Package Insert. Other excipients include: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium,

Transcription

1 Package Insert SCHEDULING STATUS Schedule 4 PROPIETARY NAME & DOSAGE FORM ZYTIGA 250 mg tablets COMPOSITION Each tablet contains 250 mg of abiraterone acetate. Other excipients include: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate, magnesium stearate and colloidal silicon dioxide PHARMACOLOGICAL CLASSIFICATION A Hormone inhibitors. PHARMACOLOGICAL ACTION Pharmacodynamic properties Mechanism of action Abiraterone acetate 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 of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see Warnings and special 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 Page 1 of 27

2 tumour. Treatment with abiraterone acetate decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH agonists (or orchiectomy). Pharmacodynamic effects Abiraterone acetate 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 abiraterone acetate, versus 10 % of patients treated with placebo, had at least a 50 % decline from baseline in PSA levels. Pharmacokinetics Following administration 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 Pharmacodynamic properties). 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 abiraterone acetate with meals has the potential to result in highly variable exposures. Therefore, abiraterone acetate must not be taken with food. Abiraterone acetate 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 and Directions for Use). Page 2 of 27

3 Distribution The plasma protein binding of 14 C-abiraterone in human plasma is 99,8 %. The apparent volume of distribution is approximately l, suggesting that abiraterone extensively distributes to peripheral tissues. Metabolism Following oral administration of 14 C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed 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 represents 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 14 C-abiraterone acetate 1 g, approximately 88 % of the radioactive dose is recovered in faeces and approximately 5 % in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55 % and 22 % of the administered dose, respectively). Patients with hepatic impairment The pharmacokinetics of abiraterone acetate 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 1 g 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 dose adjustment is necessary for patients with pre-existing mild hepatic impairment. Page 3 of 27

4 For patients who develop hepatotoxicity during treatment with abiraterone acetate, suspension of treatment and dose adjustment may be required (see sections Dosage and Directions for Use and Warnings and special precautions). Patients with renal impairment The pharmacokinetics of abiraterone acetate was compared in patients with end-stage renal disease on a stable haemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1 g dose did not increase in subjects with endstage renal disease on dialysis. Administration of abiraterone acetate in patients with renal impairment, including severe renal impairment, does not require dose reduction (see Dosage and Directions for Use). Clinical efficacy The efficacy of abiraterone acetate was established in a randomised placebo-controlled multicenter phase 3 clinical study of patients with metastatic advanced prostate cancer (castration resistant prostate cancer) who had received prior chemotherapy containing a taxane. Patients were using an LHRH agonist or were previously treated with orchiectomy (n = 1 195). In the active treatment arm, abiraterone acetate was administered at a dose of 1 g daily in combination with low dose prednisone or prednisolone 5 mg twice daily (n = 797). Control patients received placebo and low dose prednisone or prednisolone 5 mg twice daily (n = 398). In a planned analysis conducted after 552 deaths were observed, 42 % (333 of 797) of patients treated with abiraterone acetate 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 abiraterone (see Table 1). Table 1: Overall survival of patients treated with either ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRH agonists or prior orchiectomy ABIRATERONE ACETATE (n = 797) PLACEBO (n = 398) Deaths 333 (42 %) 219 (55 %) Page 4 of 27

5 Median overall survival in months (95 % CI) 14,8 (14,1; 15,4) 10,9 (10,2; 12,0) p-value < 0,0001 Hazard ratio* (95 % CI) 0,646 (0,543; 0,768) * Hazard ratio < 1 favours Abiraterone acetate. INDICATIONS ZYTIGA is indicated with prednisone or prednisolone for the treatment of metastatic advanced prostate cancer (castration resistant prostate cancer) in adult patients who have received prior chemotherapy containing docetaxel. CONTRA-INDICATIONS ZYTIGA is contra-indicated in: - women who are or may potentially be pregnant (see Pregnancy and Lactation) - patients with hypersensitivity to the active substance or to any of the excipients (see Composition). - Moderate to severe hepatic impairment (Child-Pugh class B and C) WARNINGS AND SPECIAL PRECAUTIONS Hypertension, hypokalaemia and fluid retention due to mineralocorticoid excess 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 < 50 % or NYHA Class III or IV heart failure has not been established. Before treatment with ZYTIGA, hypertension must be controlled and hypokalaemia must be corrected. ZYTIGA may cause hypertension, hypokalaemia and fluid retention (see Side-effects) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see Pharmacodynamic properties). 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 Page 5 of 27

6 by increases in blood pressure, hypokalaemia or fluid retention, e.g. those with heart failure, recent myocardial infarction or ventricular dysrhythmia. Blood pressure, serum potassium and fluid retention should be monitored at least monthly. Hepatotoxicity Marked increases in liver enzymes leading to ZYTIGA discontinuation or dose modification occurred in controlled clinical studies (see Side-effects). 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, in particular serum ALT, should be measured immediately. If at any time the ALT 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 may take place only after return of liver function tests to the patient s baseline and at a reduced dose level (see Dosage and Directions for Use). If patients develop severe hepatotoxicity (ALT 20 times the upper limit of normal) anytime while on therapy, ZYTIGA should be discontinued and patients should not be re-treated with ZYTIGA. 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 previous). In patients on prednisone or prednisolone who are subjected to unusual stress, increased dosage of corticosteroids may be indicated before, during and after the stressful situation. Galactose intolerance ZYTIGA contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not ZYTIGA. Page 6 of 27

