Protyga 250 mg Uncoated tablets.

PROTYGA is indicated with low-dose corticosteroids (prednisone or prednisolone) in adult males for the treatment of:

• High-risk metastatic hormone treatment nau00efve prostate cancer (mHNPC) or newly diagnosed high-risk metastatic hormone sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (LHRH agonist or surgical castration). High-risk is defined as having at least 2 of the following 3 risk factors: 1. Gleason score of u2265 8; 2. Presence of 3 or more bone lesions; 3. Presence of measurable visceral (excluding lymph node disease) metastasis.
• Metastatic castration resistant prostate cancer with bone metastases who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.
• Metastatic advanced prostate cancer (castration resistant prostate cancer) who have received prior chemotherapy containing docetaxel.

Posology

The recommended dose of PROTYGA is 1 g (four 250 mg tablets) as a single daily dose that must not be taken with food. Taking PROTYGA with food increases systemic exposure to abiraterone (see section 4.5 and 5.2). Patients should be maintained on PROTYGA until radiographic progression and symptomatic/clinical progression and until PSA progression (confirmed 25 % increase over the patient's baseline/nadir).

Dosage of prednisone or prednisolone

For metastatic hormone nau00efve prostate cancer (mHNPC) or hormone sensitive prostate cancer (mHSPC), PROTYGA is used with 5 mg prednisone or prednisolone once daily. For metastatic castration-resistant prostate cancer (mCRPC), PROTYGA is used with 10 mg prednisone or prednisolone daily.

Recommended monitoring

Serum transaminases and bilirubin should be measured prior to starting treatment with PROTYGA, every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly (see section 4.4).

In the event of a missed daily dose of either PROTYGA, prednisone or prednisolone, treatment should be resumed the following day with the usual daily dose.

Hepatic impairment

No dose adjustment is necessary for patients with pre-existing mild hepatic impairment, Child-Pugh class A. There are no data on the clinical safety and efficacy of multiple doses of PROTYGA when administered to patients with moderate or severe hepatic impairment (Child-Pugh class B or C). No dose adjustment can be predicted. PROTYGA should not be used in patients with moderate to severe hepatic impairment (see section 4.3). For patients who develop hepatotoxicity during treatment with PROTYGA (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increases above 5 times the upper limit of normal or bilirubin increases above 3 times the upper limit of normal), treatment should be withheld immediately until liver function tests are back to pre-treatment status (see section 4.4). Re-treatment following return of liver function tests to the patient's baseline may be given at a reduced dose of 500 mg (two tablets) once daily. For patients being re-treated, serum transaminases and bilirubin should be monitored at a minimum of every two weeks for the first three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500 mg daily, treatment should be discontinued. Reduced doses should not be taken with food (see previous). If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, PROTYGA should be discontinued and patients should not be re-treated with PROTYGA.

Renal impairment

No dose adjustment is necessary for patients with renal impairment (see section 5.2).

Paediatric population

There is no relevant use of PROTYGA in paediatric patients, as prostate cancer is not present in the paediatric population.

Method of administration

PROTYGA is for oral use. PROTYGA should be taken on an empty stomach, at least one hour before or at least two hours after a meal. The tablets should be swallowed whole with water. For precautions to be taken before handling or administering PROTYGA, see section 6.6. Women who are or may be pregnant should not handle PROTYGA without gloves.

PROTYGA is contraindicated in:

• Patients with hypersensitivity to abiraterone or to any of the excipients listed in section 6.1.
• Pregnancy and lactation (see section 4.6).
• Moderate to severe hepatic impairment (Child-Pugh class B and C) (see section 4.2, 4.4 and 5.2).
• Women should not use PROTYGA.
• Women who are pregnant, trying to get pregnant or may potentially be pregnant (see section 4.6).
• Concomitant administration with rifampicin (see section 4.5).
• PROTYGA with prednisone or prednisolone is contraindicated in combination with Radium 223.

