Ketoconazole

DEFINITION

Ketoconazole is a topical as well as an oral antifungal agent. It is an azole antifungal in the drug class of imidazoles.

PURPOSE

Topical ketoconazole creams and shampoos are used to treat:

• tinea corporis, a fungal (ringworm) skin infection that causes red, scaly rashes
• tinea cruris or “jock itch,” a fungal skin infection of the groin or buttocks
• tinea pedis or “athlete’s foot,” fungal infection of the skin on the feet and between the toes
• tinea versicolor, a fungal skin infection that causes light-colored or brown spots on the chest, back, arms, legs, or neck
• onychomycosis, a fungal infection of the fingernail or toenail bed
• other dermatophytoses—parasitic fungi infections of the skin, nails, or hair
• seborrheic dermatitis—red, scaly, itchy skin on the face, scalp, or chest that may be caused, in part, by yeast that normally lives on the skin
• cutaneous candidiasis or yeast infections of the skin
• in combination with other medications, skin conditions that are frequently worsened by fungal infections, such as diaper rash, eczema (an allergic reaction), impetigo (a bacterial infection), and psoriasis (an autoimmune disorder)

In 2013, the U.S. Food and Drug Administration (FDA) limited the use of oral ketoconazole and added labels warning of potentially severe liver injury, adrenal gland problems, and harmful drug interactions. Ketoconazole tablets are only indicated when other treatments are not tolerated or have failed for:

• blastomycosis—a potentially serious disease of the skin, lymph nodes, and lungs caused by yeast-like fungi of the genus Blastomyces
• coccidioidomycosis or valley fever—a rare disease caused by inhaling microscopic spores of the soil fungus Coccidioides immitis or cocci, which is on the increase in the southwestern United States
• histoplasmosis—a respiratory disease caused by the fungus Histoplasma capsulatum
• chromomycosis—a fungal skin disease caused by various pigmented fungi
• paracoccidioidomycosis—the South American form of blastomycosis, caused by the fungus Paracoccidioides brasiliensis

Oral ketoconazole is no longer indicated for candida or dermatophyte infections unless other drugs are not available or tolerated. Ketoconazole cannot treat fungal meningitis since it does not penetrate the cerebrospinal fluid.

Off-label use

High doses may be used for other non-FDA-approved purposes, including Cushing syndrome (a condition caused by excess corticosteroid hormone) and advanced.

DESCRIPTION

Ketoconazole is an imidazole derivative that slows the growth of fungal pathogens. Topical ketoconazole can be quite effective, with symptoms improving upon first application.

The triazole antifungal oral medications, fluconazole, and itraconazole have a higher affinity for fungal cell membranes for internal and systemic infections. Usually, they are more effective at lower doses with fewer adverse effects.

However, some of the side effects of ketoconazole can be useful for treating other conditions. In humans, ketoconazole inhibits enzymes that convert cholesterol to steroid hormones such as cortisol and testosterone.

Thus, ketoconazole can suppress glucocorticoid synthesis in patients with Cushing syndrome. At very high oral doses (400 milligrams [mg] three times daily), ketoconazole acts as an antiandrogen to block testosterone production in advanced androgen-dependent prostate cancer.

It also acts as a weak androgen receptor antagonist, preventing testosterone and dihydrotestosterone from binding to their receptors.

U.S. brand names

In addition to various generic ketoconazole products, U.S. brand names include:

• Ketozole cream
• Nizoral cream
• Extina foam
• Xolegel
• Nizoral shampoo
• Nizoral AD shampoo
• Nizoral oral tablets

Canadian brand names

Canadian brand names include Nizoral, Apo-Ketoconazole, and Ketoderm.

International brand names

There are many international brand names for ketoconazole, including:

• Arcolane
• Cetoconazol
• Dezor
• Diazon
• Fungoral
• Ketozol
• Nizoral
• Oronazol

Origins

The FDA approved the prescription Nizoral 2% topical shampoo in 1990. Generic 2% topical shampoos, creams, aerosol foams, and 200 mg oral tablets were approved in 1999.