7 Effects on ability to drive and use machines ZYTIGA has no or negligible influence on the ability to drive or use machines. INTERACTIONS Administration of ZYTIGA with food significantly increases the absorption of abiraterone acetate. The efficacy and safety of ZYTIGA given with food have not been established. ZYTIGA must not be taken with food (see Dosage and Directions for Use and Pharmacokinetic properties). 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 by approximately 200 %. The AUC 24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33 %. Caution is advised when ZYTIGA is administered with medicines activated by or metabolised by CYP2D6, particularly with medicines that have a narrow therapeutic index. Dose reduction of narrow therapeutic index medicines metabolised by CYP2D6 should be considered (e.g.propafenone, flecainide and haloperidol). PREGNANCY AND LACTATION Pregnancy: ZYTIGA is contraindicated in women who are or may potentially be pregnant (see Contra-indications). Women of childbearing potential There are no human data on the use of ZYTIGA in pregnancy and ZYTIGA is not for use in women of childbearing potential. Maternal use of a CYP17 inhibitor is expected to produce changes in hormone levels that could affect development of the foetus. 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 Page 7 of 27

8 a woman of childbearing potential, a condom is required along with another effective contraceptive method. Fertility Reproductive toxicology studies were not conducted with abiraterone acetate. No fertility data are available. Lactation ZYTIGA is not for use in women. It is not known if either abiraterone acetate or its metabolites are excreted in human breast milk. DOSAGE AND DIRECTIONS FOR USE The recommended dose of ZYTIGA is 1 g (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. Taking ZYTIGA with food increases systemic exposure to abiraterone (see Interactions and Pharmacokinetics). Patients should be maintained on ZYTIGA until radiographic progression and symptomatic/clinical progression and until PSA progression (confirmed 25 % increase over the patient s baseline/nadir). ZYTIGA is used with low dose prednisone or prednisolone. The recommended dose of prednisone or prednisolone is 10 mg daily. 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 Warnings and special precautions). 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. Page 8 of 27

9 Hepatic impairment No dose adjustment is necessary for patients with pre-existing mild hepatic impairment, Child-Pugh class A. ZYTIGA should not be used in patients with pre-existing moderate or severe hepatic impairment, Child-Pugh class B or C (see Contra-indications and Pharmacokinetics). For patients who develop hepatotoxicity during treatment with ZYTIGA (alanine aminotransferase (ALT) 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 normalise (see Warnings and special 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 retreated, serum transaminases and bilirubin should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500 mg daily, treatment should be discontinued. Reduced doses should not be taken with food (see Dosage and Directions for use). If patients develop severe hepatotoxicity (ALT 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 (see Pharmacokinetic properties). Paediatric population: There is no relevant use of ZYTIGA in paediatric patients, as prostate cancer is not present in the paediatric population. Method of administration Precautions to be taken before handling or administering ZYTIGA Based on its mechanism of action, ZYTIGA may harm a developing foetus; therefore, women (including healthcare professionals), who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g. gloves (see Pregnancy and Lactation). Page 9 of 27

10 SIDE-EFFECTS Summary of the safety profile The most common adverse reactions seen with ZYTIGA are peripheral oedema, hypokalaemia, hypertension and urinary tract infection. ZYTIGA may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. In a phase 3 study anticipated mineralocorticoid effects were seen more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalaemia 17 % versus 8 %, hypertension 9 % versus 7 % and fluid retention (peripheral oedema) 25 % versus 17 %, respectively. In patients treated with ZYTIGA, grades 3 and 4 hypokalaemia and grades 3 and 4 hypertension were observed in 4 % and 1 % of patients, respectively. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see Warnings and special precautions). Tabulated summary of clincal adverse reactions In studies of patients with metastatic advanced prostate cancer who were using a luteinising hormone-releasing hormone (LHRH) agonist, or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1 g daily in combination with low dose prednisone or prednisolone (10 mg daily). Patients were intolerant to or had failed up to two prior chemotherapy regimens, one of which contained a taxane. Adverse reactions observed during clinical studies with ZYTIGA 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 2: Adverse reactions identified in clinical studies with ZYTIGA Infections and infestations Endocrine disorders very common: urinary tract infection uncommon: adrenal insufficiency Page 10 of 27

11 Metabolism and nutrition disorders very common: hypokalaemia common: hypertriglyceridaemia Cardiac disorders common: cardiac failure*, angina pectoris,dysrhythmia, atrial fibrillation, tachycardia Vascular disorders Hepatobiliary disorders General disorders and administration very common: hypertension common: increased alanine aminotransferase very common: peripheral oedema site conditions * Cardiac failure also includes congestive heart failure, left ventricular dysfunction and fraction decreased ejection The following grade 3 adverse reactions occurred in patients treated with ZYTIGA: hypokalaemia in 3 %; urinary tract infection in 2 %; peripheral oedema, increased alanine aminotransferase, hypertension, cardiac failure and atrial fibrilliation, in 1 % each. Grade 3 hypertriglyceridaemia and angina pectoris occurred in < 1 % of patients. Grade 4 peripheral oedema, hypokalaemia, urinary tract infection, and cardiac failure occurred in < 1 % of patients. Description of selected adverse reactions Cardiovascular effects The phase 3 study conducted with ZYTIGA excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable angina, New York Heart Association Class III or IV heart disease or with a 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 agonists, which has been associated with diabetes, myocardial infarction, cerebrovascular accident and sudden cardiac death. The incidence of cardiovascular adverse reactions in the phase 3 study was low in patients who received ZYTIGA and was similar to the incidence in patients who received placebo. Hepatotoxicity Page 11 of 27

