Ketoconazole

Ketoconazole is an antifungal agent belonging to the pharmacological class of Azole Antifungal Derivatives

Ketoconazole has been approved to relieve symptoms and also for the treatment and maintenance of Cutaneous candidiasis, Dandruff, Seborrheic Dermatitis, Tinea Infections, Cushing’s syndrome, Prostate cancer.

Ketoconazole, an antifungal medication, exhibits absorption characteristics influenced by the acidity of its environment. The bioavailability of ketoconazole is reported to be 76%. In terms of distribution, ketoconazole has a wide-ranging effect on various tissues, including the skin, tendons, tears, and saliva. However, it has minimal penetration into the central nervous system, bones, and seminal fluid. Ketoconazole can cross the placenta and enter breast milk based on animal studies. It exhibits significant binding to plasma albumin, with approximately 84% of the drug bound to this protein. Metabolism of ketoconazole involves the formation of various metabolites, with the primary metabolite being M2, produced through the oxidation of the imidazole component. The metabolism process primarily involves the enzyme CYP3A4, along with some contributions from CYP2D6. Elimination of ketoconazole occurs primarily through hepatic metabolism, with only a small portion (2-4%) of the drug excreted unchanged in the urine.

The common side effects involved in using Ketoconazole are Nausea, Vomiting, Abdominal pain, Diarrhea, Constipation, Dizziness, Headache, Fatigue, Skin rash, Itching

Ketoconazole is available in the form of Tablets, Creams, and Shampoo.

Ketoconazole is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Ketoconazole belongs to the pharmacological class of Azole Antifungal Derivatives

Ketoconazole acts on 14-α-sterol demethylase, an enzyme belonging to the cytochrome P-450 group, which plays a crucial role in converting lanosterol to ergosterol. By inhibiting this enzyme, ketoconazole hinders the synthesis of ergosterol, leading to reduced levels of ergosterol in the fungal cell membrane. As a result, the permeability of the fungal cell increases. Additionally, this metabolic inhibition leads to the accumulation of a toxic metabolite called 14α-methyl-3,6-diol.

Ketoconazole has been approved to relieve symptoms and also for the treatment and maintenance of Cutaneous candidiasis, Dandruff, Seborrheic Dermatitis, Tinea Infections, Cushing’s syndrome, and Prostate cancer.

When a single oral dose of 200 mg of ketoconazole is administered, it leads to a maximum plasma concentration (Cmax) of 2.5-3 mcg/mL, reached within 1-4 hours (Tmax). The administration of ketoconazole with food consistently results in an increase in Cmax and a delay in Tmax.

Ketoconazole is found to be available in the form of Tablets, Creams, and Shampoo.

Ketoconazole can be used in the following treatment:

• Cutaneous candidiasis
• Dandruff
• Seborrheic Dermatitis
• Tinea Infections
• Cushing’s syndrome
• Prostate cancer

Ketoconazole can help to relieve symptoms and also for the treatment and maintenance of Cutaneous candidiasis, Dandruff, Seborrheic Dermatitis, Tinea Infections, Cushing’s syndrome, and Prostate cancer.

Ketoconazole is approved for use in the following clinical indications:

• Cutaneous candidiasis
• Dandruff
• Seborrheic Dermatitis
• Tinea Infections
• Cushing’s syndrome
• Prostate cancer

Cutaneous candidiasis:

• Topical cream 2%: Apply once daily to cover the affected area and the surrounding area directly for a duration of 2 weeks. Please note that Canadian labeling suggests a treatment duration of 2 to 3 weeks.

Dandruff:

• Shampoo 1% (OTC labeling): Apply to wet hair, create lather, and rinse thoroughly. Repeat the process. Use every 3 to 4 days for up to 8 weeks, or follow the instructions provided by a healthcare professional. Subsequently, apply the shampoo only as necessary to manage dandruff.
• Shampoo 2% (Canadian product only): Apply 5 to 10 mL to wet scalp, create lather, leave it on for 3 to 5 minutes, and then rinse. Use once every 1 to 2 weeks for preventive purposes, or apply twice weekly for 2 to 4 weeks as a treatment.

