ERLEADA 240mg tablets medication leaflet

Erleada 240 mg film-coated tablets

Each film-coated tablet contains 240 mg of apalutamide.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Bluish grey to grey, oval-shaped, film-coated tablets (21 mm long x 10 mm wide), debossed with“E240” on one side.

Erleada is indicated:

- in adult men for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC)who are at high risk of developing metastatic disease (see section 5.1).

- in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) incombination with androgen deprivation therapy (ADT) (see section 5.1).

Treatment with apalutamide should be initiated and supervised by specialist physicians experienced inthe medical treatment of prostate cancer.

The recommended dose is 240 mg (one 240 mg tablet) as an oral single daily dose.

Medical castration with gonadotropin releasing hormone analogue (GnRHa) should be continuedduring treatment in patients not surgically castrated.

If a dose is missed, it should be taken as soon as possible on the same day with a return to the normalschedule the following day. Extra tablets should not be taken to make up the missed dose.

If a ≥ Grade 3 toxicity or an intolerable adverse reaction is experienced by the patient, dosing shouldbe held rather than permanently discontinuing treatment until symptoms improve to ≤ Grade 1 ororiginal grade, then should be resumed at the same dose or a reduced dose (180 mg or 120 mg), ifwarranted. For the most common adverse reactions, (see section 4.8).

No dose adjustment is necessary for elderly patients (see sections 5.1 and 5.2).

No dose adjustment is necessary for patients with mild to moderate renal impairment.

Caution is required in patients with severe renal impairment as apalutamide has not been studied inthis patient population (see section 5.2). If treatment is started, patients should be monitored for theadverse reactions listed in section 4.8 and dose reduce as per section 4.2 Posology and method ofadministration.

No dose adjustment is necessary for patients with baseline mild or moderate hepatic impairment(Child-Pugh Class A and B, respectively).

Erleada is not recommended in patients with severe hepatic impairment as there are no data in thispatient population and apalutamide is primarily hepatically eliminated (see section 5.2).

There is no relevant use of apalutamide in the paediatric population.

Oral use.

The tablet should be swallowed whole to ensure that the full intended dose is taken. The tablet shouldnot be crushed or split. The tablet can be taken with or without food.

Taking Erleada with non-fizzy beverage or soft food

For patients who cannot swallow the tablet whole, Erleada can be dispersed in non-fizzy water andthen mixed with one of the following non-fizzy beverages or soft foods; orange juice, green tea,applesauce, drinkable yogurt, or additional water as follows:1. Place the whole Erleada 240 mg tablet in a cup. Do not crush or split the tablet.2. Add about 10 mL (2 teaspoons) of non-fizzy water to make sure that the tablet is completely inwater.3. Wait 2 minutes until the tablet is broken up and spread out, then stir the mixture.4. Add in 30 mL (6 teaspoons or 2 tablespoons) of one of the following non-fizzy beverages or softfoods; orange juice, green tea, applesauce, drinkable yogurt, or additional water and stir themixture.

5. Swallow the mixture immediately.6. Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately.7. Do not save the medicinal product/food mixture for later use.

Administration by nasogastric feeding tube

Erleada 240 mg tablet can also be administered through a nasogastric feeding tube (NG tube) 8 Frenchor greater as follows:1. Place the whole Erleada 240 mg tablet in the barrel of a syringe (use at least a 20 mL syringe)and draw up 10 mL of non-fizzy water into the syringe.2. Wait 10 minutes and then shake vigorously to disperse the contents completely.3. Administer immediately through the NG feeding tube.4. Refill the syringe with non-fizzy water and administer. Repeat until no tablet residue is left inthe syringe or feeding tube.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Women who are or may become pregnant (see section 4.6).

Erleada is not recommended in patients with a history of seizures or other predisposing factorsincluding, but not limited to, underlying brain injury, recent stroke (within one year), primary braintumours or brain metastases. If a seizure develops during treatment with Erleada, treatment should bediscontinued permanently. The risk of seizure may be increased in patients receiving concomitantmedicinal products that lower the seizure threshold.

In two randomised studies (SPARTAN and TITAN), seizure occurred in 0.6% of patients receivingapalutamide and in 0.2% of patients treated with placebo. These studies excluded patients with ahistory of seizure or predisposing factors for seizure.

There is no clinical experience in re-administering Erleada to patients who experienced a seizure.