12 Medicine-associated hepatotoxicity with elevated ALT, aspartate transaminase (AST) and total bilirubin commonly occur in patients treated with ZYTIGA. Across all clinical studies, liver function test elevations (ALT or AST increases of > 5 x ULN or bilirubin increases > 1,5 x ULN) were reported in approximately 2 % of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 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. ALT increase and AST increase was reported in 3,9 % and 2,7 % in the ZYTIGA arm vs. 3,8 % and 1,3 % in the placebo arm respectively. Hyperbilirubinaemia was reported in 1,3 % in the ZYTIGA arm vs. 1,8 % in the placebo arm. When elevations of either ALT or AST > 5 x ULN, or elevations in bilirubin > 3 x ULN were observed, ZYTIGA was withheld or discontinued. Treatment was withheld or discontinued in 0,8 % of subjects in the ZYTIGA as well as the placebo arms. In two instances marked increases in liver function tests occurred (see Warnings and special 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 ZYTIGA, both patients had normalisation of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the risk for hepatotoxicity was mitigated by exclusion of patients with active hepatitis or baseline ALT and AST 2,5 x ULN in the absence of liver metastases and > 5 x ULN if liver metastases were present. 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 Dosage and Directions for Use). 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 associated with ZYTIGA is not understood. KNOWN SYMPTOMS OF OVERDOSE AND PARTICULARS OF ITS TREATMENT There is no specific antidote. In the event of an overdose, administration of ZYTIGA should be withheld and general supportive measures undertaken, including monitoring for dysrhythmias. Liver function also should be assessed. Page 12 of 27

13 IDENTIFICATION White to off-white, oval tablets 16 mm long, debossed with AA250 on one side. PRESENTATION ZYTIGA is available in high density polyethylene round white bottles fitted with a white polypropylene cap and packed into an outer carton. Package size is 120 tablets. STORAGE INSTRUCTIONS Store at or below 30 C. Keep well closed. KEEP OUT OF REACH OF CHILDREN. Special precautions for disposal and other handling Women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g. gloves (see Pregnancy and Lactation). REGISTRATION NUMBER 46/21.12/0379 NAME AND ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION JANSSEN PHARMACEUTICA (Pty.) Ltd. (Reg No.: 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATE OF PUBLICATION OF THE PACKAGE INSERT 31 July 2014 Page 13 of 27

14 VOUBILJET SKEDULERINGSTATUS Skedule 4 HANDELSNAAM EN DOSEERVORM ZYTIGA 250 mg tablette SAMESTELLING Elke tablet bevat 250 mg abirateroonasetaat. Die ander bestanddele sluit in: laktosemonohidraat, mikrokristallyne sellulose, natriumkroskarmellose, povidoon, natriumlourielsulfaat, magnesiumstearaat en kolloïdale silikondioksied. FARMAKOLOGIESE KLASSIFIKASIE A Hormooninhibeerders. FARMAKOLOGIESE WERKING Farmakodinamiese eienskappe Werkingsmeganisme Abirateroonasetaat word in vivo omgeskakel na abirateroon, 'n remmer van die biosintese van androgene. Meer bepaal rem abirateroon selektief die ensiem 17α-hidroksilase/C17,20-liase (CYP17). Hierdie ensiem kom tot uitdrukking in die weefsels van die testes, byniere en prostaatgewasse en word daar benodig vir die biosintese van androgene. CYP17 kataliseer die omsetting van pregnenoloon en progesteroon tot voorlopers van testosteroon, DHEA en androsteendioon, onderskeidelik deur 17α-hidroksilering en verbreking van die C17,20-binding. Remming van CYP17 lei ook tot verhoogde vorming van mineralokortikoïede deur die byniere (kyk Waarskuwings en spesiale voorsorgmaatreëls). Page 14 of 27

15 'n Androgeengevoelige prostaatkarsinoom reageer op 'n behandeling wat die androgeenkonsentrasies verlaag. Behandelings waar androgeen ontneem word, soos met LHRHagoniste of orgidektomie, verlaag die androgeenproduksie in die testes, maar het geen invloed op die androgeenproduksie deur die byniere of in die tumor nie. Behandeling met abirateroonasetaat verlaag die serumtestosteroon tot onopspoorbare vlakke (met kommersiële bepalingsmetodes) wanneer dit saam met LHRH agoniste gegee word (of orgidektomie). Farmakodinamiese effekte Abirateroonasetaat verlaag testosteroon en ander androgene in die serum tot vlakke laer as die wat bereik word by gebruik van LHRH-analoë alleen, of deur middel van orgidektomie. Dit vloei voort uit die selektiewe remming van die CYP17-ensiem, wat nodig is vir die biosintese van androgene. Prostaatspesifieke antigeen (PSA) dien as biomerker by pasiënte met prostaatkanker. In 'n fase 3 kliniese navorsingstudie met pasiënte by wie vorige chemoterapie met taksane misluk het, het 38 % van die pasiënte wat met abirateroonasetaat behandel was, 'n afname in PSA van minstens 50 % ten opsigte van hul basislynwaardes gehad, teenoor 10 % van die pasiënte wat met plasebo behandel is. Farmakokinetika Die farmakokinetika van abirateroon en abirateroonasetaat na toediening van abirateroonasetaat is ondersoek by gesonde persone, by pasiënte met gemetastaseerde gevorderde prostaatkanker en by persone sonder kanker, met lewer- of nierinkorting. Abirateroonasetaat word in vivo vinnig omgeskakel na abirateroon, 'n remmer van die biosintese van androgene (kyk Farmakodinamiese eienskappe). Absorpsie Na orale toediening van abirateroonasetaat op 'n nugter maag neem dit ongeveer 2 uur om die maksimum plasma-abirateroonkonsentrasie te bereik. Toediening van abirateroonasetaat met voedsel lei, in vergelyking met toediening op 'n nugter maag, tot 'n 17-keer verhoogde gemiddelde sistemiese blootstelling aan abirateroon, afhangende van die vetgehalte van die maaltyd. Gegewe die normale variasie in die samestelling van maaltye, kan die Page 15 of 27