Seborrheic dermatitis:

• Topical cream 2%: Apply twice daily to the affected area for a duration of 4 weeks or until a clinical response is observed.
• Topical foam 2%: Apply twice daily to the affected area for 4 weeks.
• Topical gel 2%: Apply once daily to the affected area for 2 weeks.
• Shampoo 2% (Canadian product only): Apply 5 to 10 mL to wet scalp, create lather, leave it on for 3 to 5 minutes, and then rinse. Apply twice weekly for 2 to 4 weeks.

Tinea infections:

• Tinea corporis/tinea cruris: Topical cream 2%: Apply once daily to the affected area and the surrounding area until there is a clinical resolution, typically lasting 1 to 3 weeks.
• Tinea pedis (labeled use)/tinea manuum (off-label use): Topical cream 2%: Apply once daily to the affected area and the surrounding area until 1 week after there is a clinical resolution, usually for a total of 4 to 6 weeks.
• Tinea versicolor:
• Topical cream 2%: Apply once daily to the affected area and the immediate surrounding skin for a duration of 2 weeks. Canadian labeling suggests a treatment duration of 2 to 3 weeks.
• Shampoo 2%: Apply to the affected area(s) of damp skin, create lather, leave it on for 5 minutes, and then rinse. Typically, one application is sufficient; however, some experts prefer a once-daily application for 3 consecutive days.

Cushing syndrome (off-label use):

• Oral administration: Start with an initial dose of 400 to 600 mg per day, divided into 2 or 3 doses. The dose can be increased by 200 mg per day every 7 to 28 days, up to a maximum dose of 1,200 mg per day, also divided into 2 or 3 doses. The recommended dosage range is 200 to 1,200 mg per day. In most studies, the effective dose ranges from 600 to 800 mg per day, divided into 2 doses
• Fungal infections:
• Systemic fungal infections: Take 200 mg orally once daily. If the response is not sufficient, the dose may be increased to 400 mg once daily. Continue treatment until the active fungal infection is resolved. Some infections may require a treatment duration of up to 6 months.

Prostate cancer, advanced (off-label use):

• Oral administration: Take 400 mg three times daily in combination with oral hydrocortisone until the disease progresses.

• Dosage strengths of Ketoconazole

Ketoconazole Tablets (oral): 200 mg

Ketoconazole Cream (topical): 2% (20 mg/g)

Ketoconazole Shampoo (topical): 1% (10 mg/mL), 2% (20 mg/mL)

Ketoconazole is available in the form of Tablets, Cream, Shampoo.

Dosage Adjustments in Pediatric Patients:

Fungal Infections

• Treatment of systemic fungal infections in children ≥2 years and adolescents: The recommended oral dosage is 3.3 to 6.6 mg/kg/day administered once daily. The maximum daily dose should not exceed 400 mg/day. The duration of therapy varies based on factors such as the specific pathogen, patient characteristics, and the nature of the disease. It is important to note that systemic ketoconazole should only be used when alternative effective antifungal therapy is not available or tolerated due to the potential for serious adverse reactions. The usual adult dose is 200 mg/day.

Peripheral Precocious Puberty

• Treatment of gonadotropin-independent peripheral precocious puberty: Limited data are available, and the optimal dose has not been clearly defined. For children ≥2 years and adolescents, the oral dosage ranges from 10 to 20 mg/kg/day, divided into three doses. Response to treatment, characterized by decreased testosterone levels and cessation of puberty, has been observed. Some studies report flat doses of 400 to 600 mg/day divided into 2 to 3 doses, while others describe weight-based doses as high as 30 mg/kg/day divided into three doses.