Falls and fractures

Falls and fractures occurred in patients receiving apalutamide (see section 4.8). Patients should beevaluated for fracture and fall risk before starting Erleada and should continue to be monitored andmanaged according to established treatment guidelines and use of bone-targeted agents should beconsidered.

Ischaemic heart disease and ischaemic cerebrovascular disorders

Ischaemic heart disease and ischaemic cerebrovascular disorders, including events leading to death,occurred in patients treated with apalutamide (see section 4.8). The majority of patients hadcardiac/cerebrovascular ischaemic disease risk factors. Patients should be monitored for signs andsymptoms of ischaemic heart disease and ischaemic cerebrovascular disorders. Management of riskfactors, such as hypertension, diabetes, or dyslipidaemia should be optimised as per standard of care.

Apalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly usedmedicinal products (see section 4.5). A review of concomitant medicinal products should therefore beconducted when apalutamide treatment is initiated. Concomitant use of apalutamide with medicinalproducts that are sensitive substrates of many metabolising enzymes or transporters (see section 4.5)should generally be avoided if their therapeutic effect is of large importance to the patient, and if doseadjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations.

Co-administration of apalutamide with warfarin and coumarin-like anticoagulants should be avoided.

If Erleada is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin oracenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted(see section 4.5).

Patients with clinically significant cardiovascular disease in the past 6 months includingsevere/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venousthromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transientischaemic attacks), or clinically significant ventricular arrhythmias were excluded from the clinicalstudies. Therefore, the safety of apalutamide in these patients has not been established. If Erleada isprescribed, patients with clinically significant cardiovascular disease should be monitored for riskfactors such as hypercholesterolaemia, hypertriglyceridaemia, or other cardio-metabolic disorders (seesection 4.8). Patients should be treated, if appropriate, after initiating Erleada for these conditionsaccording to established treatment guidelines.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitantmedicinal products that might prolong the QT interval (see section 4.5), physicians should assess thebenefit-risk ratio including the potential for Torsade de pointes prior to initiating Erleada.

Severe Cutaneous Adverse Reactions (SCARs)

Postmarketing reports of SCARs including drug reaction with eosinophilia and systemic symptoms(DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), which can belife-threatening or fatal, have been observed in association with Erleada treatment (see section 4.8).

Patients should be advised of signs and symptoms suggestive of DRESS or SJS/TEN. If thesesymptoms are observed, Erleada should be withdrawn immediately and patients should seekimmediate medical consultation.

Erleada must not be restarted in patients who have experienced DRESS or SJS/TEN while taking

Erleada at any time and an alternative treatment should be considered.

Interstitial Lung Disease (ILD)

Cases of ILD have been observed in patients treated with apalutamide, including fatal cases. In case ofacute onset and/or unexplained worsening of pulmonary symptoms, treatment with apalutamide shouldbe interrupted pending further investigation of these symptoms. If ILD is diagnosed, apalutamideshould be discontinued and appropriate treatment initiated as necessary (see section 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per 240 mg dose (1 tablet), that isto say essentially ‘sodium-free’.

The elimination of apalutamide and formation of its active metabolite, N-desmethyl apalutamide, ismediated by both CYP2C8 and CYP3A4 to a similar extent at steady-state. No clinically meaningfulchanges in their overall exposure is expected as a result of drug interaction with inhibitors or inducersof CYP2C8 or CYP3A4. Apalutamide is an inducer of enzymes and transporters and may lead to anincrease in elimination of many commonly used medicinal products.

Potential for other medicinal products to affect apalutamide exposures

Medicinal products that inhibit CYP2C8

CYP2C8 plays a role in the elimination of apalutamide and in the formation of its active metabolite. Ina drug-drug interaction study, the Cmax of apalutamide decreased by 21% while AUC increased by68% following co-administration of apalutamide 240 mg single dose with gemfibrozil (strong

CYP2C8 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted activemetabolite), Cmax decreased by 21% while AUC increased by 45%. No initial dose adjustment isnecessary when Erleada is co-administered with a strong inhibitor of CYP2C8 (e.g., gemfibrozil,clopidogrel) however, a reduction of the Erleada dose based on tolerability should be considered (seesection 4.2). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure ofapalutamide.

