ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
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`1.
`
`NAME OF THE MEDICINAL PRODUCT
`
`ZYTIGA 250 mg tablets
`
`2.
`
`QUALITATIVE AND QUANTITATIVE COMPOSITION
`
`Each tablet contains 250 mg of abiraterone acetate.
`
`Excipients with known effect
`Each tablet contains 189 mg of lactose and 6.8 mg of sodium.
`
`For the full list of excipients, see section 6.1.
`
`3.
`
`PHARMACEUTICAL FORM
`
`Tablet
`White to off-white oval tablets (15.9 mm long x 9.5 mm wide), debossed with AA250 on one side.
`
`4.
`
`CLINICAL PARTICULARS
`
`4.1 Therapeutic indications
`
`ZYTIGA is indicated with prednisone or prednisolone for:
`the treatment of metastatic castration resistant prostate cancer 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 metastatic 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 (four 250 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.
`
`Medical castration with luteinising hormone releasing hormone (LHRH) analogue should be
`continued during treatment in patients not surgically castrated.
`
`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).
`
`In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated
`with ZYTIGA, consider maintaining the patient’s potassium level at ≥ 4.0 mM.
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`For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalaemia, oedema and
`other non-mineralocorticoid toxicities, treatment should be withheld and appropriate medical
`management should be instituted. Treatment with ZYTIGA should not be reinitiated until symptoms
`of the toxicity have resolved to Grade 1 or baseline.
`In the event of a missed daily dose of either ZYTIGA, prednisone or prednisolone, treatment should
`be resumed the following day with the usual daily dose.
`
`Hepatotoxicity
`For patients who develop hepatotoxicity during treatment (alanine aminotransferase [ALT] increases
`or aspartate aminotransferase [AST] increases above 5 times the upper limit of normal [ULN]),
`treatment should be withheld immediately (see section 4.4). Re-treatment following return of liver
`function tests to the patient’s baseline may be given at a reduced dose of 500 mg (two tablets) once
`daily. For patients being re-treated, serum transaminases should be monitored at a minimum of every
`two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of
`500 mg daily, treatment should be discontinued.
`
`If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy,
`treatment should be discontinued and patients should not be re-treated.
`
`Hepatic impairment
`No dose adjustment is necessary for patients with pre-existing mild hepatic impairment, Child-Pugh
`Class A.
`
`Moderate hepatic impairment (Child-Pugh Class B) has been shown to increase the systemic exposure
`to abiraterone by approximately four-fold following single oral doses of abiraterone acetate 1,000 mg
`(see section 5.2). 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. The use of ZYTIGA should be cautiously
`assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh
`the possible risk (see sections 4.2 and 5.2). ZYTIGA should not be used in patients with severe
`hepatic impairment (see sections 4.3, 4.4 and 5.2).
`
`Renal impairment
`No dose adjustment is necessary for patients with renal impairment (see section 5.2). However, there
`is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is
`advised in these patients (see section 4.4).
`
`Paediatric population
`There is no relevant use of ZYTIGA in the paediatric population.
`
`Method of administration
`ZYTIGA is for oral use.
`The tablets should be taken 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.
`
`4.3 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)].
`
`4.4
`
`Special warnings and precautions for use
`
`Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess
`ZYTIGA may cause hypertension, hypokalaemia and fluid retention (see section 4.8) as a
`consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1).
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`Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive,
`resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in
`treating patients whose underlying medical conditions might be compromised by increases in blood
`pressure, hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart
`failure), severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and
`those with severe renal impairment.
`
`ZYTIGA should be used with caution in patients with a history of cardiovascular disease. 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 (study 301) or Class II to IV heart failure (study 302) or cardiac ejection fraction
`measurement of < 50%. In study 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 study 302) was not established (see sections 4.8 and 5.1).
`
`Before treating patients with a significant risk for congestive heart failure (e.g.a history of cardiac
`failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider
`obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with ZYTIGA,
`cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and
`fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium,
`fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart
`failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities
`corrected. QT prolongation has been observed in patients experiencing hypokalaemia in association
`with ZYTIGA treatment. Assess cardiac function as clinically indicated, institute appropriate
`management and consider discontinuation of this treatment if there is a clinically significant decrease
`in cardiac function (see section4.2).