Cushing Syndrome (Second-line Therapy)

• Treatment of Cushing syndrome as second-line therapy: Limited data is available for children ≥12 years and adolescents. The initial oral dosage is typically 400 to 600 mg/day, divided into 2 or 3 doses. The dose can be increased by 200 mg/day every 7 to 28 days based on patient response (assessed through urinary or plasma cortisol levels) and tolerability. The maximum recommended dosage is 800 to 1,200 mg/day, divided into 2 or 3 doses. In a compassionate use trial involving adult and pediatric patients with Cushing syndrome, the median final dose of ketoconazole was 600 mg/day, administered in divided doses.

Dandruff

• Treatment of dandruff (flaking, scaling, and itching):

Ketoconazole 1% Shampoo: For children ≥12 years and adolescents, the recommended regimen is to use the shampoo every 3 to 4 days for up to 8 weeks and then use it only as needed to control dandruff. This is based on over-the-counter (OTC) labeling.

Ketoconazole 2% Shampoo (Canadian labeling): For children ≥12 years and adolescents, the recommended regimens are as follows:

Prophylaxis: Use the shampoo with 5 to 10 mL once every 1 to 2 weeks.

Treatment: Use the shampoo with 5 to 10 mL twice weekly for 2 to 4 weeks.

Seborrheic Dermatitis (Treatment)

• Treatment of seborrheic dermatitis:

Cream: Limited data is available, and the use in infants and children ≤2 years should be done under medical guidance. The cream should be applied to the affected area once or twice daily for 10 to 15 days.

Foam: For children ≥12 years and adolescents, the foam should be applied to the affected area twice daily for 4 weeks.

Gel: For children ≥12 years and adolescents, the gel should be applied to the affected area once daily for 2 weeks.

Shampoo:

Infants: Limited data is available, and the use of ketoconazole 1% or 2% shampoo in infants should be done under medical guidance. The shampoo should be used with a small amount twice weekly for 1 month.

Children and Adolescents: Limited data are available, and the use of ketoconazole 1% or 2% shampoo in children and adolescents should be done under medical guidance. The shampoo should be used with a small amount several times weekly up to daily until disease control is achieved and then decreased to once weekly to reduce the risk of relapse.

Canadian labeling (ketoconazole 2%): For children ≥12 years and adolescents, the recommended regimen is to use the shampoo with 5 to 10 mL twice weekly for 2 to 4 weeks.

While there are no specific dietary restrictions associated with the use of ketoconazole, it is important to note the following considerations:

• Acidic Beverages: When co-treating with drugs that reduce gastric acidity (e.g., acid-neutralizing medicines like aluminum hydroxide or acid secretion suppressors like H2-receptor antagonists and proton pump inhibitors), Ketoconazole should be administered with an acidic beverage, such as non-diet cola. This helps maintain the effectiveness of ketoconazole by improving its absorption.
• Timing of Acid Neutralizing Medicines: If using acid-neutralizing medicines (e.g., aluminum hydroxide), it is recommended to administer them at least 1 hour before or 2 hours after taking Ketoconazole. This spacing helps avoid interference with the absorption of ketoconazole.
• Alcohol Consumption: Patients should be advised against consuming alcohol while on treatment with Ketoconazole. Alcohol consumption may contribute to the risk of hepatotoxicity, which is a potential adverse effect associated with the use of ketoconazole.

