Teronred 250 250 mg Film-coated tablets.

TERONRED 250 is indicated with low-dose corticosteroids (prednisone or prednisolone) in a dul t males for th e 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 TERONRED 250 is 1 000 mg (four 250 mg tablets) as a single daily dose that must not be taken with food. Taking TERONRED 250 with food increases systemic exposure to abiraterone (see sections 4.5 and 5.2).

Patients should be maintained on TERONRED 250 until radiographic progression and symptomatic/clinical progression and until PSA progression (confirmed 25 % increase over the patientu2019s baseline/nadir).

Dosage of prednisone or prednisolone

For metastatic hormone nau00efve prostate cancer (mHNPC) or hormone sensitive prostate cancer (mHSPC), TERONRED 250 is used with 5 mg prednisone or prednisolone once daily. For metastatic castration-resistant prostate cancer (mCRPC), TERONRED 250 is used with 10 mg prednisone or prednisolone daily.

Recommended monitoring

Serum transaminases and bilirubin should be measured prior to starting treatment with TERONRED 250, 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 patient missing the daily dose of TERONRED 250, 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 abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No dose adjustment can be predicted. TERONRED 250 should not be used in patients with moderate or severe hepatic impairment (see section 4.3).

For patients who develop hepatotoxicity during treatment with TERONRED 250 (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] increases above 5 times the upper limit of normal [ULN] 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 patientu2019s 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 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, TERONRED 250 treatment should be discontinued and patients should not be re-treated with TERONRED 250.

Renal impairment

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

Pediatric population

There is no relevant use of TERONRED 250 in the pediatric population, as prostate cancer is not present in the pediatric population.

Method of administration:

TERONRED 250 is for oral use. TERONRED 250 must be taken on an empty stomach, at least one hour before or at least two hours after eating a meal. TERONRED 250 tablets should be swallowed whole with water.

Precautions to be taken before handling or administering TERONRED 250

Based on its mechanism of action, TERONRED 250 may cause harm to a developing foetus; therefore women (including healthcare professionals), who are pregnant or who may be pregnant should not handle TERONRED 250 without protection e.g. gloves (see sections 4.6 and 6.6).

TERONRED 250 is contraindicated in:

• Patients who have a known hypersensitivity to abiraterone acetate or its excipients listed in section 6.1.
• Women should not use TERONRED 250.
• Women who are pregnant, trying to get pregnant or may potentially be pregnant and women who are breastfeeding (see section 4.6).
• Moderate to severe hepatic impairment (Child-Pugh Class B and C) (see sections 4.2, 4.4 and 5.2).
• Concomitant administration with rifampicin (see section 4.5).
• TERONRED 250 with prednisone or prednisolone is contraindicated in combination with Ra-223 (radium 223).

Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess

TERONRED 250 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 the 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 digoxin), 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 once a month. TERONRED 250 should be used with caution in patients with a history of cardiovascular disease. The safety of TERONRED 250 in patients with left ventricular ejection fraction measurement of < 50 % or NYHA Class II to IV heart failure has not been established. Before treating patients with TERONRED 250, hypertension must be controlled and hypokalaemia corrected.

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 TERONRED 250, 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 TERONRED 250 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.

Hepatotoxicity and hepatic impairment

Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies (see section 4.8). Serum transaminase and bilirubin levels should be measured prior to starting treatment with TERONRED 250, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases, ALT (alanine aminotransferase) or AST (aspartate aminotransferase), should be measured immediately. If at any time the ALT or AST rises above 5 times the upper limit of normal or the bilirubin rises above 3 times the upper limit of normal, treatment with TERONRED 250 should be interrupted immediately and liver function closely monitored.

Re-treatment with TERONRED 250 may take place only after liver function tests return to the patientu2019s baseline and at a reduced dose level (see section 4.2). If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, TERONRED 250 should be discontinued and patients should not be re-treated with TERONRED 250. There are no data to support the use of TERONRED 250 in patients with active or symptomatic viral hepatitis. There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). TERONRED 250 should not be used in patients with moderate to severe hepatic impairment (see section 4.3). There have been post-marketing reports of acute liver failure and fulminant hepatitis, some with fatal outcome (see section 4.8).