`
`Hepatotoxicity and hepatic impairment
`Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred
`in controlled clinical studies (see section 4.8). Serum transaminase levels should be measured prior to
`starting treatment, 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 ULN, treatment should
`be interrupted immediately and liver function closely monitored. Re-treatment may take place only
`after return of liver function tests to the patient’s baseline and at a reduced dose level (see
`section 4.2).
`
`If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy,
`treatment should be discontinued and patients should not be re-treated.
`
`Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are
`no data to support the use of ZYTIGA in this population.
`
`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). The
`use of ZYTIGA should be cautiously assessed in patients with moderate hepatic impairment, in whom
`the benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). ZYTIGA should not
`be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).
`
`There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some with
`fatal outcome (see section 4.8).
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`Corticosteroid withdrawal and coverage of stress situations
`Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are
`withdrawn from prednisone or prednisolone. If ZYTIGA is continued after corticosteroids are
`withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information
`above).
`
`In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of
`corticosteroids may be indicated before, during and after the stressful situation.
`
`Bone density
`Decreased bone density may occur in men with metastatic advanced prostate cancer (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 (see section 5.1).
`
`Intolerance to excipients
`This medicinal product contains lactose. Patients with rare hereditary problems of galactose
`intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
`medicine. This medicinal product also contains more than 1 mmol (or 27.2 mg) sodium per dose of
`four tablets. To be taken into consideration by patients on a controlled sodium diet.
`
`Potential risks
`Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer
`including those undergoing treatment with ZYTIGA.
`
`Skeletal muscle effects
`Cases of myopathy have been reported in patients treated with ZYTIGA. Some patients had
`rhabdomyolysis with renal failure. Most cases developed within the first month 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).
`
`4.5
`
`Interaction with other medicinal products and other forms of interaction
`
`Effect of food on abiraterone acetate
`Administration with food significantly increases the absorption of abiraterone acetate. The efficacy
`and safety when given with food have not been established therefore this medicinal product must not
`be taken with food (see sections 4.2 and 5.2).
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`Interactions with other medicinal products
`Potential for other medicinal products 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 1,000 mg,
`the mean plasma AUC∞ of abiraterone was decreased by 55%.
`
`Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine,
`phenobarbital, St John's wort [Hypericum perforatum]) during treatment are to be avoided, unless
`there is no therapeutic alternative.
`
`In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of
`ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the
`pharmacokinetics of abiraterone.
`
`Potential to affect exposures to other medicinal products
`Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8.
`In a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the
`CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was
`increased approximately 2.9 fold. The AUC24 for dextrorphan, the active metabolite of
`dextromethorphan, increased approximately 33%.
`
`Caution is advised when administering with medicinal products activated by or metabolised by
`CYP2D6, particularly with medicinal products that have a narrow therapeutic index. Dose reduction
`of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be
`considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol,
`propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine,
`oxycodone and tramadol (the latter three medicinal products requiring CYP2D6 to form their active
`analgesic metabolites).
`
`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,
`patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow
`therapeutic index if used concomitantly.
`
`In vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown to
`inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the
`concentrations of medicinal products eliminated by OATP1B1. There are no clinical data available to
`confirm transporter based interaction.
`
`Use with products known to prolong QT interval
`Since androgen deprivation treatment may prolong the QT interval, caution is advised when
`administering ZYTIGA with medicinal products known to prolong the QT interval or medicinal
`products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III
`(e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone,
`moxifloxacin, antipsychotics, etc.
`
`Use with Spironolactone
`Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA)
`levels. Use with ZYTIGA is not recommended (see section 5.1).
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`4.6
`
`Fertility, pregnancy and lactation
`
`Women of childbearing potential
`There are no human data on the use of ZYTIGA in pregnancy and this medicinal product is not for
`use in women of childbearing potential.
`
`Contraception in males and females
`It is not known whether 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 childbearing potential, a condom is required along with another effective contraceptive
`method. Studies in animals have shown reproductive toxicity (see section 5.3).
`
`Pregnancy
`ZYTIGA is not for use in women and is contraindicated in women who are or may potentially be
`pregnant (see section 4.3 and 5.3).
`
`Breast-feeding
`ZYTIGA is not for use in women.
`
`Fertility
`Abiraterone affected fertility in male and female rats, but these effects were fully reversible (see
`section 5.3).