Ketoconazole may be contraindicated under the following conditions:

• Coadministration of certain CYP3A4 substrates (dofetilide, quinidine, cisapride, and pimozide) is contraindicated with Ketoconazole.
• Ketoconazole can increase plasma concentrations of these drugs, leading to potential therapeutic and adverse effects, including QT prolongation and life-threatening ventricular tachyarrhythmias.
• Other drugs contraindicated with Ketoconazole include methadone, disopyramide, dronedarone, ergot alkaloids, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin, and colchicine.
• Enhanced Sedation
• Concomitant use of Ketoconazole with oral midazolam, oral triazolam, or alprazolam can result in elevated plasma concentrations of these drugs.
• This may increase and prolong the hypnotic and sedative effects, especially with repeated or chronic administration.
• Coadministration with oral triazolam, oral midazolam, or alprazolam is contraindicated.
• Myopathy
• Coadministration of HMG-CoA reductase inhibitors metabolized by CYP3A4, such as simvastatin and lovastatin, is contraindicated with Ketoconazole.
• Ergotism
• Concomitant administration of ergot alkaloids (dihydroergotamine and ergotamine) with Ketoconazole is contraindicated.
• Liver Disease
• The use of Ketoconazole is contraindicated in patients with acute or chronic liver disease.
• Hypersensitivity
• Ketoconazole are contraindicated in patients who have demonstrated hypersensitivity to the drug.

Hepatotoxicity

• Serious hepatotoxicity, including fatal cases, has been associated with oral ketoconazole use.
• Hepatic injury is typically reversible upon discontinuation of Ketoconazole, but not always.
• Baseline laboratory tests should be obtained, and alcohol consumption should be avoided.
• Prompt recognition of liver injury is crucial, with monitoring of serum ALT levels and liver tests.
• Rechallenge with oral ketoconazole should be approached cautiously, with close monitoring.

QT Prolongation and Drug Interactions

• Ketoconazole can prolong the QT interval.
• Co-administration of certain drugs (dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine) is contraindicated due to potential QT prolongation.
• Elevated plasma concentrations of these drugs, caused by ketoconazole, may lead to life-threatening ventricular dysrhythmias.

Adrenal Insufficiency

• Ketoconazole at doses of 400 mg and higher can decrease adrenal corticosteroid secretion.
• The adrenal function should be monitored, especially in patients with adrenal insufficiency or borderline adrenal function and during periods of prolonged stress.

Adverse Reactions Associated with Unapproved Uses

• Ketoconazole has been used in higher doses for advanced prostate cancer and Cushing's syndrome when other options have failed.
• The safety and effectiveness of ketoconazole in these uses have not been established or approved by the FDA.

Hypersensitivity

• Anaphylaxis and hypersensitivity reactions, including urticaria, have been reported after the first dose of ketoconazole.

It is generally recommended to avoid consuming alcohol while taking ketoconazole. Alcohol can interact with ketoconazole and increase the risk of certain side effects. Here are some alcohol-related warnings associated with the use of ketoconazole:

Increased risk of liver damage: Both ketoconazole and alcohol can individually affect liver function. When used together, they can increase the risk of liver damage or impair liver function. This can lead to symptoms such as abdominal pain, yellowing of the skin or eyes (jaundice), dark urine, and fatigue. It is important to avoid alcohol consumption to protect your liver while taking ketoconazole.

Enhanced drowsiness and dizziness: Ketoconazole and alcohol can both cause drowsiness and dizziness. When used together, these effects can be intensified, impairing your coordination and judgment. It is crucial to avoid alcohol to prevent an increased risk of accidents or injuries.

Worsening gastrointestinal side effects: Both ketoconazole and alcohol can cause gastrointestinal side effects such as nausea, vomiting, and stomach upset. Consuming alcohol can exacerbate these symptoms and make them more severe. It is advisable to avoid alcohol to minimize gastrointestinal discomfort while taking ketoconazole.

The presence of ketoconazole has been detected in breast milk, indicating that it can be transferred to nursing infants. Therefore, it is advised that mothers undergoing treatment with Ketoconazole should refrain from breastfeeding.

Teratogenic Effects - Category C

Teratogenic effects: Ketoconazole has demonstrated teratogenic effects in rats, specifically syndactylia (webbed digits) and oligodactylia (reduced number of digits), when administered in the diet at a dosage of 80 mg/kg/day (2 times the maximum recommended human dose based on body surface area). However, it should be noted that these effects may be attributed to maternal toxicity, which was also observed at this and higher dosage levels.

