ZYTIGA 500 mg film-coated tablets

Update in shelf life from 2 years to 3 years. Update to section 2 of the SmPC to add an equivalency statement 

Changes made to the SmPCs and PIL to update:

• The dosing instructions,
• Use of abiraterone versus abiraterone acetate within the same labels,
• Addition of Sodium statement,
• Addition of UK (NI) to the label along with various spelling corrections and minor updates.

Changes made to the SmPCs and PIL to update:

• The dosing instructions,
• Use of abiraterone versus abiraterone acetate within the same labels,
• Addition of Sodium statement,
• Addition of UK (NI) to the label along with various spelling corrections and minor updates.

Changes made to the SmPCs and PIL to update:

• The dosing instructions,
• Use of abiraterone versus abiraterone acetate within the same labels,
• Addition of Sodium statement,
• Addition of UK (NI) to the label along with various spelling corrections and minor updates.

Section 4.8-Undesirable effects has been updated to add anaphylactic reactions.

Section 4 - possible side effects has been updated to add serious allergic reactions with difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash.

Other medicines and ZYTIGA

Ask your doctor or pharmacist for advice before taking any medicine. 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is important because ZYTIGA may increase the effects of a number of medicines including heart medicines, tranquilisers, some medicines for diabetes, herbal medicines (e.g., St John’s wort) and others. Your doctor may want to change the dose of these medicines. Also, some medicines may increase or decrease the effects of ZYTIGA. This may lead to side effects or to ZYTIGA not working as well as it should.

4.4          Special warnings and precautions for use

Hypoglycaemia

Cases of hypoglycaemia have been reported when ZYTIGA plus prednisone/prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (see section 4.5); therefore, blood sugar should be monitored in patients with diabetes.

4.5          Interaction with other medicinal products and other forms of interaction

…………………

In a CYP2C8 drug‑drug 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 1,000 mg abiraterone acetate. Although these results indicate that no clinically meaningful increases in exposure are expected when ZYTIGA is combined with medicinal products that are predominantly eliminated by CYP2C8. PPatients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly. Examples of medicinal products metabolised by CYP2C8 include pioglitazone and repaglinide (see section 4.4).

5.1     Pharmacodynamic properties

A statistically significant improvement in OS in favor of AA-P plus ADT was observed with a 3834% reduction in the risk of death compared to Placebo plus ADT (HR=0.6210.66; 95% CI: 0.5090.56, 0.7560.78; p<0.0001, crossing the pre-specified boundary for OS at Interim Analysis 1 of 0.010 (see Table 3 and Figure 2).

………

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for ZYTIGA vs. placebo treatment in all prospectively‑defined secondary endpoints. measures as follows:

Time to skeletal-related event (SRE): There was a 30% reduction in the risk of skeletal-related events (HR = 0.703; 95% CI: [0.539, 0.916], p = 0.0086). The median time to SRE has not been reached for the ZYTIGA or placebo study arm.

Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was 33.2 months for patients receiving ZYTIGA and 7.4 months for patients receiving placebo (HR = 0.299; 95% CI: [0.255, 0.352], p <0.0001).

Time to subsequent therapy: The median time to subsequent therapy at the time of interim analysis was not reached for patients receiving ZYTIGA and was 21.6 months for patients receiving placebo (HR = 0.415; 95% CI: [0.346, 0.497], p <0.0001).

Time to initiation of chemotherapy: The median time to initiation of chemotherapy was not reached for patients receiving ZYTIGA and was 38.9 months for patients receiving placebo (HR = 0.443; 95% CI: [0.349, 0.561], p < 0.0001).

Time to pain progression: The median time to pain progression was not reached for patients receiving ZYTIGA and was 16.6 months for patients receiving placebo (HR = 0.695; 95% CI: [0.583, 0.829], p <0.0001).

The majority of exploratory endpoints favored treatment with abiraterone acetate and prednisone (AA-P) over Placebo.

4.2     Posology and method of administration

Method of administration

ZYTIGA is for oral use.