16 inname van abirateroonasetaat met voedsel moontlik lei tot hoogs wisselende blootstellings. Gevolglik moet abirateroon nie saam met voedsel geneem word nie. Abirateroonasetaat moet ten minste twee uur na maaltye geneem word en geen voedsel moet vir ten minste een uur nadat ZYTIGA geneem is, ingeneem word nie. Die tablette moet heel, met water ingesluk word (kyk Dosis en gebruiksaanwysings). Verspreiding Die plasma-proteïenbinding van 14 C-abirateroon in mens plasma is 99,8 %. Die skynbare verspreidingsvolume is ongeveer l, wat daarop dui dat abirateroon in hoë mate na die perifere weefsels versprei. Metabolisme Na orale toediening van 14 C-abirateroonasetaat in die vorm van kapsules, word abirateroonasetaat gehidroliseer tot abirateroon, wat vervolgens afgebreek word by wyse van sulfatering, hidroksilasie en oksidasie, veral in die lewer. Die grootste deel van die sirkulerende radioaktiwiteit (ongeveer 92 %) word in die vorm van metaboliete van abirateroon aangetref. Van die 15 bespeurbare metaboliete verteenwoordig twee hoofmetaboliete, abirateroonsulfaat en N-oksied-abirateroonsulfaat, elk ongeveer 43 % van die totale radioaktiwiteit. Uitskeiding Die gemiddelde halfleeftyd van abirateroon is ongeveer 15 uur in plasma, gegrond op gegewens van gesonde persone. Na orale toediening van 1 g 14 C-abirateroonasetaat word ongeveer 88 % van die radioaktiewe dosis teruggevind in die feses en ongeveer 5 % in die urien. Die belangrikste verbindings in die feses is onveranderde abirateroonasetaat en abirateroon (onderskeidelik ongeveer 55 % en 22 % van die toegediende dosis). Pasiënte met lewerinkorting Die farmakokinetika van abirateroonasetaat is ondersoek by persone met reeds bestaande ligte of matige lewerinkorting (onderskeidelik Child-Pugh Klasse A en B) en by gesonde kontrolepersone. Die sistemiese blootstelling aan abirateroon na 'n eenmalige orale dosis van 1 g het onderskeidelik Page 16 of 27

17 met ongeveer 11 % en 260 % gestyg by persone met reeds bestaande ligte en matige lewerinkorting. Die gemiddelde halfleeftyd van abirateroon is ongeveer 18 uur langer by persone met ligte lewerinkorting en tot ongeveer 19 uur langer by persone met matige lewerinkorting. Vir pasiënte met reeds bestaande ligte lewerinkorting is geen aanpassing van die dosis nodig nie. Vir pasiënte wat tydens die behandeling met abirateroonasetaat lewertoksisiteit ontwikkel, kan dit nodig wees om die behandeling op te skort en die dosis aan te pas (kyk afdelings Dosis en gebruiksaanwysings en Waarskuwings en spesiale voorsorgmaatreëls). Pasiënte met nierinkorting Die farmakokinetika van abirateroonasetaat is by pasiënte met terminale niersiekte op 'n stabiele hemodialise-program vergelyk met bypassende kontrolepersone met normale nierfunksie. Die sistemiese blootstelling aan abirateroon na 'n eenmalige mondelike dosis van 1 g het nie toegeneem by persone met terminale niersiekte op hemodialise nie. By toediening aan pasiënte met nierinkorting, insluitende ernstige nierinkorting, is geen verlaging van die dosis nodig nie (kyk Dosis en gebruiksaanwysings). Kliniese doeltreffendheid Die doeltreffendheid van abirateroonasetaat is vasgestel in 'n ewekansige plasebo-beheerde kliniese multisentrum-fase-3-studie by pasiënte met gemetastaseerde gevorderde prostaatkanker (kastrasiebestande prostaatkanker) wat voorheen chemoterapie wat 'n taksaan ingesluit het, ontvang het. In die arm met die aktiewe behandeling is abirateroonasetaat toegedien teen 'n dosis van 1 g per dag in kombinasie met 'n lae dosis van prednisoon of prednisoloon by 5 mg twee keer per dag (n = 797). Kontrolepasiënte het plasebo en 'n lae dosis prednisoon of prednisoloon van 5 mg twee keer per dag ontvang (n = 398). In 'n beplande analise, uitgevoer nadat daar 552 sterfgevalle waargeneem is, was 42 % (333 van die 797) van die pasiënte wat met abirateroonasetaat behandel is oorlede, in vergelyking met 55 % (219 van die 398) van die pasiënte wat met plasebo behandel is. By die pasiënte wat met abirateroon behandel is, was daar 'n statisties beduidende verbetering van die mediane algehele oorlewing waargeneem (kyk Tabel 1). Page 17 of 27