CYP3A4 plays a role in the elimination of apalutamide and in the formation of its active metabolite. Ina drug-drug interaction study, the Cmax of apalutamide decreased by 22% while AUC was similarfollowing co-administration of Erleada as a 240 mg single dose with itraconazole (strong CYP3A4inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite),

Cmax decreased by 22% while AUC was again similar. No initial dose adjustment is necessary when

Erleada is co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole, ritonavir,clarithromycin) however, a reduction of the Erleada dose based on tolerability should be considered(see section 4.2). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure ofapalutamide.

Medicinal products that induce CYP3A4 or CYP2C8

The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not beenevaluated in vivo. Based on the drug-drug interaction study results with strong CYP3A4 inhibitor orstrong CYP2C8 inhibitor, CYP3A4 or CYP2C8 inducers are not expected to have clinically relevanteffects on the pharmacokinetics of apalutamide and the active moieties therefore no dose adjustment isnecessary when Erleada is co-administered with inducers of CYP3A4 or CYP2C8.

Potential for apalutamide to affect exposures to other medicinal products

Apalutamide is a potent enzyme inducer and increases the synthesis of many enzymes andtransporters; therefore, interaction with many common medicinal products that are substrates ofenzymes or transporters is expected. The reduction in plasma concentrations can be substantial, andlead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites.

Drug metabolising enzymes

In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong

CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weakinhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do notaffect CYP1A2 and CYP2D6 at therapeutically relevant concentrations. The effect of apalutamide on

CYP2B6 substrates has not been evaluated in vivo and the net effect is presently unknown. Whensubstrates of CYP2B6 (e.g., efavirenz) are administered with Erleada, monitoring for an adversereaction and evaluation for loss of efficacy of the substrate should be performed and dose adjustmentof the substrate may be required to maintain optimal plasma concentrations.

In humans, apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of

CYP2C9. In a drug-drug interaction study using a cocktail approach, co-administration of apalutamidewith single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC ofmidazolam (CYP3A4 substrate), 85% decrease in the AUC of omeprazole (CYP2C19 substrate), and46% decrease in the AUC of S-warfarin (CYP2C9 substrate). Apalutamide did not cause clinicallymeaningful changes in exposure to the CYP2C8 substrate. Concomitant use of Erleada with medicinalproducts that are primarily metabolised by CYP3A4 (e.g., darunavir, felodipine, midazolam,simvastatin), CYP2C19 (e.g., diazepam, omeprazole), or CYP2C9 (e.g., warfarin, phenytoin) canresult in lower exposure to these medicinal products. Substitution for these medicinal products isrecommended when possible or evaluation for loss of efficacy should be performed if the medicinalproduct is continued. If given with warfarin, INR should be monitored during Erleada treatment.

Induction of CYP3A4 by apalutamide suggests that UDP-glucuronosyl transferase (UGT) may also beinduced via activation of the nuclear pregnane X receptor (PXR). Concomitant administration of

Erleada with medicinal products that are substrates of UGT (e.g., levothyroxine, valproic acid) canresult in lower exposure to these medicinal products. When substrates of UGT are co-administeredwith Erleada, evaluation for loss of efficacy of the substrate should be performed and dose adjustmentof the substrate may be required to maintain optimal plasma concentrations.

Drug transporters

Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistanceprotein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. A drug-druginteraction study using a cocktail approach showed that co-administration of apalutamide with singleoral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine(P-gp substrate) and 41% decrease in the AUC of rosuvastatin (BCRP/OATP1B1 substrate) but had noimpact on Cmax. Concomitant use of Erleada with medicinal products that are substrates of P-gp (e.g.,colchicine, dabigatran etexilate, digoxin), BCRP or OATP1B1 (e.g., lapatinib, methotrexate,rosuvastatin, repaglinide) can result in lower exposure of these medicinal products. When substrates of

P-gp, BCRP or OATP1B1 are co-administered with Erleada, evaluation for loss of efficacy of thesubstrate should be performed and dose adjustment of the substrate may be required to maintainoptimal plasma concentrations.

Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3(OAT3) and multidrug and toxin extrusions (MATEs) by apalutamide and its N-desmethyl metabolitecannot be excluded. No in vitro inhibition of organic anion transporter 1 (OAT1) was observed.

