Zytiga

Zytiga

abiraterone

Manufacturer:

Johnson & Johnson
Full Prescribing Info
Contents
Abiraterone acetate.
Description
ZYTIGA uncoated tablets contain 250 mg of arbiraterone acetate.
Excipients/Inactive Ingredients: colloidal silicon dioxide; croscarmellose sodium; lactose monohydrate; magnesium stearate; microcrystalline cellulose; povidone; sodium lauryl sulfate.
Action
Pharmacotherapeutic group: Other hormone antagonists and related agents. ATC Code: L02BX03.
Pharmacology: Pharmacodynamics: Mechanism of Action: Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumor tissues. It catalyzes the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see Hypertension, hypokalemia and fluid retention due to mineralocorticoid excess under Precautions).
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Treatment with ZYTIGA decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH agonists (or orchiectomy).
Pharmacodynamic Effects: ZYTIGA decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH agonists alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. Prostate specific antigen (PSA) serves as a biomarker in patients with prostate cancer. In a phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 38% of patients treated with ZYTIGA, versus 10% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.
Clinical studies: The efficacy of ZYTIGA was established in three randomized placebo controlled multicenter Phase 3 clinical studies (studies 3011, 302 and 301) of patients with hormone sensitive metastatic prostate cancer and metastatic 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 or prednisolone 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 patients who were asymptomatic or mildly symptomatic and had not received prior chemotherapy, whereas study 301 enrolled patients who received prior chemotherapy containing a taxane. In both studies patients were using an LHRH agonist or were previously treated with orchiectomy. In the active treatment arms, ZYTIGA was administered at a dose of 1000 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.
Because changes in PSA serum concentration do not always predict clinical benefit, in all studies patients were maintained on ZYTIGA until discontinuation criteria were met as specified for each study as follows.
Study 3011 (patients with newly diagnosed high-risk hormone sensitive prostate cancer (mHSPC): In Study 3011, (n=1199) the median age of enrolled patients was 67 years. The ECOG performance status was 0 or 1 for 97% of patients. Patients with uncontrolled hypertension, significant heart disease, or NYHA Class II or worse heart failure were excluded. 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.
In the 3011 study, 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).
At the planned rPFS analysis there were 593 events; 239 (40.0%) of patients treated with ZYTIGA and 354 (58.8%) of patients treated with placebo had radiographic evidence of progression or had died. A significant difference rPFS between treatment groups was observed (see Table 1 and Figure 1).


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At the planned first interim analysis (IA-1) for overall survival, four hundred and six (406; 47.7% of the total number of deaths required at the final analysis) deaths had occurred (169 subjects in the AA-P group and 237 subjects in the Placebo group). A statistically significant improvement in OS in favor of AA-P plus ADT was observed with a 38% reduction in the risk of death (HR=0.621; 95% CI: 0.509, 0.756) compared to Placebo plus ADT. Median survival was not reached in the AA-P group versus 34.7 months in the Placebo group (p<0.0001, crossing the pre-specified boundary for OS at Interim Analysis 1 of 0.010) (see Table 2 and Figure 2). The study was unblinded based on the magnitude of clinical benefit observed and patients in the placebo group were offered treatment with ZYTIGA. Survival continued to be followed after this IA.


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Subgroup analyses consistently favor treatment with ZYTIGA (see Figure 3).