18 Tabel 1: Algehele oorlewing van pasiënte wat of met ZYTIGA of met plasebo behandel is, in kombinasie met prednisoon of prednisoloon plus LHRH-agoniste of voorafgaande orgidektomie ABIRATEROONASETAAT (n = 797) PLASEBO (n = 398) Sterftes 333 (42 %) 219 (55 %) Mediane algehele oorlewing in maande (95 % VI) 14,8 (14,1; 15,4) 10,9 (10,2; 12,0) p-waarde < 0,0001 Gevaar verhouding* (95 % VI) 0,646 (0,543; 0,768) * Gevaar verhouding < 1 begunstig abirateroonasetaat. INDIKASIES ZYTIGA is met prednisoon of prednisoloon aangedui vir die behandeling van gemetastaseerde gevorderde prostaatkanker (kastrasiebestande prostaatkanker) by volwasse pasiënte wat voorheen chemoterapie wat dosetaksel ingesluit het, ontvang het. KONTRAÏNDIKASIES ZYTIGA is teenaangedui by: - vroue wat swanger is of moontlik swanger kan wees (kyk Swangerskap en laktasie) - pasiënte wat oorgevoelig is vir die aktiewe bestanddeel of vir enige van die hulpstowwe (kyk Samestelling). - Matige tot ernstige lewerinkorting (Child-Pugh-klasse B en C) WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS Hipertensie, hipokalemie en vogretensie as gevolg van 'n oormaat mineralokortikoïede ZYTIGA moet met versigtigheid gebruik word by pasiënte met 'n geskiedenis van kardiovaskulêre siekte. Die veiligheid van ZYTIGA by pasiënte met 'n linkerventrikel-uitwerpfraksie (LVEF) van Page 18 of 27

19 < 50 % of hartversaking, NYHA klasse III of IV, is nie vasgestel nie. Vóór die behandeling met ZYTIGA moet hipertensie onder beheer wees en hipokalemie gekorrigeer word. ZYTIGA kan hipertensie, hipokalemie en vogretensie veroorsaak (kyk Newe-effekte) as gevolg van verhoogde konsentrasies mineralokortikoïede deur die remming van CYP17 (kyk Farmakodinamiese eienskappe). Gelyktydige toediening van 'n kortikosteroïed onderdruk die stimulasie deur adrenokortikotrofiese hormoon (AKTH), met gevolglike laer insidensie en erns van hierdie neweeffekte. Versigtigheid word aangeraai by die behandeling van pasiënte by wie onderliggende mediese toestande moontlik kan vererger deur verhoging van die bloeddruk, by hipokalemie (byvoorbeeld pasiënte wat hartglikosiede gebruik) of vogretensie, byvoorbeeld diegene met hartversaking, onlangse miokardinfark of ventrikulêre disritmie. Bloeddruk, serumkalium en vogretensie moet ten minste maandeliks gemoniteer word. Hepatotoksisiteit In beheerde kliniese navorsingstudies het aansienlike verhogings in lewerensieme voorgekom, wat gelei het tot staking van ZYTIGA, of aanpassing van die dosis (kyk Newe-effekte). Die serumtransaminases- en bilirubienkonsentrasies moet voor aanvang van behandeling met ZYTIGA, elke twee weke tydens die eerste drie maande van die behandeling en daarna maandeliks, bepaal word. Indien kliniese simptome of tekens ontwikkel wat dui op lewertoksisiteit, moet serumtransaminases, veral ALT, onmiddellik bepaal word. Indien ALT op enige tydstip meer as 5 keer en bilirubien meer as 3 keer die boonste grens van die normaalwaarde bereik, moet die behandeling met ZYTIGA onmiddellik onderbreek word en die lewerfunksie noukeurig gekontroleer word. Die behandeling met ZYTIGA kan slegs hervat word nadat die lewerfunksiewaardes weer tot by die pasiënt se basislynwaardes gedaal het en slegs by 'n laer dosis (kyk Dosis en gebruiksaanwysings). Indien pasiënte op enige tydstip ernstige lewertoksisiteit ontwikkel (ALT 20 keer die bogrens van die normaalwaarde), moet ZYTIGA gestaak word en pasiënte moet nie weer met ZYTIGA behandel word nie. Page 19 of 27