GnRH Analog

In mHSPC subjects receiving leuprolide acetate (a GnRH analog), co-administration with apalutamidehad no apparent effect on the steady-state exposure of leuprolide.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Erleadawith medicinal products known to prolong the QT interval or medicinal products able to induce

Torsade 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 (e.g. haloperidol), etc. should be carefully evaluated (see section 4.4).

Interaction studies have only been performed in adults.

It is not known whether apalutamide or its metabolites are present in semen. Erleada may be harmfulto a developing foetus. For patients having sex with female partners of reproductive potential, acondom should be used along with another highly effective contraceptive method during treatment andfor 3 months after the last dose of Erleada.

Erleada is contraindicated in women who are or may become pregnant (see section 4.3). Based on ananimal reproductive study and its mechanism of action, Erleada may cause foetal harm and loss ofpregnancy when administered to a pregnant woman. There are no data available from the use of

Erleada in pregnant women.

It is unknown whether apalutamide/metabolites are excreted in human milk. A risk to the sucklingchild cannot be excluded. Erleada should not be used during breast-feeding.

Based on animal studies, Erleada may decrease fertility in males of reproductive potential (seesection 5.3).

Erleada has no or negligible influence on the ability to drive and use machines. However, seizureshave been reported in patients taking Erleada. Patients should be advised of this risk in regards todriving or operating machines.

The most common adverse reactions are fatigue (26%), skin rash (26% of any grade and 6% Grade 3or 4), hypertension (22%), hot flush (18%), arthralgia (17%), diarrhoea (16%), fall (13%), and weightdecreased (13%). Other important adverse reactions include fractures (11%), decreased appetite (11%)and hypothyroidism (8%).

Adverse reactions observed during clinical studies and/or in post-marketing experience are listedbelow 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); veryrare (< 1/10 000) and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions

System Organ Class Adverse reaction and frequency

Endocrine disorders common: hypothyroidisma

Metabolism and nutrition disorders very common: decreased appetitecommon: hypercholesterolaemia,hypertriglyceridaemia

Nervous system disorders common: dysgeusia, ischaemic cerebrovasculardisordersbuncommon: seizurec (see section 4.4), restlesslegs syndrome

Cardiac disorders common: ischaemic heart diseasednot known: QT prolongation (see sections 4.4 and4.5)

Vascular disorders very common: hot flush, hypertension

Respiratory, thoracic and mediastinal not known: interstitial lung diseaseedisorders

Gastrointestinal disorders very common: diarrhoea

Skin and subcutaneous tissue disorders very common: skin rashfcommon: pruritus, alopecianot known: drug reaction with eosinophilia andsystemic symptoms (DRESS)e, Stevens-Johnsonsyndrome/toxic epidermal necrolysis (SJS/TEN)e,lichenoid eruption

Musculoskeletal and connective tissue very common: fractureg, arthralgiadisorders common: muscle spasm

General disorders and administration site very common: fatigueconditions

Investigations very common: weight decreased

Injury, poisoning and procedural very common: fallcomplicationsa Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroxine decreased, autoimmune thyroiditis,thyroxine free decreased, tri-iodothyronine decreasedb Includes transient ischaemic attack, cerebrovascular accident, cerebrovascular disorder, ischaemic stroke, carotidarteriosclerosis, carotid artery stenosis, hemiparesis, lacunar infarction, lacunar stroke, thrombotic cerebral infarction,vascular encephalopathy, cerebellar infarction, cerebral infarction, and cerebral ischaemiac Includes tongue bitingd Includes angina pectoris, angina unstable, myocardial infarction, acute myocardial infarction, coronary arteryocclusion, coronary artery stenosis, acute coronary syndrome, arteriosclerosis coronary artery, cardiac stress testabnormal, troponin increased, myocardial ischaemiae See section 4.4f See “Skin rash” under “Description of selected adverse reactions”g Includes rib fracture, lumbar vertebral fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture,humerus fracture, thoracic vertebral fracture, upper limb fracture, fractured sacrum, hand fracture, pubis fracture,acetabulum fracture, ankle fracture, compression fracture, costal cartilage fracture, facial bones fracture, lower limbfracture, osteoporotic fracture, wrist fracture, avulsion fracture, fibula fracture, fractured coccyx, pelvic fracture,radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebral fracture, femoral neck fracture,tibia fracture. See below.

Skin rash

Skin rash associated with apalutamide was most commonly described as macular or maculo-papular.

