Ketoconazole (Systemic)

• It is used to treat fungal infections.
• This medicine is not for use to treat fungal infections of the skin, nails, or brain. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Belly pain.
• Upset stomach.
• Loose stools (diarrhea).
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about ketoconazole, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about ketoconazole. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using ketoconazole.

Review Date: October 4, 2017

• Nizoral

Alters the permeability of the cell wall by blocking fungal cytochrome P450; inhibits biosynthesis of triglycerides and phospholipids by fungi; inhibits several fungal enzymes that results in a build-up of toxic concentrations of hydrogen peroxide; for management of prostate cancer, ketoconazole inhibits androgen synthesis

Distribution

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

Metabolism

Partially hepatic via CYP3A4 to inactive metabolites

Excretion

Feces (57%); urine (13%)

Time to Peak

Serum: 1-2 hours

Half-Life Elimination

Biphasic: Initial: 2 hours; Terminal: 8 hours

Protein Binding

~99% (mainly albumin)

Cushing syndrome

Data from a retrospective multicenter study support the use of ketoconazole in the management of patients with Cushing disease. The study authors found the side effects of ketoconazole to be acceptable; however, close monitoring of liver enzymes is advised. Additional trials may be necessary to further define the role of ketoconazole in this condition.

Based on the Endocrine Society’s Clinical Practice Guidelines for Treatment of Cushing’s Syndrome, ketoconazole is an effective and recommended agent for the medical treatment of Cushing syndrome. Medical treatment for this condition using a steroidogenesis inhibitor (eg, ketoconazole) is recommended as second line therapy after transsphenoidal selective adenomectomy (with or without radiation therapy or radiosurgery), primary treatment of occult or metastatic ectopic ACTH secretion, or as adjunctive treatment to decrease cortisol levels in adrenocortical carcinoma. Access Full-Off Label Monograph

Prostate cancer, advanced

Data from two prospective, randomized trials in patients with prostate cancer and the antiandrogen withdrawal (AAWD) phenomenon support the use of ketoconazole (in combination with oral hydrocortisone) in the treatment of this condition [Ryan 2007], [Small 2003].

Fungal infections (systemic): Oral: 200 mg once daily; may increase to 400 mg once daily if response is insufficient. Continue until active fungal infection is resolved; some infections may require a treatment duration of up to 6 months.

Prostate cancer, advanced (off-label use): Oral: 400 mg 3 times daily (in combination with oral hydrocortisone) until disease progression (Ryan 2007; Small 2004)

Cushing syndrome (off-label use): Oral: Initial: 400 to 600 mg daily in 2 or 3 divided doses; may increase dose by 200 mg daily every 7 to 28 days up to a maximum of 1,200 mg daily in 2 or 3 divided doses; dosage range: 200 to 1,200 mg daily; mean effective dose in most studies: 600 to 800 mg daily in 2 divided doses (Castinetti 2014; ES [Nieman 2015]; Miller 1993)

A 20 mg/mL oral suspension may be made with tablets and one of three different vehicles (a 1:1 mixture of Ora-Sweet® and Ora-Plus®, a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®, or a 1:4 mixture of cherry syrup and Simple Syrup, NF). Crush twelve 200 mg tablets in a mortar and reduce to a fine powder. Add 20 mL of chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “refrigerate”. Stable for 60 days.

Concerns related to adverse effects:

• Adrenal suppression: High doses of ketoconazole may depress adrenocortical function; returns to baseline upon discontinuation of therapy. Recommended maximum dosing should not be exceeded. Monitor adrenal function as clinically necessary, particularly in patients with adrenal insufficiency and in patients under prolonged stress (eg, intensive care, major surgery).

• Bone fragility: In animal studies, increased long bone fragility with cases of fracture has been observed with high-dose ketoconazole. Careful dose selection may be advisable for patients susceptible to bone fragility (eg, postmenopausal women, elderly).

• Hypersensitivity reactions: Cases of hypersensitivity reactions (including rare cases of anaphylaxis) have been reported; some reactions occurred after the initial dose.

• Myopathy: Coadministration with HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin) may increase the risk of myopathy. Concomitant use is contraindicated.

• Sedation: Coadministration with midazolam, triazolam, and alprazolam may result in elevated plasma concentrations of the benzodiazepines, leading to prolonged hypnotic and sedative effects. Concomitant use is contraindicated.

Disease-related concerns:

• Achlorhydria: Absorption is reduced in patients with achlorhydria; administer with acidic liquids (eg, soda pop). Avoid concomitant use of drugs that decrease gastric acidity (eg, proton pump inhibitors, antacids, H2-blockers).

• CNS infections: Ketoconazole has poor penetration into cerebral-spinal fluid and should not be used to treat fungal meningitis.

• Hepatic impairment: [US Boxed Warning]: Ketoconazole has been associated with hepatotoxicity, including fatal cases and cases requiring liver transplantation; some patients had no apparent risk factors for hepatic disease. Patients should be advised of the hepatotoxicity risks and monitored closely. Toxicity was observed after a median duration of therapy of ~4 weeks, but has also been noted after as little as 3 days; may occur when patients receive high doses for short durations or low doses for long durations. Most cases have been observed in the treatment of onychomycosis. Use with caution in patients with preexisting hepatic impairment, those on prolonged therapy and/or taking other hepatotoxic drugs concurrently. Hepatic dysfunction is typically (but not always) reversible upon discontinuation. Obtain liver function tests at baseline and frequently throughout therapy; serum ALT should be monitored weekly throughout therapy. Discontinue therapy for elevated hepatic enzymes that persist or worsen or if accompanied by signs/symptoms (eg, jaundice, nausea/vomiting, dark urine) of hepatic injury.

• Prostate cancer: In European clinical trials of men with metastatic prostate cancer, fatalities were reported in a small number of study participants within 14 days of initiating high-dose ketoconazole (1,200 mg daily); a causal effect has not been established.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• QT prolongation: [US Boxed Warning]: Concomitant use with cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, and ranolazine is contraindicated due to the possible occurrence of life-threatening ventricular arrhythmias such as torsade de pointes.

Other warnings/precautions:

• Appropriate use: [US Boxed Warning]: Use only when other effective antifungal therapy is unavailable or not tolerated and the benefits of ketoconazole treatment are considered to outweigh the risks. Ketoconazole oral tablets are approved to treat systemic fungal infections and should not be prescribed to treat skin and nail fungal infections. The risks of serious liver damage, adrenal gland problems and drug-drug interactions outweigh any potential benefit.