Ketoconazole

Pregnancy category: C

Lactation: Drug enters breast milk

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Inhibits cytochrome P450-dependent synthesis of ergosterol, which in turn inhibits cell-membrane formation

Cushing syndrome (off-label): Inhibition of P450 enzymes includes the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol

Absorption

Rapid (~75%)

Bioavailability: Decreases as gastric pH increases

Peak plasma time: 1-2 hr

Distribution

Well distributed into inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissue, testes; crosses blood-brain barrier poorly, with only negligible amounts reaching CSF

Protein bound: 93-96%

Metabolism

Partially metabolized in liver via CYP3A4 to inactive compounds

Elimination

Half-life: Biphasic: initial, 2 hr; terminal, 8 hr

Excretion: Feces (57%), urine (13%)

Ketoconazole comes as a tablet to take by mouth. It is usually taken once a day Take ketoconazole at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ketoconazole exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may increase your dose if your condition does not improve.

You may need to take ketoconazole for 6 months or longer to cure your infection completely. Continue to take ketoconazole until your doctor tells you that you should stop, even if you feel better. Do not stop taking ketoconazole without talking to your doctor. If you stop taking ketoconazole too soon, your infection may come back after a short time.

High doses of ketoconazole are sometimes used to treat Cushing syndrome (a condition that occurs when there is too much corticosteroid hormone in the body) and advanced prostate cancer (cancer of a male reproductive gland). Ketoconazole has not been shown to be safe or effective for these uses. Talk to your doctor about using ketoconazole for your condition.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Before taking ketoconazole,

• tell your doctor and pharmacist if you are allergic to ketoconazole or any other medications or any of the ingredients in ketoconazole tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor if you are taking alprazolam (Niravam, Xanax);eplerenone (Inspra); ergot alkaloids such as ergotamine (Ergomar, in Cafergot, in Migergot), dihydroergotamine (D.H.E 45, Migranal), and methylergonovine (Methergine); felodipine (Plendil); irinotecan (Camptosar); lovastatin (Mevacor); lurasidone (Latuda); midazolam (Versed); nisoldipine (Sular); simvastatin (Zocor); tolvaptan (Samsca); and triazolam (Halcion). Your doctor will probably tell you not to take ketoconazole if you are taking one or more of these medications or any of the medications listed in the IMPORTANT WARNING section.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: aliskiren (Tekturna, in Valturna, in Amturnide); anticoagulants ('blood thinners') such as dabigatran (Pradaxa), rivaroxaban (Xarelto) and warfarin (Coumadin); aprepitant (Emend); aripiprazole (Abilify); atorvastatin (Lipitor); bosentan (Tracleer); budesonide (Uceris); buspirone (BuSpar); carbamazepine (Tegretol); calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac), nicardipine (Cardene), nifedipine (Adalat, Procardia), and verapamil (Calan, Covera, Isoptin, Verelan); cancer medications such as bortezomib (Velcade); busulfan (Myleran); dasatinib (Sprycel); docetaxel (Taxotere), erlotinib (Tarceva); ixabepilone (Ixempra); lapatinib (Tykerb); nilotinib (Tasigna);paclitaxel (Taxol), trimetrexate (Neutrexin), vincristine (Vincasar), vinblastine, and vinorelbine (Navelbine); ciclesonide (Alvesco); cilostazol (Pletal); cinacalcet (Sensipar); colchicine (Colcrys, in Col-Probenecid); dexamethasone; digoxin (Lanoxin); eletriptan (Relpax); fentanyl (Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis); fesoterodine (Toviaz); fluticasone (Flonase, Flovent); haloperidol (Haldol); HIV medications such as darunavir (Prezista), efavirenz (Sustiva), fosamprenavir (Lexiva),indinavir (Crixivan), maraviroc (Selzentry), nevirapine (Viramune), ritonavir (Norvir), and saquinavir (Invirase, Fortovase); immunosuppressants such as cyclosporine (Neoral, Sandimmune), everolimus (Afinitor, Zortress),sirolimus (Rapamune), and tacrolimus (Prograf); imatinib (Gleevec); medications for erectile dysfunction such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra); medications for indigestion, heartburn, or ulcers such as cimetidine (Tagamet), famotidine (Pepcid), lansoprazole (Prevacid), nizatidine (Axid), omeprazole (Prilosec), and ranitidine (Zantac); medications to treat tuberculosis such as isoniazid (INH, Nydrazid), rifabutin (Mycobutin), rifampin (Rifadin, Rimactane); methylprednisolone (Medrol); nadolol (Corgard); oxycodone (Oxecta, Oxy Contin, in Percocet, others); phenytoin (Dilantin); praziquantel (Biltricide); quetiapine (Seroquel); ramelteon (Rozerem); repaglinide (Prandin, in PrandiMet); risperidone (Risperdal); salmeterol (Serevent, in Advair);saxagliptin (Onglyza); solifenacin (Vesicare); immunosuppressants such as cyclosporine (Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Prograf); tamsulosin (Flomax, in Jalyn); telithromycin (Ketek); and tolterodine (Detrol) . Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with ketoconazole, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• if you are taking an antacid containing aluminum, calcium, or magnesium (Maalox, Mylanta, Tums, others), take it 1 hour before or 2 hours after you take ketoconazole.
• tell your doctor if you have or have ever had the conditions mentioned in the IMPORTANT WARNING section or adrenal insufficiency (condition in which the adrenal glands do not make enough steroid hormones).
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking ketoconazole, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking ketoconazole.
• you should know that drinking alcoholic beverages (including wine, beer, and medications that contain alcohol such as cough syrup) while taking ketoconazole increases the risk that you will develop liver damage and may cause unpleasant symptoms such as flushing, rash, nausea, headache, and swelling of the hands, feet, ankles, or lower legs if you drink alcohol while you are taking ketoconazole.