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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=0.433; 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. A statistically significant improvement in prostate cancer-specific OS was observed for AA-P treatment compared with Placebo (HR=0.547, p<0.0001). A confirmed PSA response was observed in 91.0% of subjects in the AA-P group and 66.8% of subjects in the Placebo group (relative risk=1.362; p<0.0001). The overall response rate (complete plus partial response) in subjects with measurable disease at baseline was significantly higher in the AA-P group compared with those in the Placebo group (p=0.0002).
The time to degradation analyses of patient reported outcome (PRO) measures consistently demonstrated that treatment with AA-P delayed degradation and progression of pain, functional status, fatigue and health-related quality of life. Based on the change from baseline using repeated measures mixed-effect model statistically significant differences were observed between AA-P and Placebo as early as Cycle 2 and maintained throughout the study.
Study 302 (asymptomatic or mildly symptomatic patients who did not receive prior chemotherapy): In study 302, (n=1088) the median age of enrolled patients was 71 years for patients treated with ZYTIGA plus prednisone or prednisolone and 70 years for patients treated with placebo plus prednisone or prednisolone. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients in both arms. Patients with visceral metastases were excluded. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0-1 (asymptomatic) in 66% of patients and 2-3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours. In addition to the co-primary endpoint measures, benefit was also assessed using time to opiate use for cancer pain, time to initiation of cytotoxic chemotherapy, time to deterioration in ECOG performance score by ≥1 point and time to PSA progression based on Prostate Cancer Working Group-2 (PCWG2) criteria.
In the 302 study treatments were discontinued at the time of unequivocal clinical progression. Treatment could also be discontinued at the time of confirmed radiographic progression at the discretion of the investigator.
Radiographic progression free survival was assessed with the use of sequential imaging studies a defined by PCWG2 criteria (for bone lesions) and modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria (for soft tissue lesions). Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.
At the planed rPFS analysis there were 401 events: 150 (28%) of patients treated with ZYTIGA and 251 (46%) of patients treated with placebo had radiographic evidence of progression or had died. A significant difference in rPFS between treatment group was observed (see Figure 4).


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However, subject data continued to be collected through the date of the second interim analysis of Overall survival (OS). The investigator radiographic review of rPFS performed as a follow up sensitivity analysis is presented in Table 1 and Figure 2.
Six hundred and seven (607) subject had radiographic progression or died: 271 (50%) in the abiraterone acetate group and 336 (62%) in the placebo group. Treatment with abiraterone acetate decreased the risk of radiographic progression or death by 47% compared with placebo (HR=0.530; 95% CI: 0.451; 0.623; p <0.0001). The median rPFS was 16.5 months in the abiraterone acetate group and 8.3 months in the placebo group. (See Table 4 and Figure 5.)


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A planned interim analysis (IA) for overall survival was conducted after 333 deaths were observed. The study was unblinded based on the magnitude of clinical benefit observed and patients in the placebo group were offered treatment with ZYTIGA. Overall survival was longer for ZYTIGA than placebo with a 25% reduction in risk of death (HR=0.752; 95% CI: [0.606, 0.934], p=0.0097), but OS was not mature and interim results did not meet the pre-specified stopping boundary for statistical significance (see Table 5). Survival continued to be followed after this IA.
The planned final analysis for OS was conducted after 741 deaths were observed (median follow-up of 49 months). Sixty-five percent (354 of 546) of patients treated with ZYTIGA, compared with 71% (387 of 542) of patients treated with placebo, had died. A statistically significant OS benefit in favor of the ZYTlGA-treated group was demonstrated with a 19.4% reduction in risk of death (HR=0.806; 95% CI: [0.697, 0.931], p=0.0033) and an improvement in median OS of 4.4 months (ZYTIGA 34.7 months, placebo 30.3 months) (see Table 5 and Figure 6). This improvement was demonstrated despite subsequent therapy being common, irrespective of whether patients initially received abiraterone acetate or placebo. Subsequent therapies in the abiraterone acetate and placebo patient groups included abiraterone acetate, 69 (13%) and 238 (44%); docetaxel, 311 (57%) and 331 (61%); cabazitaxel, 100 (18%) and 105 (19%); and enzalutamide 87 (16%) and 54 (10%) patients respectively.


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Subgroup analyses consistently favor treatment with ZYTIGA (see Figure 7).