There is a lack of adequate and well-controlled studies in pregnant women. Therefore, the use of Ketoconazole during pregnancy should only be considered if the potential benefits outweigh the potential risks to the fetus.

Nonteratogenic effects: In rat studies, ketoconazole has demonstrated embryotoxicity when administered at doses higher than 80 mg/kg during the first trimester of gestation. Additionally, dystocia (difficult labor) was observed in rats given oral ketoconazole during the third trimester of gestation at doses higher than 10 mg/kg (approximately one-fourth of the maximum human dose based on body surface area comparison).

There are no specific food warnings associated with the use of ketoconazole. However, it is generally recommended to take ketoconazole with a meal or acidic beverage (such as non-diet cola) to enhance its absorption. Taking it with food can also help reduce gastrointestinal side effects such as nausea and abdominal discomfort.

The adverse reactions related to Ketoconazole can be categorized as follows:

Common:

• Nausea
• Vomiting
• Abdominal pain
• Headache
• Dizziness
• Skin rash
• Itching
• Diarrhea
• Fatigue
• Impaired liver function (elevated liver enzymes)

Less common:

• Allergic reactions
• Anorexia (loss of appetite)
• Constipation
• Indigestion
• Altered taste sensation
• Hair loss
• Muscle or joint pain
• Photosensitivity (increased sensitivity to sunlight)

Rare adverse:

• Severe allergic reactions (e.g., anaphylaxis)
• Stevens-Johnson syndrome (a severe skin condition)
• Toxic epidermal necrolysis (a life-threatening skin condition)
• Hepatotoxicity (liver damage)
• Adrenal insufficiency
• QT interval prolongation (can lead to abnormal heart rhythms)

Metabolism of Ketoconazole:

Ketoconazole is primarily metabolized through the CYP3A4 metabolic pathway. Other substances that share this pathway or affect CYP3A4 activity can influence the pharmacokinetics of ketoconazole. Additionally, ketoconazole can modify the pharmacokinetics of drugs that share this metabolic pathway.

Pediatric Considerations:

Interaction studies for ketoconazole have been conducted only in adults, and the relevance of these results in pediatric patients is unknown.

Drugs that Decrease Ketoconazole Plasma Concentrations:

Medications that reduce gastric acidity, such as acid-neutralizing medicines (e.g., aluminum hydroxide) and acid secretion suppressors (e.g., H2-receptor antagonists and proton pump inhibitors), can impair the absorption of ketoconazole from Ketoconazole. When coadministered:

Ketoconazole should be taken with an acidic beverage (e.g., non-diet cola).

Acid neutralizing medicines (e.g., aluminum hydroxide) should be taken at least 1 hour before or 2 hours after Ketoconazole.

Antifungal activity should be monitored, and the Ketoconazole dose may need adjustment.

Drugs that Decrease Ketoconazole Efficacy:

Concomitant use of potent enzyme inducers of CYP3A4, such as isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine, may reduce the bioavailability of ketoconazole. Administering these drugs with Ketoconazole is not recommended unless the benefits outweigh the risk of reduced ketoconazole efficacy. Antifungal activity should be monitored, and the Ketoconazole dose may need adjustment.

Drugs that Increase Ketoconazole Plasma Concentrations:

Potent inhibitors of CYP3A4, like ritonavir, ritonavir-boosted darunavir, and ritonavir-boosted fosamprenavir (antivirals), can increase the bioavailability of ketoconazole. When coadministered with Ketoconazole, patients should be closely monitored for increased or prolonged effects of ketoconazole. The Ketoconazole dose may need to be decreased, and ketoconazole plasma concentrations should be measured when appropriate.