Ketoconazole may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

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

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

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

Ketoconazole may cause a decrease in the number of sperm (male reproductive cells) produced, especially if it is taken at high doses. Talk to your doctor about the risks of taking this medication if you are a man and would like to have children.

Ketoconazole may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking ketoconazole.

Do not let anyone else take your medication. Ask your pharmacist if you have any questions about refilling your prescription. If you still have symptoms of infection after you finish the ketoconazole, call your doctor.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Nizoral^®

Common Side Effects of Ketoconazole

Tell your doctor if any of the following side effects become severe or don't go away:

• Headache
• Stomach pain, diarrhea, or constipation
• Heartburn or gas
• Change in the ability to taste
• Change in tongue color
• Dry mouth
• Difficulty sleeping
• Nervousness
• Numbness, tingling, or burning of the hands or feet
• Hair loss
• Flushing
• Chills
• Muscle pain
• Sensitivity to light
• Nosebleeds
• Breast enlargement in men
• Decreased sexual ability

Serious Side Effects of Ketoconazole

Tell your doctor immediately if you experience any of the symptoms listed in the Warning section or any of the following serious side effects:

• Rash, hives, or itching
• Swelling of the eyes, face, lips, tongue, hands, feet, ankles, or lower legs
• Hoarseness
• Extreme tiredness
• Weakness
• Difficulty breathing or swallowing

When Ketoconazole Cream 2% was applied dermally to intact or abraded skin of Beagle dogs for 28 consecutive days at a dose of 80 mg, there were no detectable plasma levels using an assay method having a lower detection limit of 2 ng/ml.

After a single topical application to the chest, back and arms of normal volunteers, systemic absorption of ketoconazole was not detected at the 5 ng/ml level in blood over a 72-hour period.

Two dermal irritancy studies, a human sensitization test, a phototoxicity study and a photoallergy study conducted in 38 male and 62 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity and no photoallergenic potential due to Ketoconazole Cream 2%.

Microbiology

Ketoconazole is a broad spectrum synthetic antifungal agent which inhibits the in vitro growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans, Malassezia ovate (Pityrosporum ovale) and C. tropicalis; and the organism responsible for tinea versicolor, Malassezia furfur (Pityrosporum orbiculare). Only those organisms listed in the INDICATIONS Section have been proven to be clinically affected. Development of resistance to ketoconazole has not been reported.

Mode of Action

In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated that the therapeutic effect of ketoconazole in seborrheic dermatitis is due to the reduction of M. ovale, but this has not yet been proven.

XOLEGEL is indicated for the topical treatment of seborrheic dermatitis in immunocompetent adults and children 12 years of age and older.

Safety and efficacy of XOLEGEL for treatment of fungal infections have not been established.

Ketoconazole is a prescription medication used to treat fungal infections, including the following: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis for patients in which other treatments have failed or who are intolerant to other therapies.

Ketoconazole tablets are not for people with fungal nail infections.

Ketoconazole is also available in topical forms - a gel, cream, foam, and shampoo - to treat forms of dermatitis and fungal infections of the skin. A form of the shampoo is available without a prescription for the treatment of dandruff.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

You should not use ketoconazole topical if you are allergic to it.

Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antifungal medication.

Do not use bandages or dressings over the treated skin areas, unless your doctor has told you to.

Avoid getting this medication in your eyes, nose, or mouth.

Stop using ketoconazole topical and call your doctor if you have severe burning, irritation, redness, pain, or oozing where the medicine is applied.

Ketoconazole topical gel is flammable. Do not use it while you are smoking or near an open flame.

Do not use this medication on a child younger than 12 years old.

Your pharmacist can provide more information about ketoconazole topical.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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This medicine should be used only when you cannot use other antifungal medications. Ketoconazole can cause serious harm to your liver that may result in liver transplant or cause death.

Call your doctor at once if you have any signs of liver damage, such as nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Some medicines can interact with ketoconazole and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs: alprazolam, cisapride, dihydroergotamine, disopyramide, dofetilide, dronedarone, eplerenone, ergotamine, lovastatin, methadone, midazolam, nisoldipine, pimozide, quinidine, ranolazine, simvastatin, or triazolam. Certain drug interactions can cause life-threatening irregular heartbeats.

Call your doctor right away if you have a headache with chest pain and severe dizziness, and fast or pounding heartbeats.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using ketoconazole.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Do not share this medicine with another person, even if they have the same symptoms you have.