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In addition to the observed improvement in overall survival and rPFS, benefit was demonstrated for ZYTIGA vs. placebo treatment in all prospectively defined secondary endpoint measures as follows: Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was 11.1 months for patients receiving ZYTIGA and 5.6 months for patients receiving placebo (HR=0.488; 95% CI: [0.420, 0.568], p<0.0001). The time to PSA progression was approximately doubled with ZYTIGA treatment (HR=0.488). The proportion of subjects with a confirmed PSA response was greater in the ZYTIGA group than in the placebo group (62% versus 24%; p <0.0001).
Time to opiate use for cancer pain: The median time to opiate use for prostate cancer pain was not reached for patients receiving ZYTIGA and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001).
Time to initiation of cytotoxic chemotherapy: The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving ZYTIGA and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p<0.0001).
Time to deterioration in ECOG performance score by ≥1 point: The median time to deterioration in ECOG performance score by ≥1 point was 12.3 months for patients receiving ZYTIGA and 10.9 months for patients receiving placebo (HR=0.821; 95% CI: [0.714, 0.943], p=0.0053).
The following study endpoints demonstrated a statistically significant advantage in favor of ZYTIGA treatment: Objective response: Objective response was defined as the proportion of subjects with measurable disease achieving a complete or partial response according to RECIST criteria (baseline lymph node size was required to be ≥2 cm to be considered a target lesion). The proportion of subjects with measurable disease at baseline who had an objective response was 36% in the ZYTIGA group and 16% in the placebo group (p<0.0001).
Pain: Treatment with ZYTIGA significantly reduced the risk of average pain intensity progression by 18% compared with placebo (p=0.0490). The median time to progression was 26.7 months in the ZYTIGA group and 18.4 months in the placebo group.
Time to degradation in the FACT-P (Total Score): Treatment with ZYTIGA decreased the risk of FACT-P (Total Score) degradation by 22% compared with placebo (p=0.0028). The median time to degradation in FACT-P (Total Score) was 12.7 months in the ZYTIGA group and 8.3 months in the placebo group.
Study 301 (patients who had received prior chemotherapy): Eleven percent of patients enrolled in study 301 had an ECOG performance score of 2; 70% had radiographic evidence of disease progression with or without PSA progression; 70% had received one prior cytotoxic chemotherapy and 30% received two. Liver metastasis was present in 11% of patients treated with ZYTIGA.
It was recommended that patients be maintained on their study drugs until there was PSA progression (confirmed 25% increase over the patient's baseline/nadir) together with protocol-defined radiographic progression and symptomatic or clinical progression. The primary efficacy endpoint was overall survival.
In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treated with ZYTIGA, compared with 55% (219 of 398) of patients treated with placebo, had died. A statistically significant improvement in median overall survival was seen in patients treated with ZYTIGA (see Table 2 and Figure 3). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for the final analysis) were observed. Results from this updated survival analysis were consistent with those in the primary survival analysis (see Table 6).


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At all evaluation time points after the initial few months of treatment, a higher proportion of patients treated with ZYTIGA remained alive, compared with the proportion of patients treated with placebo (see Figure 8).


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Subgroup survival analyses showed a consistent survival benefit for treatment with ZYTIGA (see Figure 9).


