Method of administration

ZYTIGA should be taken at least two hours after eating and no food should be eaten for at least one hour after taking the tablets. These should be swallowed whole with water.

4.3 Contraindications

 - Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

- Women who are or may potentially be pregnant (see section 4.6)

4.4 Special warnings and precautions for use

 Hypertension, hypokalaemia and fluid retention due to mineralocorticoid excess

The phase 3 study conducted with ZYTIGA excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class III or IV heart disease or cardiac ejection fraction measurement of < 50%. ZYTIGA should be used with caution in patients with a history of cardiovascular disease. Safety in patients with left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure has not been established. Before treatment hypertension must be controlled and hypokalaemia must be corrected.

ZYTIGA may cause hypertension, hypokalaemia and fluid retention (see section 4.8) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure), severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment. Blood pressure, serum potassium and fluid retention should be monitored before treatment and at least monthly thereafter.

Hepatotoxicity

Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies (see section 4.8). Serum transaminase levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases, in particular serum ALT, should be measured immediately. If at any time the ALT rises above 5 times the upper limit of normal, treatment should be interrupted immediately and liver function closely monitored. Re-treatment may take place only after return of liver function tests to the patient's baseline and at a reduced dose level (see section 4.2).

If patients develop severe hepatotoxicity (ALT 20 times the upper limit of normal) anytime while on therapy, treatment should be discontinued and patients should not be re-treated.

Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are no data to support the use of ZYTIGA in this population.

Corticosteroid withdrawal and coverage of stress situations

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If ZYTIGA is continued after corticosteroids are withdrawn, patients shoul