Hypertension, hypokalaemia and fluid retention due to mineralocorticoid excess

PROTYGA 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). Concomitant use of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. PROTYGA should be used with caution in patients with a history of cardiovascular disease. The safety of PROTYGA in patients with left ventricular ejection fraction < 50 % or New York Heart Association (NYHA) class III or IV heart failure has not been established. Hypertension must be controlled and hypokalaemia must be corrected, before treatment with PROTYGA. 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 dysrhythmia and those with severe renal impairment. Blood pressure, serum potassium and fluid retention should be monitored at least monthly. Before treating patients with a significant risk for congestive heart failure (e.g. a history of cardiac failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with PROTYGA, cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium, fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities corrected. QT prolongation has been observed in patients experiencing hypokalaemia in association with PROTYGA treatment. Assess cardiac function as clinically indicated, institute appropriate management and consider discontinuation of this treatment if there is a clinically significant decrease in cardiac function (see section 4.2).

Hepatotoxicity and hepatic impairment

Marked increases in liver enzymes have led to PROTYGA discontinuation or dose modification. Serum transaminase and bilirubin levels should be measured prior to starting treatment with PROTYGA, every two weeks for the first three months of treatment, and monthly thereafter. If clinical signs and symptoms suggestive of hepatotoxicity develop, serum transaminases, should be measured immediately. If at any time ALT or AST rises above 5 times the upper limit of normal or bilirubin rises above 3 times the upper limit of normal, treatment with PROTYGA should be stopped immediately and the liver function should be monitored closely. Re-treatment with PROTYGA may take place only after return of liver function tests to the patientu2019s baseline and at a reduced dose level (see section 4.2). PROTYGA should be discontinued if patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while taking PROTYGA. These patients should not be re-treated with PROTYGA. There are no data on the clinical safety and efficacy of multiple doses of PROTYGA when administered to patients with moderate or severe hepatic impairment (Child Pugh Class B or C). PROTYGA should not be used in patients with moderate to severe hepatic impairment (see section 4.3). There are no data to support the use of PROTYGA in patients with active or symptomatic viral hepatitis. Acute liver failure and fulminant hepatitis, some with fatal outcome have been reported (see section 4.8).

Testosterone deficiency is associated with higher serum and hepatic levels of triglycerides and higher serum levels of low-density lipoprotein (LDL) in the body, with significant increases in fasting plasma glucose and insulin levels. Patients who receive androgen deprivation therapy (ADT) are at a greater risk of being diagnosed with non-alcoholic fatty liver disease (NAFLD) and to show significant increase and/or incidences of liver disease. As Abiraterone (as contained in PROTYGA) is commonly used in conjunction with ADT (see section 4.1), the same can be expected.

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 therapy. If PROTYGA is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess. In patients on prednisone or prednisolone who are subjected to unusual stress, increased dosage of corticosteroids may be indicated before, during and after the stressful situation.

Use with chemotherapy

The safety and efficacy of concomitant use of PROTYGA with cytotoxic chemotherapy have not been established.

Use in combination with Radium 223

Treatment with PROTYGA and prednisone/prednisolone in combination with Radium 223 is contraindicated (see section 4.3) due to an increased risk of fractures and a trend for increased mortality. It is recommended that subsequent treatment with Radium 223 is not initiated for at least 5 days after the last administration of PROTYGA in combination with prednisone/prednisolone.

Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of PROTYGA in combination with a glucocorticoid could increase this effect.

Prior use of ketoconazole

Lower rates of response might be expected in patients previously treated with ketoconazole for prostate cancer.

Hyperglycaemia

The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured frequently in patients with diabetes.

Potential risks

Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with PROTYGA.

Skeletal muscle effects

Cases of myopathy and rhabdomyolysis have been reported in patients treated with PROTYGA. Most cases developed within the first 6 months of treatment and recovered after PROTYGA withdrawal. Caution is recommended in patients concomitantly treated with medicines known to be associated with myopathy/rhabdomyolysis.

Interactions with other medicinal products

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure to PROTYGA (see section 4.5).

Effect of food on PROTYGA

The absorption of abiraterone acetate, as in PROTYGA, significantly increases when taken with food. The safety and efficacy of PROTYGA when given with food have not been established. PROTYGA must not be taken with food (see section 4.2 and 5.2).