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In addition to the observed improvement in overall survival, all secondary study endpoints favored ZYTIGA and were statistically significant after adjusting for multiple testing as follows: Patients receiving ZYTIGA demonstrated a significantly higher total PSA response rate (defined as a ≥50% reduction from baseline), compared with patients receiving placebo: 38% versus 10%, p<0.0001.
The median time to PSA progression was 10.2 months for patients treated with ZYTIGA and 6.6 months for patients treated with placebo (HR=0.580; 95% CI: [0.462, 0.728], 0.0001).
The median radiographic progression-free survival was 5.6 months for patients treated with ZYTIGA and 3.6 months for patients who received placebo (HR=0.673; 95% CI: [0.585, 0.776], p<0.0001).
Pain: The proportion of patients with pain palliation was statistically significantly higher in the ZYTIGA group than in the placebo group (44% versus 27%, p=0.0002). A responder for pain palliation was defined as a patient who experienced at least a 30% reduction from baseline in the BPI-SF worst pain intensity score over the last 24 hours without any increase in analgesic usage score observed at two consecutive evaluations four weeks apart. Only patients with a baseline pain score of ≥4 and at least one post-baseline pain score were analyzed (n=512) for pain palliation.
A lower proportion of patients treated with ZYTIGA had pain progression compared to patients taking placebo at 6 (22% vs. 28%), 12 (30% vs. 38%) and 18 months (35% vs. 46%). Pain progression was defined as an increase from baseline of ≥30% in the BPI-SF worst pain intensity score over the previous 24 hours without a decrease in analgesic usage score observed at two consecutive visits, or an increase of ≥30% in analgesic usage score observed at two consecutive visits. The time to pain progression at the 25th percentile was 7.4 months in the ZYTIGA group, versus 4.7 months in the placebo group.
Skeletal-Related Events: A lower proportion of patients in the ZYTIGA group had skeletal-related events compared with the placebo group at 6 months (18% vs. 28%), 12 months (30% vs. 40%), and 18 months (35% vs. 40%). The time to first skeletal-related event at the 25th percentile in the ZYTIGA group was twice that of the control group at 9.9 months vs. 4.9 months. A skeletal-related event was defined as a pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone.
Pharmacokinetics: General Introduction: Following introduction of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor (see Pharmacology: Pharmacodynamics: Mechanism of Action as previously mentioned).
Absorption: Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hours.
Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 17-fold increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking ZYTIGA with meals has the potential to result in highly variable exposures. Therefore, ZYTIGA must not be taken with food. ZYTIGA should be taken at least two hours after eating and no food should be eaten for at least one hour after taking ZYTIGA. The tablets should be swallowed whole with water (see Dosage & Administration).
Distribution and Protein Binding: The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5630 L, suggesting that abiraterone extensively distributes to peripheral tissues.
Metabolism: Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represent approximately 43% of total radioactivity.
Elimination: The mean half-life of abiraterone in plasma is approximately 15 hours based on data from healthy subjects. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22 % of the administered dose, respectively).
Special Populations: Renal Impairment: The pharmacokinetics of abiraterone was compared in patients with end-stage renal disease on a stable hemodialysis schedule, versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1000 mg dose did not increase in patients with end-stage renal disease on dialysis. Administration of ZYTIGA in patients with renal impairment including severe renal impairment does not require dose reduction (see Dosage & Administration).
Hepatic Impairment: The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone after a single oral 1000 mg dose increased by approximately 11% and 260% in subjects with mild and moderate pre-existing hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. No dosage adjustment is necessary for patients with pre-existing mild hepatic impairment. 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. ZYTIGA should be used with caution in patients with moderate hepatic impairment, only if the benefit clearly outweighs the possible risk (see Hepatic impairment under Dosage & Administration and Hepatotoxicity and Hepatic impairment under Precautions). ZYTIGA should not be used in patients with severe hepatic impairment. For patients who develop hepatotoxicity during treatment with ZYTIGA suspension of treatment and dosage adjustment may be required (see Hepatic impairment under Dosage & Administration and Hepatotoxicity and Hepatic impairment under Precautions).