While using ketoconazole, you may need frequent blood tests to check your liver function.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antifungal medicine. Ketoconazole will not treat a viral infection such as the common cold or flu.

Store at room temperature away from moisture and heat.

Get emergency medical help if you have signs of an allergic reaction: hives; fever; difficulty breathing, chest pain; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;

• unusual weakness or tired feeling, nausea and vomiting; or

• liver problems--upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

Common side effects may include:

• mild nausea or stomach pain;

• diarrhea; or

• headache.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Storage

Oral

20–25°C;384 protect from moisture.384

In the U.S.

• Nizoral

Available Dosage Forms:

• Tablet

Therapeutic Class: Antifungal

Chemical Class: Imidazole

Take ketoconazole exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Do not stop taking ketoconazole without checking first with your doctor.

ketoconazole should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

It is best to take ketoconazole with food.

Keep using ketoconazole for the full treatment time, even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon.

If you are taking ketoconazole together with an antacid-containing aluminum, it should be taken with an acidic beverage (such as non-diet cola). Antacid-containing aluminum should be taken at least 1 hour before or 2 hours after taking ketoconazole.

Dosing

The dose of ketoconazole will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ketoconazole. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For fungal infections:
    • Adults—At first, 200 milligrams (mg) once a day. Your doctor may increase your dose as needed.
    • Children 2 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 3.3 to 6.6 milligrams (mg) per kilogram (kg) of body weight per day.
    • Children younger than 2 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of ketoconazole, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Initial dose: 200 mg orally once a day
If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
Duration of therapy: 6 months (usual duration for systemic infection)

Comments:
-Use of ketoconazole is only recommended when other effective antifungal therapy is not available or tolerated and the benefits outweigh the risks.
-Ketoconazole should not be used for fungal meningitis (penetrates poorly into CSF).
-The Infectious Diseases Society of America (IDSA) guidelines recommend amphotericin B and itraconazole as preferred therapies for blastomycosis and histoplasmosis.

Uses: For treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis

Initial dose: 200 mg orally once a day
If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
Duration of therapy: 6 months (usual duration for systemic infection)

Comments:
-Use of ketoconazole is only recommended when other effective antifungal therapy is not available or tolerated and the benefits outweigh the risks.
-Ketoconazole should not be used for fungal meningitis (penetrates poorly into CSF).
-The Infectious Diseases Society of America (IDSA) guidelines recommend amphotericin B and itraconazole as preferred therapies for blastomycosis and histoplasmosis.

Uses: For treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis

2 years or older: 3.3 to 6.6 mg/kg orally once a day
Duration of therapy: 6 months (usual duration for systemic infection)

Comments:
-Ketoconazole should not be used unless the benefit outweighs the risks.
-Ketoconazole should not be used for fungal meningitis (penetrates poorly into CSF).
-The IDSA guidelines recommend amphotericin B and itraconazole as preferred therapies for blastomycosis and histoplasmosis.

Uses: For treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis

2 years or older: 3.3 to 6.6 mg/kg orally once a day
Duration of therapy: 6 months (usual duration for systemic infection)

Comments:
-Ketoconazole should not be used unless the benefit outweighs the risks.
-Ketoconazole should not be used for fungal meningitis (penetrates poorly into CSF).
-The IDSA guidelines recommend amphotericin B and itraconazole as preferred therapies for blastomycosis and histoplasmosis.

Uses: For treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis

Administration advice:
-Take with a meal.
-Administer ketoconazole with an acidic drink (such as non-diet cola) if gastric acidity is reduced (e.g., in patients with achlorhydria due to certain diseases, in patients using acid secretion suppressors or acid-neutralizing therapy); administer acid-neutralizing agents at least 1 hour before or 2 hours after ketoconazole.

Storage requirements:
-Protect from moisture.

General:
-There should be laboratory as well as clinical documentation of infection before starting ketoconazole therapy.
-Therapy should continue until active fungal infection has subsided.
-Ketoconazole requires acidity for dissolution and absorption; absorption impaired when gastric acid production is reduced.
-Ketoconazole may potentially interact with many drugs; such interactions may be serious and/or life-threatening; the manufacturer product information should be consulted.

Monitoring:
-Endocrine: Adrenal function in patients with adrenal insufficiency, with borderline adrenal function, or under prolonged periods of stress
-General: Antifungal activity and/or ketoconazole plasma levels when certain drugs coadministered
-Hematologic: Laboratory tests such as prothrombin time, INR (at baseline)
-Hepatic: Laboratory tests such as serum GGT, alkaline phosphatase, ALT, AST, total bilirubin (at baseline); testing for viral hepatitides (at baseline); serum ALT (weekly for duration of therapy); full set of liver tests (if ALT increases to above ULN or 30% above baseline, or if symptoms of liver injury develop); for recurring liver injury (frequently if drug restarted after interruption due to increased ALT or symptoms of liver injury)

Patient advice:
-Report any signs/symptoms suggesting liver dysfunction (including unusual fatigue, anorexia, nausea and/or vomiting, abdominal pain, jaundice, dark urine, pale stools).
-Do not consume alcohol during therapy.