Interactions with other medicines

Potential for PROTYGA to affect exposure to other medicines: Abiraterone, as in PROTYGA, is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8. Caution is advised when PROTYGA is administered with medicines activated by or metabolised by CYP2D6, particularly with medicines that have a narrow therapeutic index. Dose reduction of narrow therapeutic index medicines metabolised by CYP2D6 should be considered (e.g. paroxetine propafenone, flecainide, haloperidol, metoprolol, propranolol, venlafaxine, risperidone, codeine, oxycodone and tramadol). Although no meaningful increases in exposure are expected when PROTYGA is combined with medicines that are predominantly eliminated by CYP2C8, patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly.

Potential for other medicines to affect PROTYGA exposures: Rifampicin, a strong inducer of CYP3A4, decreases the mean plasma AUC of abiraterone, as contained in PROTYGA, by 55 % (see section 4.3). Other strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbitone, St John's wort [Hypericum perforatum]) during treatment with PROTYGA are to be avoided. Co-administration of ketoconazole, a strong inhibitor of CYP3A4, has no clinically meaningful effect on the pharmacokinetics of abiraterone.

Concomitant use with medicines known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering PROTYGA with medicines known to prolong the QT interval or medicines able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antidysrhythmic medicines, methadone, moxifloxacin, antipsychotics, etc.

Concomitant use with spironolactone

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with PROTYGA is not recommended.

Concomitant use with eplerenone

There is no data available on the concomitant use of eplerenone with PROTYGA.

Women should not use PROTYGA.

Pregnancy

PROTYGA is contraindicated in pregnant or potentially pregnant women (see section 4.3). Pregnant women or women of child-bearing potential should handle PROTYGA with gloves (see section 6.6). Women of childbearing potential PROTYGA is not indicated for use in women of childbearing potential. Maternal use of a CYP17 inhibitor is expected to produce changes in hormone levels that could affect the development of the foetus.

Contraception in males and females

Animal studies have shown reproductive toxicity. The presence of PROTYGA or its metabolites in semen is unknown. If patient on treatment with PROTYGA is engaged in sexual activity with a pregnant woman, a condom is required. If the patient is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method until one week after the last dose of PROTYGA.

Fertility

In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was completely reversible in 4 to 16 weeks after abiraterone, as in PROTYGA, was stopped. It is recommended to store semen before starting treatment with PROTYGA in patients who might want to father a child.

Breastfeeding

PROTYGA is not for use in women. It is not known if either abiraterone acetate or its metabolites are excreted in human breast milk.

PROTYGA may affect the ability to drive or use machines. Patients should not drive and use machines before they know how treatment with PROTYGA affects their ability to drive and use machines.

System Organ Class Frequency Side effects Infections and Infestations Frequent Urinary tract infection, sepsis Endocrine disorders Less frequent Adrenal insufficiency Metabolism and nutrition disorders Frequent Hypokalaemia, hypertriglyceridaemia Cardiac disorders Frequent Less frequent Frequency unknown Cardiac failure (including congestive heart failure, left ventricular dysfunction and decreased left ventricular ejection fraction), angina pectoris, atrial fibrillation, tachycardia Cardiac dysrhythmias Myocardial infarction, QT prolongation Vascular disorders Frequent Hypertension Respiratory, thoracic and mediastinal disorders Less frequent Allergic alveolitis Gastrointestinal disorders Frequent Diarrhoea, dyspepsia Hepato-biliary disorders Frequent Hepatotoxicity, abnormal hepatic functions, including elevated hepatic function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. Less frequent Frequency unknown Hepatitis fulminant, acute hepatic failure Non-alcoholic fatty acid liver disease Skin and subcutaneous tissue disorders Frequent Rash Musculoskeletal, and connective tissue disorders Frequent Less frequent Fractures (including osteoporosis and all fractures with the exception of pathological fracture) Myopathy, rhabdomyolysis Renal and urinary disorders Frequent Less frequent Haematuria Renal failure secondary to rhabdomyolysis General disorders and administration site conditions Frequent Peripheral oedema Injury, poisoning and procedural complications Frequent Fractures (includes osteoporosis and all fractures with the exception of pathological fractures)

Reporting of suspected adverse reactions: Reporting of suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In overdose, the undesirable effects can be precipitated and/or be of increased severity (see section 4.8). There is no specific antidote. Treatment with PROTYGA must be discontinued. Treatment is symptomatic and supportive which includes relevant monitoring of cardiac and hepatic function, serum potassium and blood pressure.