Ketozole 2% topical prescription cream was approved in 2002. Xolegel 2% topical prescription gel was approved in 2006. Extina 2% topical prescription aerosol foam was approved in 2007. Ketoconazole shampoo is available without a prescription for treating dandruff.

Topical ketoconazole is on the list of essential medicines of the World Health Organization (WHO), and 50 mg capsules are on WHO’s the list of essential medicines for children.

However, the European Medicines Agency banned oral ketoconazole in 2013. It was previously banned in France and Australia.

RECOMMENDED DOSAGE

The affected area and surrounding skin are covered with ketoconazole cream, usually once daily for two to six weeks.

Prescription ketoconazole shampoo is generally used once (over-the-counter ketoconazole shampoo can be used every three to four days for up to eight weeks and as needed).

The affected skin is wetted with a small amount of water, and the prescription shampoo is applied to the affected skin and a large surrounding area.

It is lathered with the fingers, left on for five minutes, and then rinsed off with water.

The usual adult dosage of oral ketoconazole for blastomycosis, chromomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis is 200 mg once daily for six months. The dosage may be increased to 400 mg. Ketoconazole tablets should be taken with a meal and an acidic drink such as non-diet cola.

Pediatric

The usual oral dosages in children two years and older—when other antifungal therapy is not available or tolerated, and benefits outweigh risks—is 3.3–6.6 mg per kilogram (kg, or 2.2 lb.) of body weight once daily for six months.

PRECAUTIONS

The use of ketoconazole cream should continue even after symptoms improve to cure the infection completely. Ketoconazole shampoo may remove the curl from “permed” hair.

Oral ketoconazole comes with a boxed warning:

• It should exclusively be used when other medications are unavailable or not tolerated.
• It may cause liver damage requiring a liver transplant or leading to death, even in patients with healthy liver or risk factors for liver damage.
• Alcohol should be avoided during treatment because it can increase the risk of liver damage.
• Patients should tell their doctors if they drink or have ever drunk large amounts of alcohol or have ever had liver disease.
• The doctor should be informed urgently if any of the following symptoms occur: extreme tiredness, loss of appetite, sudden weight loss, nausea, vomiting, yellowing of the skin or eyes, dark yellow urine, pale stools, and pain upper-right stomach, fever, or rash.
• Ketoconazole can cause an irregular heart rhythm called QT prolongation, leading to fainting, seizures, unconsciousness, or sudden death. The doctor should be called instantly if any of the following symptoms occur: fast, pounding, irregular heartbeat; dizziness, light-headedness, or fainting; loss of consciousness.
• Patients must not take disopyramide, dofetilide, dronedarone, pimozide, quinidine, cisapride, methadone, or ranolazine while taking ketoconazole.
• Tests are required to check responses to ketoconazole.
• Patients should discuss the risks of ketoconazole with their doctor.

Patients should tell their doctors, laboratory personnel, and dentists that they are taking ketoconazole before laboratory tests or surgery. Ketoconazole should be continued until the doctor orders it stopped since stopping too soon may cause the infection to return quickly. Ketoconazole may decrease sperm production, especially at high doses.

Pregnant or breastfeeding

Ketoconazole is in FDA pregnancy category C—animal studies indicate adverse effects on a fetus from oral ketoconazole. It should only be used while pregnant if potential benefits outweigh potential risks to the fetus. Topical ketoconazole should be used with caution during breastfeeding. Oral ketoconazole is excreted in human milk, and its use is not recommended while breastfeeding.

Other conditions and allergies

Patients should tell their doctor and pharmacist if they are allergic to ketoconazole, ingredients in ketoconazole tablets, or any other medications, creams, or shampoos. If using ketoconazole cream, patients should tell their doctor if they are allergic to sulfites or have ever had asthma. Patients should consult urgently with their doctor if they have ever had any medical condition, especially liver disease or adrenal insufficiency. The adrenal glands do not make sufficient steroid hormones. Patients with acute or chronic liver disease should not take oral ketoconazole.

