxic hepatitis following ketoconazole treatment. Scand J Infect Dis 1984; 123-125.
    70) Tabor E: Potential toxicity of ketoconazole. J Infect Dis 1985; 152:233.
    71) Tkach JR & Rinaldi MG: Severe hepatitis associated with ketoconazole: therapy for chronic mucocutaneous candidiasis. Cutis 1982; 29:482-484.
    72) Tucker WS, Snell BB, & Island DP: Reversible adrenal insufficiency induced by ketoconazole. JAMA 1985; 253:2413-2414.
    73) Umstead GS, Babiak LM, & Tejwani S: Immune hemolytic anemia associated with ketoconazole therapy. Clin Pharm 1987; 6:499-500.
    74) Valsecchi R, Pansera B, & Di Landro A: Contact dermatitis from ketoconazole. Contact Dermatitis 1993; 29:162-163.
    75) Van Der Meer JW, Kenning JJ, & Scheigrond HW: The influence of gastric acidity on the bioavailability of ketoconazole. J Antimicrob Chemother 1980; 6:552-554.
    76) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    77) Vanuytsel L, Ang KK, & Vantongelen K: Ketoconazole therapy for advanced prostatic cancer: feasibility and treatment results. J Urol 1987; 137:905-908.
    78) 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.
    79) Verschueren GL & Bruynzlel DP: Hypersensitivity to ketoconazole. Contact Dermatitis 1992; 26:47-48.
    80) Welsh O & Rodriguez M: Treatment of dermatomycoses with ketoconazole. Rev Infect Dis 1980; 2:582-585.
    81) Welsh O, Gonzalea JG, Diaz M, et al: Therapeutic evaluation of ketoconazole in patients with coccidioidomycosis. Rev Infect Dis 1980; 2:651-654.
    82) Zimmerman M, Duruz H, & Guinand O: Torsades de pointes after treatment with terfenadine and ketoconazole. European Heart J 1992; 13:1002-1003.
    83) Zollner E, Delport S, & Bonnici F: Fatal liver failure due to ketoconazole treatment of a girl with Cushing's syndrome. J Pediatr Endocrinol Metab 2001; 14(3):335-338.