20 Onttrekking van kortikosteroïede en hantering van strestoestande As die behandeling met prednisoon of prednisoloon by pasiënte onttrek word, word versigtigheid aangeraai en moet bynierinkorting gekontroleer word. Indien ZYTIGA voortgesit word nadat die behandeling met kortikosteroïede gestaak is, moet pasiënte gekontroleer word vir simptome van oormaat aan mineralokortikoïede (kyk bostaande inligting). By pasiënte op prednisoon of prednisoloon wat ongewone stres ondervind, kan 'n verhoogde dosis van kortikosteroïede vóór, tydens en na die stresvolle situasie aangewese wees. Galaktose intoleransie ZYTIGA bevat laktose. Pasiënte met seldsame oorerflike probleme, soos galaktose intoleransie, die Lapp-laktase tekort of glukose-galaktose wanabsorpsie, moet nie ZYTIGA neem nie. Effek op die vermoë om te bestuur en masjinerie te gebruik ZYTIGA het geen invloed op die vermoë om te bestuur of masjinerie te gebruik nie, of die invloed is negeerbaar. INTERAKSIES Toediening van ZYTIGA met voedsel verhoog die absorpsie van abirateroonasetaat beduidend. Die doeltreffendheid en veiligheid van ZYTIGA, indien saam met voedsel gegee, is nie vasgestel nie. ZYTIGA moet nie saam met voedsel geneem word nie (kyk Dosis en gebruiksaanwysings en Farmakokinetiese eienskappe). In 'n navorsingstudie vir die bepaling van die effekte van abirateroonasetaat (plus prednisoon) op 'n enkele dosis dekstrometorfaan, substraat vir CYP2D6, was die sistemiese blootstelling (AOK) aan dekstrometorfaan met ongeveer 200 % verhoog. Die AOK 24 van dekstrorfaan, die aktiewe metaboliet van dekstrometorfaan, het met ongeveer 33 % gestyg. Versigtigheid word aangeraai as ZYTIGA gelyktydig met geneesmiddels wat geaktiveer of gemetaboliseer word deur CYP2D6, veral geneesmiddels met 'n nou terapeutiese indeks, toegedien Page 20 of 27

21 word. By geneesmiddels met 'n nou terapeutiese indeks, wat deur CYP2D6 gemetaboliseer word (bv. propafenoon, flekaïnied en haloperidol), moet 'n dosisverlaging oorweeg word. SWANGERSKAP EN LAKTASIE Swangerskap: ZYTIGA word teenaangedui by vroue wat swanger is, of moontlik swanger kan wees (kyk Kontraïndikasies). Vroue wat swanger kan raak Daar is geen inligting oor die gebruik van ZYTIGA tydens die swangerskap by die mens nie en ZYTIGA is nie bedoel vir gebruik by vroue wat swanger kan raak nie. Daar kan verwag word dat maternale gebruik van 'n CYP17-remmer veranderinge in hormoonvlakke teweeg sal bring, wat die ontwikkeling van die fetus kan aantas. Voorbehoeding by mans en vrouens Dit is nie bekend of abirateroon of die metaboliete daarvan in die semen teenwoordig is nie. 'n Kondoom word benodig indien die pasiënt seksueel verkeer met 'n swanger vrou. Indien die pasiënt seksueel verkeer met 'n vrou wat kan swanger raak, word 'n kondoom benodig tesame met 'n ander doeltreffende voorbehoedmiddel. Vrugbaarheid Reproduktiewe toksikologiese navorsingstudies is nie met abirateroonasetaat uitgevoer nie. Daar is geen inligting oor vrugbaarheid beskikbaar nie. Laktasie ZYTIGA is nie bedoel vir gebruik by vroue nie. Dit is nie bekend of abirateroonasetaat of die metaboliete daarvan in mens borsmelk uitgeskei word nie. DOSIS EN GEBRUIKSAANWYSINGS Die aanbevole dosis ZYTIGA is 1 g (vier 250 mg tablette) as 'n enkele daaglikse dosis wat nie met voedsel geneem moet word nie. ZYTIGA moet ten minste twee uur na maaltye geneem word en geen kos moet vir ten minste een uur nadat ZYTIGA geneem is, geëet word nie. Die tablette moet Page 21 of 27

22 heel, met water ingesluk word. Indien ZYTIGA met kos ingeneem word, verhoog dit die sistemiese blootstelling aan abirateroon (kyk Interaksies en Farmakokinetika). Pasiënte moet op ZYTIGA onderhou word tot radiografiese vordering en simptomatiese/kliniese vooruitgang en tot PSA vooruitgang ( n bevestigde 25 % toename ten opsigte van die pasiënt se basislynwaarde /laagtepunt). ZYTIGA word gebruik tesame met 'n lae dosis prednisoon of prednisoloon. Die aanbevole dosis van prednisoon of prednisoloon is 10 mg per dag. Die serumtransaminase- en bilirubienkonsentrasies moet voor aanvang van behandeling met ZYTIGA, elke twee weke tydens die eerste drie maande van die behandeling en daarna maandeliks, bepaal word. Bloeddruk, serumkalium en vogretensie moet ten minste maandeliks gemoniteer word (kyk Waarskuwings en spesiale voorsorgmaatreëls). In geval van 'n oorgeslaande daaglikse dosis van ZYTIGA, prednisoon of prednisoloon, moet die behandeling die volgende dag met die gewone daaglikse dosis voortgesit word. Lewerinkorting Geen aanpassing in dosis is nodig vir pasiënte met bestaande ligte lewerinkorting, Child-Pugh-klas A, nie. ZYTIGA moet nie gebruik word by pasiënte met reeds bestaande ernstige lewerinkorting, Child- Pugh-klasse B of C nie (kyk Kontraïndikasies en Farmakokinetika). Vir pasiënte wat lewertoksisiteit tydens behandeling met ZYTIGA ontwikkel (waar alanienaminotransferase (ALT) tot 5 keer bo die boonste normale grens styg, of bilirubien tot meer as 3 keer die boonste normale grens), moet behandeling onmiddellik weerhou word totdat lewerfunksietoetse genormaliseer het (kyk Waarskuwings en spesiale voorsorgmaatreëls). Nadat die lewerfunksietoetswaardes teruggekeer het tot die basislynwaardes van die pasiënt, kan die behandeling hervat word by 'n verlaagde dosis van 500 mg (twee tablette) een keer per dag. By pasiënte by wie die behandeling hervat word, moet serumtransaminases ten minste elke twee weke vir drie maande gekontroleer word en daarna maandeliks. Indien die lewertoksisiteit by die verlaagde Page 22 of 27