The tablets should be taken at least one hour before or 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

4.8     Undesirable effects

ZYTIGA may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. In Phase 3 studies, anticipated mineralocorticoid adverse reactions were seen more commonly in patients treated with abiraterone acetate than in patients treated with placebo: hypokalaemia 18% vs.8%, hypertension 22% vs. 16% and fluid retention (peripheral oedema) 23% vs. 17%, respectively. In patients treated with abiraterone acetate versus patients treated with placebo:, CTCAE (version 4.0) Grades 3 and 4 hypokalaemia were observed in 6% andversus 21% of patients, CTCAE (version 4.0) Grades 3 and 4 hypertension were observed in 87% andversus 5% of patients, and fluid retention (peripheral oedema) Grades 3 and 4 were observed in 1% andversus 1% of patients, respectively. Mineralocorticoid reactions generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see section 4.4).

4.3         Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Women who are or may potentially be pregnant (see section 4.6).
• Severe hepatic impairment [Child‑Pugh Class C (see sections 4.2, 4.4 and 5.2)].
• ZYTIGA with prednisone or prednisolone is contraindicated in combination with Ra-223.
   
  4.4       Special warnings and precautions for use
  Skeletal muscle effects
  Cases of myopathy and rhabdomyolysis have been reported in patients treated with ZYTIGA. Some patients had rhabdomyolysis with renal failure. Most cases developed within the first 6 months of treatment and recovered after ZYTIGA withdrawal. Caution is recommended in patients concomitantly treated with medicinal products 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 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 ZYTIGA in combination with prednisone/prednisolone.

4.1     Therapeutic indications

ZYTIGA is indicated with prednisone or prednisolone for:

·                the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT) (see section 5.1)

·                the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1)

·                the treatment of mCRPCetastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel‑based chemotherapy regimen.

4.2     Posology and method of administration

This medicinal product should be prescribed by an appropriate healthcare professional.

Posology

The recommended dose is 1,000 mg (two 500 mg tablets) as a single daily dose that must not be taken with food (see “Method of administration” below). Taking the tablets with food increases systemic exposure to abiraterone (see sections 4.5 and 5.2).

ZYTIGA is to be taken with low dose prednisone or prednisolone. The recommended dose of prednisone or prednisolone is 10 mg daily.

Dosage of prednisone or prednisolone

For mHSPC, ZYTIGA is used with 5 mg prednisone or prednisolone daily.

For mCRPC, ZYTIGA is used with 10 mg prednisone or prednisolone daily.  

Recommended monitoring

Serum transaminases should be measured prior to starting treatment, every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly. However, patients with a significant risk for congestive heart failure should be monitored every 2 weeks for the first three months of treatment and monthly thereafter (see section 4.4).

4.4     Special warnings and precautions for use

ZYTIGA should be used with caution in patients with a history of cardiovascular disease. The Pphase 3 studies 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 (NYHA) III or IV heart failure (study 301) or Class II to IV heart failure (studiesy 3011 and 302) or cardiac ejection fraction measurement of < 50%. In studiesy 3011 and 302, patients with atrial fibrillation, or other cardiac arrhythmia requiring medical therapy were excluded. Safety in patients with left ventricular ejection fraction (LVEF) < 50% or NYHA Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in studiesy 3011 and 302) was not established (see sections 4.8 and 5.1).

Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer (castration resistant prostate cancer). The use of ZYTIGA in combination with a glucocorticoid could increase this effect.

Potential risks

4.8     Undesirable effects

Summary of the safety profile

In an analysis of adverse reactions of composite Phase 3 studies with ZYTIGA, adverse reactions that were observed in ≥10% of patients wereThe most common adverse reactions seen are peripheral oedema, hypokalaemia, hypertension and urinary tract infection, and alanine aminotransferase increased and/or aspartate aminotransferase increased.

Other important adverse reactions include, cardiac disorders, hepatotoxicity, fractures, and allergic alveolitis.

ZYTIGA may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. In clinical Phase 3 studies, anticipated mineralocorticoid adverse reactions were seen more commonly in patients treated with abiraterone acetate than in patients treated with placebo: hypokalaemia 2118% vs.118%, hypertension 1622% vs. 1116% and fluid retention (peripheral oedema) 2623% vs. 2017%, respectively. In patients treated with abiraterone acetate, CTCAE (version 34.0) Grades 3 and 4 hypokalaemia were observed in 6% and 2% of patients, and CTCAE (version 43.0) Grades 3 and 4 hypertension were observed in 48% and 25% of patients, and fluid retention (peripheral oedema) Grades 3 and 4 were observed in 1% and 1% of patients, respectively. Mineralocorticoid reactions generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see section 4.4).