Oral ketoconazole absorption is decreased in patients with reduced stomach acidity from disease or medication.

SIDE EFFECTS

Patients should consult their doctors if any of the following side effects of topical ketoconazole are severe or persistent:

• irritation, itching, or stinging
• dry skin
• oily or dry hair or scalp
• changes in hair texture
• scalp blisters

The doctor should be alerted immediately if any of the following uncommon side effects occur with topical ketoconazole:

• redness, tenderness, swelling, pain, or warmth
• rash
• hives
• difficulty breathing or swallowing

The doctor should be alerted if any of the following symptoms of oral ketoconazole are severe or persistent:

• headache
• stomach pain
• diarrhea
• constipation
• heartburn
• gas
• changes in food tastes
• dry mouth
• change in tongue color
• difficulty falling or staying asleep
• nervousness
• numbness, burning, or tingling of the limbs
• muscle pain
• hair loss
• flushing
• chills
• light sensitivity
• nosebleeds
• breast enlargement in males
• decrease in sexual ability

The following uncommon but serious side effects of oral ketoconazole require immediately contacting the doctor or obtaining emergency medical treatment:

• symptoms listed in the boxed warning
• rash
• hives
• itching
• swelling of the eyes, face, lips, tongue, hands, feet, ankles, or lower legs
• hoarseness
• difficulty breathing or swallowing
• tiredness or weakness

INTERACTIONS

The doctor and pharmacist should be informed of any prescription and nonprescription medicines, herbs, vitamins, minerals, and dietary supplements being used by the patient. Patients should bring a list of medications and supplements to all medical appointments and carry the list with them in case of an emergency.

Drugs

In addition to the medications listed in the boxed warning, oral ketoconazole should not be taken by patients taking:

• alprazolam
• eplerenone
• ergot alkaloids such as ergotamine, dihydroergotamine, or methylergonovine
• felodipine
• irinotecan
• lovastatin
• lurasidone
• midazolam
• nisoldipine
• simvastatin
• tolvaptan
• triazolam

Many medications can interact with ketoconazole. The following drugs may require changing dosages and/or carefully monitoring for side effects:

• aliskiren
• anticoagulants such as dabigatran, rivaroxaban, and warfarin
• aprepitant
• aripiprazole
• atorvastatin
• bosentan
• budesonide
• buspirone
• carbamazepine
• calcium channel blockers such as amlodipine , diltiazem , nicardipine, nifedipine , and verapamil
• cancer medications such as bortezomib, busulfan, dasatinib, docetaxel, erlotinib, ixabepilone, lapatinib, nilotinib, paclitaxel, trimetrexate, vincristine, vinblastine, and vinorelbine
• ciclesonide
• cilostazol
• cinacalcet
• colchicine
• dexamethasone
• digoxin
• eletriptan
• fentanyl
• fesoterodine
• fluticasone
• haloperidol
• HIV medications such as darunavir, efavirenz, fosamprenavir, indinavir, maraviroc, nevirapine, ritonavir, and saquinavir
• immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus
• imatinib
• erectile dysfunction medications such as sildenafil, tadalafil, and vardenafil
• indigestion, heartburn, or ulcer medications such as cimetidine, famotidine, lansoprazole, nizatidine, omeprazole, and ranitidine
• methylprednisolone
• nadolol
• oxycodone
• phenytoin
• praziquantel
• quetiapine
• ramelteon
• repaglinide
• risperidone
• salmeterol
• saxagliptin
• solifenacin
• tamsulosin
• telithromycin
• tolterodine
• tuberculosis medications such as isoniazid, rifabutin, and rifampin

Antacids containing aluminum, calcium, magnesium, or other acid-secretion suppressors or acid neutralizers should be taken a minimum of one hour before or two hours after taking ketoconazole.

Food and other substances

Alcohol, including beer, wine, or alcohol-containing medications such as cough syrup, increase the risk of liver damage from ketoconazole and can cause side effects such as flushing, rash, nausea, headache, and swelling of the hands, feet, ankles, or lower legs.

RESOURCES