Effects on the QT Interval: In a cardiovascular safety study in patients with metastatic advanced prostate cancer there were no significant effects of abiraterone acetate on the cardiac QT/QTc interval.
Toxicology: Carcinogenesis and Mutagenicity: Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat, abiraterone acetate increased the incidende of interstitial cell neoplasms in the testes. This finding is considered related to the pharmacological action of abiraterone and rat specific. Abiraterone acetate was not carcinogenic in female rats.
Abiraterone acetate and abiraterone were devoid of genotoxic potential in the standard panel of genotoxicity tests, including an in vitro bacterial reverse mutation assay (the Ames test), an in vitro mammalian chromosome aberration test (using human lymphocytes) and an in vivo rat micronucleus assay.
Reproductive Toxicology: In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was completely reversible in 4 to 16 weeks after abiraterone acetate was stopped.
In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reduced fetal weight and survival. Effects on the external genitalia were observed though abiraterone acetate was not teratogenic.
In these fertility and developmental toxicity studies performed in the rat, all effects were related to the pharmacological activity of abiraterone.
ZYTIGA is contraindicated in pregnancy (see Contraindications and Use in Pregnancy & Lactation).
Animal Toxicology: In all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period.
After chronic treatment from 13 weeks onward, bile duct/oval cell hyperplasia, associated with increased serum alkaline phosphatase and/or total bilirubin levels, was seen in rat and monkey livers. After a 4-week recovery period, serum parameters reversed, whereas bile duct/oval cell hyperplasia persisted.
Cataracts were seen in rats after 26 weeks of treatment. These changes were still present after a 4-week recovery period. Cataracts were not seen in monkeys after 39 weeks of treatment.
Indications/Uses
Zytiga is indicated in combination with prednisone or prednisolone for the treatment of metastatic prostate cancer (castration-resistant prostate cancer) in patients who: are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) or;
have received prior chemotherapy containing taxane.
ZYTIGA in combination with androgen deprivation therapy (ADT) and prednisone or prednisolone is indicated for the treatment of adult men with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC).
Dosage/Direction for Use
The recommended dosage of ZYTIGA is 1000 mg (four 250 mg tablets) as a single daily dose that must not be taken with food. ZYTIGA should be taken at least two hours after eating and no food should be eaten for at least one hour after taking ZYTIGA. The tablets should be swallowed whole with water (see Pharmacology: Pharmacokinetics: Absorption under Actions).
Dosage of prednisone or prednisolone: For hormone sensitive prostate cancer (mHSPC), ZYTIGA is used with 5 mg prednisone or prednisolone daily.
For metastatic castration-resistant prostate cancer (mCRPC), ZYTIGA is used with 10 mg prednisone or prednisolone daily.
Recommended monitoring: Serum transaminases and bilirubin should be measured prior to starting treatment with ZYTIGA, 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 Hypertension, hypokalemia and fluid retention due to mineralocorticoid excess and Hepatotoxicity and Hepatic Impairment under Precautions).
Hepatic Impairment: No dosage adjustment is necessary for patients with pre-existing mild hepatic impairment. 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. ZYTIGA should be used with caution in patients with moderate hepatic impairment, only if the benefit clearly outweighs the possible risk (see Pharmacology: Pharmacokinetics: Special Populations under Actions and Hepatotoxicity and Hepatic impairment under Precautions). ZYTIGA should not be used in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics: Special Populations under Actions and Hepatotoxicity and Hepatic impairment under Precautions).
For patients who develop hepatotoxicity during treatment with ZYTIGA (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 normalize (see Hepatotoxicity and Hepatic impairment under Precautions). 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 three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500 mg daily, discontinue treatment with ZYTIGA. Reduced doses should not be taken with food (see previously mentioned).
If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, ZYTIGA should be discontinued and patients should not be re-treated with ZYTIGA.
Renal Impairment: No dose adjustment is necessary for patients with renal impairment. However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.
Overdosage
Human experience of overdose with ZYTIGA is limited.
There is no specific antidote. In the event of an overdose, administration of ZYTIGA should be stopped and general supportive measure undertaken, including monitoring for arrhythmias. Liver function also should be assessed.
Contraindications
ZYTIGA is contraindicated in patients with: Hypersensitivity to the active substance or to any of the excipients listed in Description.
Women who are or may potentially be pregnant (see Use in Pregnancy & Lactation).
