ZYTIGA 500 mg film-coated tablets

  • Name:

    ZYTIGA 500 mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    Abiraterone Acetate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 04/03/19

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Summary of Product Characteristics last updated on medicines.ie: 1/3/2019

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Janssen Sciences Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 4 March 2019 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 6 - date of revision

Updated on 1 March 2019 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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).

 

 

Updated on 25 February 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

Updated on 25 February 2019 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

Updated on 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change of distributor details

Updated on 15 June 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 21 November 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 21 November 2017 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Change to section 4.1 - Therapeutic indications

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

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

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).

 

Cardiac disorders

common: cardiac failure*, angina pectoris, arrhythmia, atrial fibrillation, tachycardia

uncommon: other arrhythmias

not known: myocardial infarction, QT prolongation (see sections 4.4 and 4.5)

 

Hepatobiliary disorders

very common: alanine aminotransferase increased and/or , aspartate aminotransferase increased b

rare: hepatitis fulminant, acute hepatic failure

 

*    Cardiac failure also includes congestive heart failure, left ventricular dysfunction and ejection fraction decreased

**  Fractures includes osteoporosis and all fractures with the exception of pathological fractures

a    Spontaneous reports from post‑marketing experience

b    Alanine aminotransferase increased and/or aspartate aminotransferase increased includes ALT increased, AST increased, and hepatic function abnormal.

 

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%......

……..

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.

 

 

Updated on 20 November 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 20 November 2017 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 6 February 2017 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 3 February 2017 PIL

Reasons for updating

  • New PIL for new product