23 dosis van 500 mg per dag terugkeer, moet die behandeling beëindig word. Verlaagde dosisse moet nie met kos geneem word nie (kyk bostaande inligting). Indien pasiënte op enige tydstip ernstige lewertoksisiteit ontwikkel (ALT 20 keer die bogrens van die normaalwaarde), moet ZYTIGA gestaak word en pasiënte moet nie weer met ZYTIGA behandel word nie. Renale inkorting: Geen aanpassing in die dosis word benodig by pasiënte met renale inkorting nie (kyk Farmakokinetiese eienskappe). Pediatriese bevolking: Daar is geen relevante gebruik van ZYTIGA by pediatriese pasiënte nie, aangesien prostaatkanker nie by die pediatriese bevolking aanwesig is nie. Metode van toediening Voorsorgmaatreëls om te neem voordat ZYTIGA toegedien word. As gevolg van die werkingsmeganisme van ZYTIGA kan dit 'n ontwikkelende fetus beskadig; gevolglik moet vroue (ook professionele gesondheidsorgkundiges) wat swanger is, of vroue wat dalk swanger is, nie ZYTIGA sonder beskerming, bv. handskoene, hanteer nie (kyk Swangerskap en laktasie). NEWE-EFFEKTE Opsomming van die veiligheidsprofiel Die mees algemene newe-effekte wat met ZYTIGA waargeneem is, is perifere edeem, hipokalemie, hipertensie en urienweginfeksie. ZYTIGA kan hipertensie, hipokalemie en vloeistofretensie veroorsaak, as 'n farmakodinamiese gevolg van die werkingsmeganisme. In 'n fase-3 navorsingstudie is verwagte mineralokortikoïed neweeffekte meer dikwels waargeneem by pasiënte wat behandel is met ZYTIGA as by pasiënte wat met plasebo behandel is: hipokalemie by 17 % teenoor 8 %, hipertensie by 9 % teenoor 7 % en vogretensie (perifere edeem) by 25 % teenoor 17 %. By pasiënte wat met ZYTIGA behandel is, is graad 3 en 4 hipokalemie en graad 3 en 4 hipertensie by onderskeidelik 4 % en 1 % van die pasiënte Page 23 of 27

24 waargeneem. Gelyktydige gebruik van 'n kortikosteroïed verlaag die insidensie en die erns van hierdie newe-effekte (kyk Waarskuwings en spesiale voorsorgmaatreëls). Samevatting van kliniese newe-effekte in tabelvorm In navorsingstudies by pasiënte met gemetastaseerde gevorderde prostaatkanker, wat 'n luteïniseringshormoon-vrystellingshormoon-analoog (LHRH-A ) gebruik, of voorheen 'n orgidektomie ondergaan het, is ZYTIGA toegedien by 'n dosis van 1 g per dag in kombinasie met 'n lae dosis prednisoon of prednisoloon (10 mg per dag). Die pasiënte kon tot twee vorige chemoterapeutiese behandelingsplanne waarvan een 'n taksaan bevat het, nie verduur nie, of het nie daarop reageer het nie. Ongunstige geneesmiddelreaksies wat tydens kliniese navorsingstudies met ZYTIGA waargeneem is, word hieronder volgens frekwensiekategorie vermeld. Frekwensiekategorieë word soos volg gedefinieer: baie algemeen ( 1/10), algemeen ( 1/100 tot <1/10); ongewoon ( 1/1 000 tot <1/100). Binne elke frekwensiekategorie word die newe-effekte weergegee in afnemende mate van erns. Tabel 2: Newe-effekte waargeneem met kliniese navorsingstudies met ZYTIGA Infeksies en infestasies baie algemeen: urienweginfeksies Endokriene siektes Metabolisme en voeding siektes ongewoon: bynierontoereikendheid baie algemeen: hipokalemie algemeen: hipertrigliseridemie Hartsiektes algemeen: hartversaking*, angina pektoris, disritmie, atriale fibrillasie, tagikardie Bloedvatsiektes Hepatobiliêre siektes Algemene siektes en toestande by die baie algemeen: hipertensie algemeen: verhoogde alanienaminotransferase baie algemeen: perifere edeem plek van toediening Page 24 of 27