Severe hepatic impairment.
Special Precautions
Hypertension, hypokalemia and fluid retention due to mineralocorticoid excess: ZYTIGA may cause hypertension, hypokalemia and fluid retention (see Adverse Reactions) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see Pharmacology: Pharmacodynamics: Mechanism of Action under Actions). 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, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia.
ZYTIGA should be used with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction (LVEF) <50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in studies 3011 and 302) was not established (see Pharmacology: Pharmacodynamics: Clinical efficacy under Actions and Adverse Reactions). Before treatment with ZYTIGA, hypertension must be controlled and hypokalemia must be corrected. Blood pressure, serum potassium and fluid retention should be monitored at least monthly.
The phase 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 or Class II to IV heart failure or cardiac ejection fraction measurement of <50%.
Hepatotoxicity and Hepatic impairment: Marked increases in liver enzymes leading to drug discontinuation or dosage modification occurred in controlled clinical studies (see Adverse Reactions). Serum transaminase and bilirubin levels should be measured prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases 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 ZYTIGA should be interrupted immediately and liver function closely monitored.
Re-treatment with ZYTIGA only may take place after the return Of liver function tests to the patient's baseline and at a reduced dose level (see Hepatic impairment under Dosage & Administration).
If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, ZYTIGA should be discontinued and patients should not be re-treated with ZYTIGA.
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. ZYTIGA should be used with caution in patients with moderate hepatic impairment only if the benefit clearly outweighs the possible risk (see Pharmacology: Pharmacokinetics: Special Populations under Actions and Hepatic impairment under Dosage & Administration). ZYTIGA should not be used in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics: Special Populations under Actions and Hepatic impairment under Dosage & Administration).
Corticosteroid Withdrawal and Coverage of Stress Situations: Caution is advised and monitoring for adrenocortical insufficiency should occur if patients need to be withdrawn from prednisone or prednisolone. If ZYTIGA is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see Hypertension, hypokalemia and fluid retention due to mineralocorticoid excess as previously mentioned).
In patients on prednisone or prednisolone who are subjected to unusual stress, increased dosage of a corticosteroid may be indicated before, during and after the stressful situation.
Use with chemotherapy: The safety and efficacy of concomitant use of ZYTIGA with cytotoxic chemotherapy has not been established (see Pharmacology: Pharmacodynamics: Clinical studies under Actions).
Effects on Ability to Drive and Use Machines: No studies on the effects of ZYTIGA on the ability to drive or use machines have been performed. It is not anticipated that ZYTIGA will affect the ability to drive and use machines.
Use In Pregnancy & Lactation
Pregnancy: ZYTIGA is contraindicated in women who are or may potentially be pregnant (see Contraindications).
There are no human data on the use of ZYTIGA in pregnancy and ZYTIGA is not for use in women of child-bearing potential. Maternal use of a CYP17 inhibitor is expected to produce changes in hormone levels that could affect development of the fetus (see Pharmacology: Pharmacodynamics: Mechanism of Action and Toxicology: Reproductive Toxicology under Actions).
It is not known if abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with a woman of child-bearing potential, a condom is required along with another effective contraceptive method.
To avoid inadvertent exposure, women who are pregnant or women who may be pregnant should not handle ZYTIGA 250 mg uncoated tablet without protection, e.g., gloves.
Breast-feeding: ZYTIGA is not for use in women.
It is not known if either abiraterone acetate or its metabolites are excreted in human breast milk.
Adverse Reactions
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 were peripheral oedema, hypokalaemia, hypertension, 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 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, CTCAE (version 4.0) Grades 3 and 4 hypokalaemia were observed in 6% and 2% of patients, CTCAE (version 4.0) Grades 3 and 4 hypertension were observed in 8% and 5% 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 Precautions).
Tabulated list of adverse reactions: In studies of patients with metastatic advanced prostate cancer who were using an LHRH analogue, or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone (either 5 or 10 mg daily depending on the indication).
Adverse reactions observed during clinical studies and post-marketing experience are listed as follows by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 7.)