Drugs with Increased Plasma Concentrations by Ketoconazole:

Ketoconazole inhibits the metabolism of drugs metabolized by CYP3A4 and the drug transport by P-glycoprotein. This inhibition can lead to elevated plasma concentrations of these drugs and/or their active metabolites when administered with ketoconazole. Drugs metabolized by CYP3A4, especially those known to prolong the QT interval, may be contraindicated with Ketoconazole due to the potential risk of ventricular tachyarrhythmias, including torsade de pointes, a potentially fatal arrhythmia.

The following are the side effects involving Ketoconazole:

• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Constipation
• Dizziness
• Headache
• Fatigue
• Skin rash
• Itching
• Increased sensitivity to sunlight
• Elevated liver enzyme levels
• Liver damage (rare)
• Hormonal imbalances (e.g., decreased libido, erectile dysfunction, irregular menstrual periods)

Pregnancy:

Teratogenic Effects - Category C

Teratogenic effects: Ketoconazole has demonstrated teratogenic effects in rats, specifically syndactylia (webbed digits) and oligodactylia (reduced number of digits), when administered in the diet at a dosage of 80 mg/kg/day (2 times the maximum recommended human dose based on body surface area). However, it should be noted that these effects may be attributed to maternal toxicity, which was also observed at this and higher dosage levels.

There is a lack of adequate and well-controlled studies in pregnant women. Therefore, the use of Ketoconazole during pregnancy should only be considered if the potential benefits outweigh the potential risks to the fetus.

Nonteratogenic effects: In rat studies, ketoconazole has demonstrated embryotoxicity when administered at doses higher than 80 mg/kg during the first trimester of gestation. Additionally, dystocia (difficult labor) was observed in rats given oral ketoconazole during the third trimester of gestation at doses higher than 10 mg/kg (approximately one-fourth of the maximum human dose based on body surface area comparison).

Lactation:

The presence of ketoconazole has been detected in breast milk, indicating that it can be transferred to nursing infants. Therefore, it is advised that mothers undergoing treatment with Ketoconazole should refrain from breastfeeding.

Pediatric:

The use of Ketoconazole has not been extensively researched in children, including those under 2 years of age, and there is limited information available regarding its safety and efficacy in this population. Therefore, caution should be exercised when considering the use of Ketoconazole in pediatric patients, and the potential benefits of treatment should be carefully evaluated against the potential risks involved.

Geriatric Use:

The use of ketoconazole in geriatric patients should be approached with caution and individualized based on the patient's overall health status and specific needs. Elderly patients may be more susceptible to certain adverse effects of ketoconazole, such as liver and kidney dysfunction, as well as drug interactions. Close monitoring of liver function and regular assessment of renal function may be necessary during treatment. Additionally, dosage adjustments or alternative treatment options may be considered to minimize potential risks and ensure optimal therapeutic outcomes in geriatric patients.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Ketoconazole.

If an acute accidental overdose occurs, the recommended approach for treatment involves providing supportive and symptomatic care. In the initial hour following ingestion, activated charcoal may be administered as a measure to help mitigate the effects.

Pharmacodynamics

Ketoconazole, like other azole antifungals, exhibits fungistatic properties by inducing growth arrest in fungal cells, effectively inhibiting the growth and dissemination of the fungus throughout the body.

Pharmacokinetics

Absorption

Ketoconazole Absorption: Ketoconazole, being a weak dibasic agent, relies on acidity for dissolution and absorption. When a single 200 mg dose is taken orally with a meal, it achieves mean peak plasma concentrations of around 3.5 μg/mL within 1 to 2 hours. Optimal oral bioavailability is observed when the tablets are consumed with a meal. However, absorption of Ketoconazole is diminished in individuals with reduced gastric acidity, including those taking acid-neutralizing medicines (e.g., aluminum hydroxide) or gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors), as well as subjects with achlorhydria due to certain diseases. When Ketoconazole is administered with an acidic beverage (e.g., non-diet cola), absorption of ketoconazole is enhanced under fasted conditions in such subjects. Administration of omeprazole, a proton pump inhibitor, prior to a single 200 mg dose of ketoconazole in fasted conditions reduced the bioavailability to 17% compared to ketoconazole administered alone. However, when ketoconazole was given with non-diet cola after pretreatment with omeprazole, the bioavailability increased to 65% compared to ketoconazole alone.