25 * Hartversaking sluit ook in kongestiewe hartversaking, linkerventrikeldisfunksie en verlaagde uitwerpingsfraksie Die volgende graad 3 ongunstige geneesmiddelreaksies het voorgekom by pasiënte wat met ZYTIGA behandel is: hipokalemie by 3 %; urienweginfeksie by 2 %; perifere edeem, verhoogde alanienaminotransferase, hipertensie, hartversaking en atriale fibrillasie elk by 1 %. Graad 3 hipertrigliseridemie en angina pektoris het by < 1 % van die pasiënte voorgekom. Graad 4 perifere edeem, hipokalemie, urienweginfeksie en hartversaking het by < 1 % van die pasiënte voorgekom. Beskrywing van bepaalde newe-effekte Kardiovaskulêre reaksies Die fase 3-navorsingstudie met ZYTIGA het pasiënte uitgesluit met onbeheerde hipertensie, kliniesbeduidende hartsiekte wat na vore getree het as 'n miokardinfark of arteriële trombose in die afgelope 6 maande, ernstige of onstabiele angina, New York Heart Association klasse III of IV hartsiekte of met 'n kardiale uitwerpfraksie bepaling < 50 %. Alle ingeskrewe pasiënte (wat met medisyne of met plasebo behandel is), is gelyktydig behandel deur androgeen te ontneem, veral deur die gebruik van LHRH-agoniste, wat geassosieer word met diabetes, miokardinfark, n serebrovaskulêre voorval en skielike hartsterfte. Die insidensie van kardiovaskulêre newe-effekte in die fase 3-studie was laag by pasiënte wat ZYTIGA ontvang het en was soortgelyk aan die insidensie by pasiënte wat plasebo gekry het. Hepatotoksisiteit Medisyneverwante lewertoksisiteit met verhoogde ALT, aspartaattransaminase (AST) en totale bilirubien het algemeen voorgekom by pasiënte wat met ZYTIGA behandel is. In alle kliniese studies is verhoogde lewerfunksietoetsresultate (ALT- of AST-verhoging > 5 x BLN (boonste limiet van normaal) of bilirubienverhoging > 1,5 x BLN) aangemeld by ongeveer 2 % van die pasiënte wat ZYTIGA ontvang het, kenmerkend tydens die eerste 3 maande na aanvang van die behandeling. Pasiënte by wie ALT- of AST- basislynwaardes reeds verhoog was, was in die fase 3- kliniese navorsingstudie meer geneig om verhoogde lewerfunksietoetswaardes te ervaar as diegene wat met normale basislynwaardes begin het. Toename in ALT en toename in AST is onderskeidelik by 3,9 % en 2,7 % in die ZYTIGA-groep en by 3,8 % en 1,3 % in die plasebo-groep aangemeld. Page 25 of 27

26 Hiperbilirubinemie is by 1,3 % in die ZYTIGA-groep teenoor 1,8 % in die plasebo-groep aangemeld. Wanneer verhogings van ALT of AST > 5 x BLN of verhogings van bilirubien > 3 x BLN waargeneem is, is ZYTIGA weerhou of gestaak. Behandeling is weerhou of gestaak by 0,8 % van die persone in die ZYTIGA- sowel as die plasebo-groep. In twee gevalle het daar aansienlike verhogings van die lewerfunksietoetsresultate voorgekom (kyk Waarskuwings en spesiale voorsorgmaatreëls). Hierdie twee pasiënte, met normale lewerfunksie by basislyn, het ALT- of AST-verhogings van 15 tot 40 x BLN en bilirubienverhogings van 2 tot 6 x BLN ervaar. Na beëindiging van ZYTIGA het albei pasiënte se lewerfunksietoetsresultate genormaliseer en een pasiënt is weer behandel sonder dat die verhoogde waardes teruggekeer het. In kliniese navorsingstudies was die risiko vir hepatotoksisiteit getemper deur die uitsluiting van pasiënte met aktiewe hepatitis of ALT en AST basislynwaardes 2,5 x BLN sonder lewermetastases en > 5 x BLN waar lewermetastases aanwesig was. As daar by pasiënte wat aan die kliniese navorsingstudies deelgeneem het abnormale lewerfunksietoetsresultate ontwikkel het, is daar ingrypend opgetree deur behandeling te onderbreek en dit slegs weer te hervat nadat die lewerfunksietoetswaardes teruggekeer het tot die pasiënt se basislynwaardes (kyk Dosis en gebruiksaanwysings). Pasiënte met verhogings in ALT of AST > 20 x BLN is nie weer behandel nie. Die veiligheid van hervatting van behandeling by sulke pasiënte is onbekend. Die meganisme wat tot lewertoksisiteit lei is nie duidelik nie. BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN Daar is geen spesifieke teenmiddel nie. In geval van 'n oordosis moet toediening van ZYTIGA gestaak word en moet algemene ondersteunende maatreëls geneem word, waaronder monitering vir disritmie. Die lewerfunksie moet ook bepaal word. IDENTIFIKASIE Wit tot naaswit, ovaalvormige tablette, 16 mm lank, bedruk met AA250 aan die een kant. Page 26 of 27

27 AANBIEDING ZYTIGA is beskikbaar as hoëdigtheid- poliëtileen ronde wit bottels met 'n passende polipropileen deksel en verpak in n karton. Die verpakkingsgrootte is 120 tablette. BERGINGSINSTRUKSIES Bewaar benede 30 C Spesiale voorsorgmaatreëls vir wegdoening en ander hantering Vroue wat swanger is, of vroue wat dalk swanger is, moet nie ZYTIGA sonder beskerming, bv. handskoene, hanteer nie (kyk Swangerskap en laktasie). REGISTRAKYKOMMER 46/21.12/0379 NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIESERTIFIKAAT JANSSEN PHARMACEUTICA (Pty.) Ltd. (Reg No.: 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET 31 Julie 2014 Page 27 of 27