Usual Adult Dose for Cushing's Syndrome

Initial dose: 150 mg orally twice a day
Maintenance dose: Titrate the dosage by 150 mg daily, no more frequently than every 2 to 3 weeks based on 24-hour urine free cortisol levels and patient's tolerability, until adequate response is achieved.
Maximum dose: 1200 mg per day, administered as 600 mg twice a day

Use: Treatment of endogenous hypercortisolemia in patients with Cushing's syndrome when surgery is not an option or has not been curative

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease: Contraindicated

If Hepatotoxicity Develops During Therapy:

• If ALT or AST greater than or equal to 5 times the upper limit of normal (5 x ULN) regardless of total bilirubin level: Permanently discontinue this drug.
• If ALT or AST greater than or equal to 3 x ULN and total bilirubin greater than 2 x ULN: Permanently discontinue this drug.
• If ALT or AST greater than or equal to 3 x ULN and less than 5 x ULN, and total bilirubin less than or equal to 2 x ULN:
• Temporarily discontinue this drug.
• Monitor liver tests every 3 days until levels are stable, and then no less than every 7 to 10 days until tests have returned to baseline levels.
• Restart treatment at a lower dosage and titrate slowly once liver tests are normal, and other contributing factors are addressed.
• Before increasing dosage, monitor liver tests weekly for 1 month and routinely thereafter.
• Permanently discontinue if a liver test abnormality significantly above the patient's baseline recurs after restarting.
• If ALT or AST is greater than ULN but less than 3 x ULN, with a total bilirubin of any value:
• If liver tests increase above the patient's baseline, monitor liver tests no less than every 7 to 10 days until tests have returned to baseline levels. Consider temporary discontinuation of treatment during this time.
• If treatment is discontinued, restart at a lower dosage and titrate slowly once liver tests return to baseline and other possible contributing factors have been addressed. Before considering a dosage increase, monitor liver tests weekly for 1 month to ensure stability of liver tests.

Dose Adjustments

The dosage may be reduced to 150 mg orally once a day if needed for tolerability.

QT PROLONGATION:

• Temporarily discontinue treatment if the QTcF interval is longer than 500 msec.
• After correction of other possible contributing factors (e.g., hypokalemia, hypomagnesemia, use of concomitant drugs), treatment may be resumed at a lower dosage when the QTcF interval returns to 500 msec or less.
• If QT interval prolongation recurs after restarting treatment, permanently discontinue this drug.

• Decrease the dosage or temporarily discontinue treatment if urine free cortisol or morning serum or plasma cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, or if signs and/or symptoms consistent with hypocortisolism are reported.
• Stop this drug and administer exogenous glucocorticoid replacement therapy if morning serum or plasma cortisol levels are below target range and signs and/or symptoms of adrenal insufficiency or hypocortisolism are present.
• Reinitiate at a lower dosage when cortisol levels are within target ranges and signs and/or symptoms of hypocortisolism have resolved. The dosage may be titrated to the previous dose associated with hypocortisolism if the reduced dosage has been well tolerated and the reduced dosage does not achieve an adequate clinical response.

Precautions

US BOXED WARNINGS:

• HEPATOTOXICITY: Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving this drug. This drug is contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease. Liver enzymes should be evaluated prior to and during treatment. Treatment with this drug should be interrupted immediately if signs of hepatotoxicity occur.
• QT PROLONGATION: This drug is associated with dose-related QT interval prolongation. QT interval prolongation may lead to life-threatening ventricular dysrhythmias such as torsades de pointes. Coadministration of this drug with other drugs that prolong the QT interval associated with ventricular arrhythmias, including torsades de pointes, and use in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history) are contraindicated. An ECG should be performed, and hypokalemia and hypomagnesemia should be corrected prior to and during treatment. This drug should be temporarily discontinued if QTcF interval exceeds 500 msec.

• Patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT greater than 3 x ULN, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease
• Use with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes
• Prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history)
• Known hypersensitivity to the active component, ketoconazole, or any of the ingredients
• Use of certain drugs that are sensitive substrates of CYP450 3A4 or CYP450 3A4 and P-gp

Dialysis

Data not available

Other Comments

Administration advice:

• Before treatment initiation, obtain baseline liver tests (ALT, AST, total bilirubin); carefully consider risks/benefits of starting this drug in patients with AST or ALT above normal but at least 3 x ULN.
• Before treatment initiation, obtain baseline ECG.
• Before treatment initiation, correct hypokalemia and hypomagnesemia.
• This drug can be taken with or without food.
• If a dose is missed, take the next dose at the regularly scheduled time.

• Store at 20C to 25C (68F to 77F).

• Limitations of Use: This drug is not approved for the treatment of fungal infections; safety and efficacy have not been established for this indication.

• Frequent monitoring of liver tests as recommended:
• Monitor liver enzymes and bilirubin weekly for at least 6 weeks after starting treatment, every 2 weeks for the next 6 weeks, monthly for the next 3 months, and then as clinically indicated.
• After any dose interruption or dose increase, monitor on a weekly basis until a stable dosage is achieved.
• Perform ECG routinely to monitor effects in QT interval (especially after a stable dosage is achieved):
• Conduct ECG before each dose increase.
• Monitor potassium and magnesium blood levels periodically during treatment.
• Monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient's signs and symptoms for hypocortisolism periodically.

• Read the US FDA-approved patient labeling (Patient Information).
• Contact health care provider immediately for signs/symptoms of hepatotoxicity (e.g., right upper quadrant pain associated with nausea, unusual fatigue, signs of jaundice, unusual bruising/bleeding).
• Avoid excessive alcohol consumption while using this drug.
• Follow your healthcare provider visit schedule and laboratory tests appointments closely.
• Report to your healthcare provider the use of all prescription and nonprescription medications.
• Contact your healthcare provider immediately for signs/symptoms of QT prolongation, including if you feel severely lightheaded or faint.
• Promptly report signs/symptoms of hypocortisolism to health care provider.
• Contact health care provider if signs/symptoms of hypersensitivity reaction occur.
• Patients of childbearing potential should inform their healthcare provider of any known or suspected pregnancy.
• This drug may impair fertility.