`
`4.7 Effects on ability to drive and use machines
`
`ZYTIGA has no or negligible influence on the ability to drive and use machines.
`
`4.8 Undesirable effects
`
`Summary of the safety profile
`The most common adverse reactions seen are peripheral oedema, hypokalaemia, hypertension and
`urinary tract infection.
`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 studies, anticipated mineralocorticoid adverse
`reactions were seen more commonly in patients treated with abiraterone acetate than in patients
`treated with placebo: hypokalaemia 21% vs.11%, hypertension 16% vs. 11% and fluid retention
`(peripheral oedema) 26% vs. 20%, respectively. In patients treated with abiraterone acetate, CTCAE
`(version 3.0) Grades 3 and 4 hypokalaemia and CTCAE (version 3.0) Grades 3 and 4 hypertension
`were observed in 4% and 2% 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).
`
`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 (10 mg daily).
`
`Adverse reactions observed during clinical studies and post-marketing experience are listed below 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.
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`Endocrine disorders
`Metabolism and nutrition disorders
`
`Cardiac disorders
`
`Adverse reactions identified in clinical studies and post-marketing
`Table 1:
`System Organ Class
`Adverse reaction and frequency
`very common: urinary tract infection
`Infections and infestations
`common: sepsis
`uncommon: adrenal insufficiency
`very common: hypokalaemia
`common: hypertriglyceridaemia
`common: cardiac failure*, angina pectoris,
`arrhythmia, atrial fibrillation, tachycardia
`not known: myocardial infarction,
`QT prolongation (see sections 4.4 and 4.5)
`very common: hypertension
`rare: allergic alveolitisa
`
`Vascular disorders
`Respiratory, thoracic and mediastinal
`disorders
`Gastrointestinal disorders
`
`Hepatobiliary disorders
`
`very common: diarrhoea
`common: dyspepsia
`common: alanine aminotransferase increased,
`aspartate aminotransferase increased
`rare: hepatitis fulminant, acute hepatic failure
`common: rash
`uncommon: myopathy, rhabdomyolysis
`
`Skin and subcutaneous tissue disorders
`Musculoskeletal and connective tissue
`disorders
`Renal and urinary disorders
`General disorders and administration site
`conditions
`Injury, poisoning and procedural
`complications
`* Cardiac failure also includes congestive heart failure, left ventricular dysfunction and ejection fraction decreased
`** Fractures includes all fractures with the exception of pathological fracture
`a
`Spontaneous reports from post-marketing experience
`
`common: haematuria
`very common: oedema peripheral
`
`common: fractures**
`
`The following CTCAE (version 3.0) Grade 3 adverse reactions occurred in patients treated with
`abiraterone acetate: hypokalaemia 3%; urinary tract infection, alanine aminotransferase increased,
`hypertension, aspartate aminotransferase increased, fractures 2%; peripheral oedema, cardiac failure,
`and atrial fibrillation 1% each. CTCAE (version 3.0) Grade 3 hypertriglyceridaemia and angina
`pectoris occurred in < 1% of patients. CTCAE (version 3.0) Grade 4 peripheral oedema,
`hypokalaemia, urinary tract infection, cardiac failure and fractures occurred in < 1% of patients.
`
`Description of selected adverse reactions
`Cardiovascular reactions
`Both phase 3 studiesexcluded 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 (study 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: hypertension 14.5% vs. 10.5%, atrial fibrillation 3.4% vs. 3.4%, tachycardia
`2.8% vs. 1.7%, angina pectoris 1.9% vs. 0.9%, cardiac failure 1.9% vs. 0.6%, and arrhythmia 1.1% vs.
`0.4%.
`
`Hepatotoxicity
`Hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated with
`abiraterone acetate. Across all clinical studies, liver function test elevations (ALT or AST increases of
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`> 5 x ULN or bilirubin increases > 1.5 x ULN) were reported in approximately 4% of patients who
`received abiraterone acetate, typically during the first 3 months after starting treatment. In the 301
`clinical study, 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
`section 4.4). 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). Treatment discontinuations due to ALT and AST increases
`were reported in 1.7% and 1.3% of patients treated with abiraterone acetate and 0.2% and 0% of
`patients treated with placebo, respectively; no deaths were reported due to hepatotoxicity event.
`
`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 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 (see section 4.2). 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
`listed in Appendix V.