Skin rash included rash, rash maculo-papular, rash generalised, urticaria, rash pruritic, rash macular,conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous,stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion,dermatitis, and rash vesicular. Adverse reactions of skin rash were reported for 26% of patients treatedwith apalutamide. Grade 3 skin rashes (defined as covering > 30% body surface area [BSA]) werereported with apalutamide treatment in 6% of patients.

The median days to onset of skin rash was 83 days. Seventy-eight percent of patients had resolution ofrash with a median of 78 days to resolution. Medicinal products utilised included topicalcorticosteroids, oral anti-histamines, and 19% of patients received systemic corticosteroids. Amongpatients with skin rash, dose interruption occurred in 28% and dose reduction occurred in 14% (seesection 4.2). Skin rash recurred in 59% of patients who had dose interruption. Skin rash led toapalutamide treatment discontinuation in 7% of patients who experienced skin rash.

Falls and fractures

In Study ARN-509-003, fracture was reported for 11.7% of patients treated with apalutamide and6.5% of patients treated with placebo. Half of the patients experienced a fall within 7 days before thefracture event in both treatment groups. Falls were reported for 15.6% of patients treated withapalutamide versus 9.0% of patients treated with placebo (see section 4.4).

Ischaemic heart disease and ischaemic cerebrovascular disorders

In a randomised study (SPARTAN) of patients with nmCRPC, ischaemic heart disease occurred in 4%of patients treated with apalutamide and 3% of patients treated with placebo. In a randomised study(TITAN) in patients with mHSPC, ischaemic heart disease occurred in 4% of patients treated withapalutamide and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies,6 patients (0.5%) treated with apalutamide and 2 patients (0.2%) treated with placebo died fromischaemic heart disease (see section 4.4).

In the SPARTAN study, with a median exposure of 32.9 months for apalutamide and 11.5 months forplacebo, ischaemic cerebrovascular disorders occurred in 4% of patients treated with apalutamide and1% of patients treated with placebo (see above). In the TITAN study, ischaemic cerebrovasculardisorders occurred in a similar proportion of patients in the apalutamide (1.5%) and placebo (1.5%)groups. Across the SPARTAN and TITAN studies, 2 patients (0.2%) treated with apalutamide and nopatients treated with placebo died from an ischaemic cerebrovascular disorder (see section 4.4).

Hypothyroidism was reported for 8% of patients treated with apalutamide and 2% of patients treatedwith placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. There wereno grade 3 or 4 adverse events. Hypothyroidism occurred in 30% of patients already receiving thyroidreplacement therapy in the apalutamide arm and in 3% of patients in the placebo arm. In patients notreceiving thyroid replacement therapy, hypothyroidism occurred in 7% of patients treated withapalutamide and in 2% of patients treated with placebo. Thyroid replacement therapy, when clinicallyindicated, should be initiated or dose-adjusted (see section 4.5).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known specific antidote for apalutamide overdose. In the event of an overdose, Erleadashould be stopped and general supportive measures should be undertaken until clinical toxicity hasbeen diminished or resolved. Adverse reactions in the event of an overdose has not yet been observed,it is expected that such reactions would resemble the adverse reactions listed in section 4.8.

Pharmacotherapeutic group: Endocrine therapy, anti-androgens, ATC code: L02BB05

Apalutamide is an orally administered, selective Androgen Receptor (AR) inhibitor that binds directlyto the ligand-binding domain of the AR. Apalutamide prevents AR nuclear translocation, inhibits

DNA binding, impedes AR-mediated transcription, and lacks androgen receptor agonist activity.

Apalutamide treatment decreases tumour cell proliferation and increases apoptosis leading to potentantitumour activity. A major metabolite, N-desmethyl apalutamide, exhibited one-third the in vitroactivity of apalutamide.

Prostate Specific Antigen (PSA) reduction

Apalutamide 240 mg daily in combination with ADT in patients with mHSPC (in TITAN study)reduced PSA to undetectable levels (<0.2 ng/mL) at any time in 68% of patients compared to 32% ofpatients taking ADT alone. Median time to undetectable PSA for patients receiving apalutamide incombination with ADT was 1.9 months. Apalutamide in combination with ADT led to a ≥ 50% PSAreduction from baseline at any time in 90% of patients compared to 55% of patients taking ADT alone.

