AUDIENCE: Dermatology, Family Practice, Pharmacy, Patient
ISSUE: FDA is warning health care professionals to avoid prescribing the antifungal medicine ketoconazole oral tablets to treat skin and nail fungal infections. Use of this medication carries the risk of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions, which are not approved uses of the drug.
FDA approved label changes for oral ketoconazole tablets in 2013 to reflect these serious risks and to remove the indications for treatment of skin and nail fungal infections. However, an FDA safety review found that oral ketoconazole continues to be prescribed for these types of conditions. Since the 2013 labeling change, one patient death has been reported to the FDA due to liver failure associated with oral ketoconazole prescribed to treat a fungal infection of the nails. See the full MedWatch Communication at http://www.fda.gov/Drugs/DrugSafety/ucm500597.htm for further information.
BACKGROUND:Ketoconazole in tablet form is indicated to treat serious infections caused by fungi and should be used only when other effective therapy is not available or tolerated. It works by killing the fungus or preventing it from growing. The topical forms of ketoconazole that are applied to the skin or nails have not been associated with liver damage, adrenal problems, or drug interactions.
In a July 2013 Drug Safety Communication, FDA warned that ketoconazole tablets should not be used as a first-line treatment for any fungal infection because it can cause severe liver injury and adrenal gland problems, and advised it can lead to harmful interactions with other medicines. FDA determined that the risks outweigh the benefits for treating skin and nail fungal infections and approved label changes removing this indication from the drug label and limited its labeled indication to treating only serious fungal infections.
RECOMMENDATION:Health care professionals should use ketoconazole tablets only to treat serious fungal infections when no other antifungal therapies are available. Skin and nail fungal infections in otherwise healthy persons are not life-threatening, and so the risks associated with oral ketoconazole outweigh the benefits. Other treatment options are available over-the-counter and by prescription, but are also associated with risks that should be weighed against their benefits.
Patients should discuss with their health care professionals the risks and benefits of available therapies before using any medicine to treat skin and nail fungal infections. Patients taking ketoconazole tablets should seek medical attention right away if they experience any of these signs and symptoms of liver problems, which include loss of appetite, nausea, vomiting, or abdominal discomfort; yellowing of the skin or the whites of the eyes (jaundice); unusual darkening of the urine or lightening of the stools; or pain and discomfort in the right upper abdomen where the liver is located.
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Ketoconazole should only be used to treat fungal infections when other medications are not available or cannot be tolerated.
Ketoconazole may cause liver damage, sometimes serious enough to require liver transplantation or to cause death. Liver damage may occur in people who do not already have liver disease or any other conditions that increase the risk that they will develop liver damage. Tell your doctor if you drink or have ever drunk large amounts of alcohol and if you have or have ever had liver disease. Do not drink any alcoholic beverages during your treatment with ketoconazole because drinking alcoholic beverages may increase the risk that you will develop liver damage. If you experience any of the following symptoms, call your doctor immediately: extreme tiredness, loss of appetite, weight loss, nausea, vomiting, yellowing of the skin or eyes, dark yellow urine, pale stools, pain in the upper right part of the stomach, fever, or rash.
Ketoconazole can cause QT prolongation (an irregular heart rhythm that can lead to fainting, loss of consciousness, seizures, or sudden death). Do not take disopyramide (Norpace), dofetilide (Tikosyn), dronedarone (Multaq), pimozide (Orap), quinidine (Quinidex, Quinaglute), cisapride (Propulsid; no longer available in the US), methadone (Dolophine, Methadose), and ranolazine (Ranexa) while you are taking ketoconazole. If you experience any of the following symptoms, stop taking ketoconazole and call your doctor immediately: fast, pounding, or irregular heartbeat; fainting; dizziness; lightheadedness; or loss of consciousness.
Keep all appointments with your doctor and the laboratory. Your doctor will order certain tests to check your body's response to ketoconazole.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with ketoconazole and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer's website to obtain the Medication Guide.
Talk to your doctor about the risks of taking ketoconazole.
Why is this medication prescribed?
Ketoconazole is used to treat fungal infections when other medications are not available or cannot be tolerated. Ketoconazole should not be used to treat fungal meningitis (infection of the membranes surrounding the brain and spinal cord caused by a fungus) or fungal nail infections. Ketoconazole is in a class of antifungals called imidazoles. It works by slowing the growth of fungi that cause infection.
How should this medicine be used?
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.
Other uses for this medicine
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.
What special precautions should I follow?
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.
What special dietary instructions should I follow?
Unless your doctor tells you otherwise, continue your normal diet.
What should I do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?
Ketoconazole may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- stomach pain
- change in ability to taste food
- dry mouth
- change in tongue color
- difficulty falling asleep or staying asleep
- numbness, burning, or tingling of the hands or feet
- muscle pain
- hair loss
- sensitivity to light
- 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:
- swelling of the eyes, face, lips, tongue, hands, feet, ankles, or lower legs
- 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).
What should I know about storage and disposal of this medication?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.
In case of emergency/overdose
In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.
What other information should I know?
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.