Distribution

Plasma Protein Binding: In vitro studies reveal that approximately 99% of ketoconazole binds to the albumin fraction in the plasma. Ketoconazole exhibits wide distribution throughout the tissues; however, only a negligible amount crosses the blood-brain barrier to reach the cerebrospinal fluid.

Metabolism

Ketoconazole Metabolism: Following absorption from the gastrointestinal tract, NIZORAL is converted into several inactive metabolites. In vitro, investigations indicate that the major enzyme involved in the metabolism of ketoconazole is CYP3A4. The primary identified metabolic pathways involve oxidation and degradation of the imidazole and piperazine rings by hepatic microsomal enzymes. Additionally, oxidative O-dealkylation and aromatic hydroxylation may occur. Ketoconazole has not been shown to induce its own metabolism.

Elimination

Ketoconazole Elimination: Elimination from the plasma occurs in two phases, with a half-life of 2 hours during the first 10 hours, followed by 8 hours thereafter. Approximately 13% of the dose is excreted in the urine, with 2 to 4% remaining as unchanged drug. The primary route of excretion is through the bile into the intestinal tract, with approximately 57% of the dose excreted in the feces.

• Almeida MQ, Brito VN, Lins TS, et al. Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole. Clin Endocrinol (Oxf). 2008;69(1):93-98. [PubMed 18088394]
• Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A. Successful treatment with ketoconazole of Cushing's syndrome in pregnancy. Postgrad Med J. 1990;66(773):221-223. [PubMed 2362890]
• Berwaerts J, Verhelst J, Mahler C, Abs R. Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature. Gynecol Endocrinol. 1999;13(3):175-182. [PubMed 10451809]
• Brass C, Galgiani JN, Blaschke TF, Defelice R, O'Reilly RA, Stevens DA. Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob Agents Chemother. 1982;21(1):151-158. [PubMed 6282204]
• Bronstein MD, Machado MC, Fragoso MC. Management of endocrine disease: management of pregnant patients with Cushing's syndrome. Eur J Endocrinol. 2015;173(2):R85-R91. [PubMed 25872515]
• Brue T, Amodru V, Castinetti F. Management of endocrine disease: management of Cushing's syndrome during pregnancy: solved and unsolved questions. Eur J Endocrinol. 2018;178(6):R259-R266. [PubMed 29523633]
• Carter TC, Druschel CM, Romitti PA, et al. Antifungal drugs and the risk of selected birth defects. Am J Obstet Gynecol. 2008;198(2):191. [PubMed 18226621]
• Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing's disease: is it worth a try? J Clin Endocrinol Metab. 2014;99(5):1623-1630. doi:10.1210/jc.2013-3628 [PubMed 24471573]

1. https://www.uptodate.com/contents/miconazole-topical-drug-information?search=Miconazole&source=panel_search_result&selectedTitle=1~39&usage_type=panel&showDrugLabel=true&display_rank=1
2. https://pdf.hres.ca/dpd_pm/00024529.PDF
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018533s041lbl.pdf
4. https://www.ema.europa.eu/en/documents/product-information/ketoconazole-hra-epar-product-information_en.pdf
5. https://go.drugbank.com/drugs/DB01026
6. https://my.clevelandclinic.org/health/drugs/20386-ketoconazole-shampoo
7. https://www.drugs.com/mtm/ketoconazole.html
8. https://www.drugs.com/mtm/ketoconazole.html
9. https://reference.medscape.com/drug/nizoral-ketoconazole-342592
10. https://vcacanada.com/know-your-pet/ketoconazole