The following CTCAE (version 34.0) Grade 3 adverse reactions occurred in patients treated with abiraterone acetate: hypokalaemia 35%,; urinary tract infection 2%;, alanine aminotransferase increased and/or aspartate aminotransferase increased 4%;, hypertension 6%;, aspartate aminotransferase increased, fractures 2%; peripheral oedema, cardiac failure, and atrial fibrillation 1% each. CTCAE (version 34.0) Grade 3 hypertriglyceridaemia and angina pectoris occurred in < 1% of patients. CTCAE (version 34.0) Grade 4 peripheral oedema, hypokalaemia, urinary tract infection, alanine aminotransferase increased and/or aspartate aminotransferase increased,  hypokalemia,  cardiac failure, atrial fibrillation, and fractures occurred in < 1% of patients.

A higher incidence of hypertension and hypokalemia was observed in the hormone sensitive population (study 3011). Hypertension was reported in 36.7% of patients in the hormone sensitive population (study 3011) compared to 11.8% and 20.2% in studies 301 and 302, respectively. Hypokalemia was observed in 20.4% of patients in the hormone sensitive population (study 3011) compared to 19.2% and 14.9% in 301 and 302, respectively).

The incidence and severity of adverse events was higher in the subgroup of patients with baseline ECOG2 performance status grade and also in elderly patients (≥75 years ).

Description of selected adverse reactions

Cardiovascular reactions

TheBoth three Pphase 3 studies 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 NYHA Class III or IV heart failure (study 301) or Class II to IV heart failure (studiesy 3011 and 302) or cardiac ejection fraction measurement of < 50%......

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The incidence of cardiovascular adverse reactions in the Pphase 3 studies in patients taking abiraterone acetate versus patients taking placebo were as follows: hypertension 14.5% vs. 10.5%, atrial fibrillation 3.42.6% vs. 3.42.0%, tachycardia 2.81.9% vs. 1.70%, angina pectoris 1.97% vs. 0.98%, cardiac failure 1.90.7% vs. 0.62%, and arrhythmia 1.10.7% vs. 0.45%.

Hepatotoxicity

Hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated with abiraterone acetate. Across Phase 3all clinical studies, liver function test elevationshepatotoxicity grades 3 and 4 (e.g., ALT or AST increases of > 5 x ULN or bilirubin increases > 1.5 x ULN) were reported in approximately 46% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. In Study 3011, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients treated with ZYTIGA. Ten patients who received ZYTIGA were discontinued because of hepatotoxicity; two had Grade 2 hepatotoxicity, six had Grade 3 hepatotoxicity, and two had Grade 4 hepatotoxicity. No patient died of hepatotoxicity in Study 3011. In the 301 Phase 3 clinical studiesy, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values…..

….. In Phase 3 clinical studies, Ttreatment discontinuations due to ALT and AST increases or abnormal hepatic function were reported in 1.71% and 1.3% of patients treated with abiraterone acetate and 0.26% and 0% of patients treated with placebo, respectively; no deaths were reported due to hepatotoxicity events.

In clinical trials, the risk for hepatotoxicity was mitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver function tests. In the 3011 trial, patients with baseline ALT and AST > 2.5 X ULN, bilirubin > 1.5 X ULN or those with active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction were excluded……