Click on icon to see table/diagram/image


The following CTCAE (version 4.0) Grade 3 adverse reactions occurred in patients treated with abiraterone acetate: hypokalaemia 5%; urinary tract infection 2%; alanine aminotransferase increased and/or aspartate aminotransferase increased 4%; hypertension 6%; fractures 2%; peripheral oedema, cardiac failure, and atrial fibrillation 1% each. CTCAE (version 4.0) Grade 3 hypertriglyceridaemia and angina pectoris occurred in <1% of patients. CTCAE (version 4.0) Grade 4 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: The three Phase 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 (studies 3011 and 302) or cardiac ejection fraction measurement of <50%. All patients enrolled (both active and placebo-treated patients) were concomitantly treated with androgen deprivation therapy, predominantly with the use of LHRH analogues, which has been associated with diabetes, myocardial infarction, cerebrovascular accident and sudden cardiac death. The incidence of cardiovascular adverse reactions in the Phase 3 studies in patients taking abiraterone acetate versus patients taking placebo were as follows: atrial fibrillation 2.6% vs. 2.0%, tachycardia 1.9% vs. 1.0%, angina pectoris 1.7% vs. 0.8%, cardiac failure 0.7% vs. 0.2%, and arrhythmia 0.7% vs. 0.5%.
Hepatotoxicity: Hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated with abiraterone acetate. Across Phase 3 clinical studies, hepatotoxicity 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 6% 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 Phase 3 clinical studies, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST >5 x ULN, or elevations in bilirubin >3 x ULN were observed, abiraterone acetate was withheld or discontinued. In two instances marked increases in liver function tests occurred (see Precautions). These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40 x ULN and bilirubin elevations 2 to 6 x ULN. Upon discontinuation of treatment, both patients had normalisation of their liver function tests and one patient was re-treated without recurrence of the elevations. In study 302, Grade 3 or 4 ALT or AST elevations were observed in 35 (6.5%) patients treated with abiraterone acetate. Aminotransferase elevations resolved in all but 3 patients (2 with new multiple liver metastases and 1 with AST elevation approximately 3 weeks after the last dose of abiraterone acetate). In Phase 3 clinical studies, treatment discontinuations due to ALT and AST increases or abnormal hepatic function were reported in 1.1% of patients treated with abiraterone acetate and 0.6% of patients treated with placebo; 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. In the 301 trial, patients with baseline ALT and AST ≥2.5 x ULN in the absence of liver metastases and >5 x ULN in the presence of liver metastases were excluded. In the 302 trial, patients with liver metastases were not eligible and patients with baseline ALT and AST ≥2.5 x ULN were excluded. Abnormal liver function tests developing in patients participating in clinical trials were vigorously managed by requiring treatment interruption and permitting re-treatment only after return of liver function tests to the patient's baseline. Patients with elevations of ALT or AST >20 x ULN were not re-treated. The safety of re-treatment in such patients is unknown. The mechanism for hepatotoxicity is not understood.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Effect of food on abiraterone acetate: Administration of ZYTIGA with food significantly increases the absorption of abiraterone acetate. The efficacy and safety of ZYTIGA given with food has not been established. ZYTIGA must not be taken with food (see Pharmacology: Pharmacokinetics: Absorption under Actions and Dosage & Administration).
Interactions with other drugs: Potential for other drugs to affect abiraterone exposures: In a clinical pharmacokinetic interaction study of healthy subjects pretreated 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 of abiraterone was decreased by 55%.
Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) during treatment with ZYTIGA are to be avoided, or used with careful evaluation of clinical efficacy.
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 pharmacokinetic of abiraterone.
Potential for ZYTIGA to affect exposures to other drugs: Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a clinical 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 by approximately 200%. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.
Caution is advised when ZYTIGA is administered with drugs activated by or metabolized by CYP2D6, particularly with drugs that have a narrow therapeutic index. Dose reduction of narrow therapeutic index drugs metabolized by CYP2D6 should be considered.
In the same 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.
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 1000 mg abiraterone acetate. Although these results indicate that no clinically meaningful increases in exposure are expected when ZYTIGA is combined with drugs 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 with ZYTIGA.
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.
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.
Use with chemotherapy: The safety and efficacy of concomitant use of ZYTIGA with cytotoxic chemotherapy has not been established.
Caution For Usage
Instructions for Use and Handling and Disposal: Based on its mechanism of action, ZYTIGA may harm a developing fetus; therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves (see Use in Pregnancy & Lactation).
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.
Storage
Store below 30°C.
Shelf-Life: 24 months.
ATC Classification
L02BX03 - abiraterone ; Belongs to the class of other hormone antagonists and related agents. Used in the treatment of metastatic castration-resistant prostate cancer.
Presentation/Packing
Tab 250 mg (white to off-white, oval, debossed with AA250 on one side) x 120's.
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