Risk of non-alcoholic fatty liver disease (NAFLD)

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 NAFLD. ADT is also associated with significant increase in incidences of other liver diseases such as cirrhosis, liver necrosis, and any liver disease. A significant correlation between the number of ADT doses and the incidence of NAFLD and other liver diseases has been noted. Normal androgen levels prevent hepatic fat accumulation, whereas androgen deficiency induces hepatic steatosis.

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 TERONRED 250 is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see u201cHypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excessu201d above).

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of corticosteroids may be indicated before, during and after the stressful situation.

Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of TERONRED 250 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.

Hypoglycaemia

Cases of hypoglycaemia have been reported when abiraterone as in TERONRED 250 plus prednisone / prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (see section 4.5). Blood glucose should be monitored in patients with diabetes.

Vaccination with live attenuated bacterial or viral vaccines

Prostate cancer patients on treatment should receive guidance on age and indication appropriate vaccinations, in particular live attenuated bacterial or viral vaccines. Patients should also be advised to take extra precaution should they come into contact with someone who has received a live vaccine.

Tuberculosis and/or HIV

Prostate cancer patients with tuberculosis and/or HIV, who are not well-controlled on treatment should be monitored closely.

Use with chemotherapy

The safety and efficacy of concomitant use of TERONRED 250 with cytotoxic chemotherapy has not been established.

Skeletal muscle effects

Cases of myopathy and rhabdomyolysis have been reported in patients treated with TERONRED 250. Most cases developed within the first 6 months of treatment and recovered after TERONRED 250 was withdrawn. Caution should be exercised in patients concomitantly treated with medicines known to be associated with myopathy/rhabdomyolysis.

Potential risks

Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with TERONRED 250.

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

Combination of abiraterone and prednisone/prednisolone with Ra-223

Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated (see section 4.3) due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical trials. It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of TERONRED 250 in combination with prednisone/prednisolone.

Excipients warnings

TERONRED 250 contains lactose. Patients with the rare hereditary problems of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption should not take TERONRED 250. This medicine contains 25,52 mg sodium per daily dose of four TERONRED 250 tablets, equivalent to 1,28 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

Effect of food on TERONRED 250

Administration with food significantly increases the absorption of abiraterone acetate. The efficacy and safety when given with food have not been established therefore TERONRED 250 must not be taken with food (see sections 4.2 and 5.2).

Interactions with other medicines

Potential for other medicines to affect abiraterone exposures

It was reported that in a clinical pharmacokinetic interaction study of healthy subjects pre-treated with a strong CYP3A4 inducer rifampicin, 600 mg daily for 6 days followed by a single dose of abiraterone acetate 1000 mg, the mean plasma AUC u221e of abiraterone was decreased by 55 % (see section 4.3). Other strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbitone, St John's Wort [Hypericum perforatum]) are to be avoided during treatment with TERONRED 250.

It was reported that in a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

Potential for TERONRED 250 to affect exposures to other medicines

Abiraterone is an inhibitor of the hepatic medicine-metabolising enzymes CYP2D6 and CYP2C8. It was reported that in a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2,9-fold. The AUC 24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33 %. Caution is advised when administering with medicines activated by or metabolised by CYP2D6, particularly with medicines that have a narrow therapeutic index. Dose reduction of medicines with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicines metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the latter three medicines requiring CYP2D6 to form their active analgesic metabolites).

It was reported that in a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed. It was reported that in a CYP2C8 interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46 % and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10 % when pioglitazone was given together with a single dose of 1000 mg abiraterone acetate. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with TERONRED 250. Examples of medicines metabolised by CYP2C8 include pioglitazone and repaglinide (see section 4.4 Hypoglycaemia).

It was reported that in vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown to inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the concentrations of medicines eliminated by OATP1B1. There are no clinical data available to confirm transporter-based interaction.