`
`4.9 Overdose
`
`Human experience of overdose with ZYTIGA is limited.
`
`There is no specific antidote. In the event of an overdose, administration should be withheld and
`general supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and for
`signs and symptoms of fluid retention. Liver function also should be assessed.
`
`5.
`
`PHARMACOLOGICAL PROPERTIES
`
`5.1
`
`Pharmacodynamic properties
`
`Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents, ATC
`code: L02BX03
`
`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 tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into
`testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage
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`of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the
`adrenals (see section 4.4).
`
`Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.
`Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease
`androgen production in the testes but do not affect androgen production by the adrenals or in the
`tumour. Treatment with ZYTIGA decreases serum testosterone to undetectable levels (using
`commercial assays) when given with LHRH analogues (or orchiectomy).
`
`Pharmacodynamic effects
`ZYTIGA decreases serum testosterone and other androgens to levels lower than those achieved by the
`use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the
`CYP17 enzyme required for androgen biosynthesis. 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 abiraterone acetate, versus 10% of patients treated with placebo, had at
`least a 50% decline from baseline in PSA levels.
`
`Clinical efficacy and safety
`Efficacy was established in two randomised placebo-controlled multicentre phase 3 clinical studies
`(studies 301 and 302) of patients with metastatic castration resistant prostate cancer. 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 studies it was recommended that patients be maintained on their study treatments until
`discontinuation criteria were met as specified below for each study.
`
`In both studies spironolactone use was not allowed as spironolactone binds to the androgen receptor
`and may increase PSA levels.
`
`Study 302 (chemotherapy naïve patients)
`This study enrolled chemotherapy naïve patients who were asymptomatic or mildly symptomatic and
`for whom chemotherapy was not yet clinically indicated. A score of 0-1 on Brief Pain Inventory-Short
`Form (BPI-SF) worst pain in last 24 hours was considered asymptomatic, and a score of 2-3 was
`considered mildly symptomatic.
`
`In study 302, (n = 1,088) 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 number of patients treated with ZYTIGA by racial group was
`Caucasian 520 (95.4%), Black 15 (2.8%), Asian 4 (0.7%) and other 6 (1.1%). The Eastern
`Cooperative Oncology Group (ECOG) performance status was 0 for 76% of patients, and 1 for 24%
`of patients in both arms. Fifty percent of patients had only bone metastases, an additional 31% of
`patients had bone and soft tissue or lymph node metastases and 19% of patients had only soft tissue or
`lymph node metastases. Patients with visceral metastases were excluded. Co-primary efficacy
`endpoints were overall survival and radiographic progression-free survival (rPFS). 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.
`Study treatments were discontinued at the time of unequivocal clinical progression. Treatments could
`also be discontinued at the time of confirmed radiographic progression at the discretion of the
`investigator.
`
`10
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`WCK1127
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`

`

`Radiographic progression free survival (rPFS) was assessed with the use of sequential imaging studies
`as defined by PCWG2 criteria (for bone lesions) and modified Response Evaluation Criteria In Solid
`Tumors (RECIST) criteria (for soft tissue lesions). Analysis of rPFS utilised centrally-reviewed
`radiographic assessment of progression.
`
`At the planned 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 groups was observed (see Table 2 and Figure 1).
`
`Table 2:
`
`Study 302: Radiographic progression-free survival of patients treated with either
`ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRH
`analogues or prior orchiectomy
`ZYTIGA
`(N = 546)
`
`Placebo
`(N = 542)
`
`Radiographic
`Progression-free Survival
`(rPFS)
`Progression or death
`Median rPFS in months
`(95% CI)
`p-value*
`Hazard ratio** (95% CI)
`NE = Not estimated
`*
`p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)
`** Hazard ratio < 1 favours ZYTIGA
`
`150 (28%)
`Not reached
`(11.66; NE)
`
`251 (46%)
`8.3
`(8.12; 8.54)
`
`< 0.0001
`0.425 (0.347; 0.522)
`
`Figure 1: Kaplan Meier curves of radiographic progression-free survival in patients treated
`with either ZYTIGA or placebo in combination with prednisone or prednisolone
`plus LHRH analogues or prior orchiectomy
`
`AA = ZYTIGA
`
`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 3 and Figure 2.
`
`11
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`WCK1127
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`

`

`Six hundred and seven (607) subjects had radiographic pr