5.1     Pharmacodynamic properties

Clinical efficacy and safety

Efficacy was established in threetwo randomised placebo‑controlled multicentre Pphase 3 clinical studies (studies 3011, 301 302 and 302301) of patients with mHSPC and mCRPCetastatic castration resistant prostate cancer. Study 3011 enrolled patients who were newly diagnosed (within 3 months of randomization)  mHSPC who had high-risk prognostic factors. High-risk prognosis was defined as having at least 2 of the following 3 risk factors: (1) Gleason score of ≥8; (2) presence of 3 or more lesions on bone scan; (3) presence of measurable visceral (excluding lymph node disease) metastasis. In the active arm, ZYTIGA was administered at a dose of 1000 mg daily in combination with low dose prednisone 5 mg once daily in addition to ADT (LHRH agonist or orchiectomy), which was the standard of care treatment. Patients in the control arm received ADT and placebos for both ZYTIGA and prednisone. Study 302 enrolled docetaxel naïve patients; whereas, study 301 enrolled patients who had received prior docetaxel. Patients were using an LHRH analogue or were previously treated with orchiectomy. In the active treatment arm, ZYTIGA was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone 5 mg twice daily. Control patients received placebo and low dose prednisone or prednisolone 5 mg twice daily.

Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore, in both all studies it was recommended that patients be maintained on their study treatments until discontinuation criteria were met as specified below for each study.

In allboth studies spironolactone use was not allowed as spironolactone binds to the androgen receptor and may increase PSA levels.

Study 3011 (patients with newly diagnosed high risk mHSPC)

In Study 3011, (n=1199) the  median age of enrolled patients was 67 years. The number of patients treated with ZYTIGA by racial group was Caucasian 832 (69.4%), Asian 246 (20.5%), Black or African American 25 (2.1%), other 80 (6.7%), unknown/not reported 13 (1.1%), and American Indian or Alaska Native 3 (0.3%). The ECOG performance status was 0 or 1 for 97% of patients. Patients with known brain metastasis, uncontrolled hypertension, significant heart disease, or NYHA Class II-IV heart failure  were excluded. Patients that were treated with prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer were excluded with the exception of up to 3 months of ADT or 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease. Co-primary efficacy endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). The median baseline pain score, as measured by the Brief Pain Inventory Short Form (BPI-SF) was 2.0 in both the treatment and Placebo groups. In addition to the co‑primary endpoint measures, benefit was also assessed using time to skeletal-related event (SRE), time to subsequent therapy for prostate cancer, time to initiation of chemotherapy, time to pain progression, and time to PSA progression. Treatment continued until disease progression, withdrawal of consent, the occurrence of unacceptable toxicity, or death.                                                                                                                                       

Radiographic progression-free survival was defined as the time from randomization to the occurrence of radiographic progression or death from any cause. Radiographic progression included progression by bone scan (according to modified PCWG2) or progression of soft tissue lesions by CT or MRI (according to RECIST 1.1).

A significant difference in rPFS between treatment groups was observed (see Table 2 and Figure 1).

See SmPC for Table 2, Figure 1, Table 3 and Figure 2

Subgroup analyses consistently favor treatment with ZYTIGA. The treatment effect of AA-P on rPFS and OS across the pre-specified subgroups was favorable and consistent with the overall study population, except for the subgroup of ECOG score of 2 where no trend towards benefit was observed, however the small sample size (n=40) limits drawing any meaningful conclusion.

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for ZYTIGA vs. placebo treatment in all prospectively‑defined secondary endpoint measures as follows:

Time to skeletal-related event (SRE): There was a 30% reduction in the risk of skeletal-related events (HR = 0.703; 95% CI: [0.539, 0.916], p = 0.0086). The median time to SRE has not been reached for the ZYTIGA or placebo study arm.

Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was 33.2 months for patients receiving ZYTIGA and 7.4 months for patients receiving placebo (HR = 0.299; 95% CI: [0.255, 0.352], p <0.0001).

Time to subsequent therapy: The median time to subsequent therapy at the time of interim  analysis was not reached for patients receiving ZYTIGA and was 21.6 months for patients receiving placebo (HR = 0.415; 95% CI: [0.346, 0.497], p <0.0001).

Time to initiation of chemotherapy: The median time to initiation of chemotherapy was not reached for patients receiving ZYTIGA and was 38.9 months for patients receiving placebo (HR = 0.443; 95% CI: [0.349, 0.561], p < 0.0001).

Time to pain progression: The median time to pain progression was not reached for patients receiving ZYTIGA and was 16.6 months for patients receiving placebo (HR = 0.695; 95% CI: [0.583, 0.829], p <0.0001).

The majority of exploratory endpoints favored treatment with abiraterone acetate and prednisone (AA-P) over Placebo.