Use with medicines known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering TERONRED 250 with medicines known to prolong the QT interval or medicines able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) 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 TERONRED 250 is not recommended.

Concomitant use with eplenerone

There is no clinical study data related to concomitant use of eplenerone with TERONRED 250.

Women should not use TERONRED 250. Women of childbearing potential: There are no human data on the use of TERONRED 250 in pregnancy and TERONRED 250 is not for use in women of childbearing potential. Maternal use of a CYP 17 inhibitor is expected to produce changes in hormone levels that could affect development of the foetus. Contraception in males and females: Studies in animals have shown reproductive toxicity.

It is not known whether abiraterone or its metabolites are present in semen. During treatment and for 3 months following the last dose of TERONRED 250, patients who engage in sexual activity with pregnant women must use a condom. If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method until 3 months after the last dose of TERONRED 250. Female sexual partners (of childbearing potential) of male patients receiving TERONRED 250, should be advised to use highly effective contraception, during treatment and for 6 months after the last dose of TERONRED 250. Men should be advised not to father a child while receiving treatment and must use highly effective contraception during treatment and for at least 3 months after treatment.

Pregnancy: TERONRED 250 is contraindicated in women who are or may potentially be pregnant (see section 4.3). Pregnant women or women of child-bearing potential should handle TERONRED 250 uncoated tablets with gloves.

Breastfeeding: TERONRED 250 is not for use in women. It is not known if abiraterone acetate or its metabolites are excreted in human breast milk.

Fertility: In fertility studies in both male and female rats, abiraterone reduced fertility, which was completely reversible in 4 to 16 weeks after abiraterone acetate was stopped (see section 5.3). It is recommended to store semen before starting treatment with TERONRED 250 in patients who might want to father a child.

TERONRED 250 may affect the ability of patients to drive or use machines. Patients should not drive and use machines before they know how treatment with TERONRED 250 affects their ability to drive and use machines.

Summary of the safety profile

The most frequent adverse reactions are peripheral oedema, hypokalaemia, hypertension, urinary tract infection, and increased alanine aminotransferase and/or increased aspartate aminotransferase. Other important adverse reactions include, cardiac disorders, hepatotoxicity, fractures, and allergic alveolitis. Hypertension, hypokalaemia and fluid retention may occur as a pharmacodynamic consequence of the mechanism of action of abiraterone acetate. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see section 4.4).

Tabulated list of adverse reactions

Table 1: The following undesirable effects have been observed and reported during treatment with abiraterone acetate as in TERONRED 250:

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: Frequent, Less Frequent and Frequency unknown. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Frequent

Less frequent

Frequency unknown

Infections and infestations

urinary tract infection, sepsis

Immune system disorders

Anaphylactic reaction

Endocrine disorders

adrenal insufficiency

Metabolism and nutrition disorders

hypokalaemia, hypertriglyceridaemia

Cardiac disorders

cardiac failure (includes congestive heart failure, left ventricular dysfunction and decreased left ventricular ejection fraction), angina pectoris, atrial fibrillation, tachycardia dysrhythmia, myocardial infarction, QT prolongation

Vascular disorders

hypertension

Respiratory, thoracic and mediastinal disorders

allergic alveolitis

Gastrointestinal disorders

diarrhoea, dyspepsia

Hepatobiliary disorders

Hepatotoxicity, abnormal hepatic functions including elevated hepatic function tests such as increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and total bilirubin, cirrhosis, liver necrosis

Skin and subcutaneous tissue disorders

rash

Musculoskeletal and connective tissue disorders

fractures (includes osteoporosis and all fractures with the exception of pathological fractures), myopathy, rhabdomyolysis

Renal and urinary disorders

haematuria, renal failure (secondary to rhabdomyolysis)

General disorders and administration site conditions

peripheral oedema

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 TERONRED 250 must be discontinued. Treatment is symptomatic and supportive which includes relevant monitoring of cardiac and hepatic function, serum potassium and blood pressure.