Apalutamide 240 mg daily in combination with ADT in patients with nmCRPC (in SPARTAN study)reduced PSA to undetectable levels (<0.2 ng/mL) at any time in 38% of patients compared to nopatients (0%) taking ADT alone. Median time to undetectable PSA for patients receiving apalutamidein combination with ADT was 2.8 months. Apalutamide in combination with ADT led to a ≥ 50%

PSA reduction from baseline at any time in 90% of patients compared to 2.2% of patients taking ADTalone.

The effect of apalutamide 240 mg once daily on the QTc interval was assessed in an open-label,uncontrolled, multi-centre, single-arm dedicated QT study in 45 patients with CRPC. At steady-state,the maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). Anexposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and itsactive metabolite.

The efficacy and safety of apalutamide has been established in two Phase 3 randomised, placebo-controlled studies, Study ARN-509-003 (nmCRPC) and 56021927PCR3002 (mHSPC).

TITAN: Metastatic Hormone-sensitive Prostate Cancer (mHSPC)

TITAN was a randomised, double-blind, placebo-controlled, multinational, multicentre clinical studyin which 1052 patients with mHSPC were randomised (1:1) to receive either apalutamide orally at adose of 240 mg once daily (N = 525) or placebo once daily (N = 527). All patients were required tohave at least one bone metastasis on Technetium 99m bone scan. Patients were excluded if the site ofmetastases was limited to either the lymph nodes or viscera (e.g., liver or lung). All patients in the

TITAN study received concomitant GnRH analog or had prior bilateral orchiectomy. Around 11% ofpatients received prior treatment with docetaxel (maximum of 6 cycles, last dose ≤ 2 months prior torandomisation and maintained response prior to randomisation). The exclusion criteria includedknown brain metastases; prior treatment with other next generation anti-androgens (eg, enzalutamide),

CYP17 inhibitors (eg, abiraterone acetate), immunotherapy (eg, sipuleucel-T), radiopharmaceuticalagents or other treatments for prostate cancer; or history of seizure or condition that may predispose toseizure. Patients were stratified by Gleason score at diagnosis, prior docetaxel use, and region of theworld. Patients with both high- and low-volume mHSPC were eligible for the study. High-volumedisease was defined as either visceral metastases and at least 1 bone lesion or at least 4 bone lesions,with at least 1 bone lesion outside of the vertebral column or pelvis. Low-volume disease was definedas the presence of bone lesion(s) not meeting the definition of high-volume.

The following patient demographics and baseline disease characteristics were balanced between thetreatment arms. The median age was 68 years (range 43-94) and 23% of patients were 75 years of ageor older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three percent(63%) of patients had high-volume disease and 37% had low-volume disease. Sixteen percent (16%)of patients had prior surgery, radiotherapy of the prostate or both. A majority of patients had a Gleasonscore of 7 or higher (92%). Sixty-eight percent (68%) of patients received prior treatment with afirst-generation anti-androgen in the non-metastatic setting. Although criteria for castration resistancewere not determined at baseline, 94% of patients demonstrated a decrease in prostate specific antigen(PSA) from initiation of androgen deprivation therapy (ADT) to first dose of apalutamide or placebo.

All patients except one in the placebo group, had an Eastern Cooperative Oncology Group

Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the patients who discontinuedstudy treatment (N = 271 for placebo and N = 170 for Erleada), the most common reason fordiscontinuation in both arms was disease progression. A greater proportion (73%) of patients treatedwith placebo received subsequent anti-cancer therapy compared to patients treated with Erleada(54%).

The major efficacy outcome measures of the study were overall survival (OS) and radiographicprogression-free survival (rPFS). Efficacy results of TITAN are summarised in Table 2 and Figures 1and 2.

Table 2: Summary of efficacy results - Intent-to-treat mHSPC population (TITAN)

Erleada Placebo

Endpoint

N=525 N=527

Primary overall survivala

Deaths (%) 83 (16%) 117 (22%)

Median, months (95% CI) NE (NE, NE) NE (NE, NE)

Hazard ratio (95% CI)b 0.671 (0.507, 0.890)p-valuec 0.0053

Updated overall survivald

Deaths (%) 170 (32%) 235 (45%)

Median, months (95% CI) NE (NE, NE) 52 (42, NE)

Hazard Ratio (95% CI)b 0.651 (0.534, 0.793)p-valuec,e <0.0001

Radiographic progression-free survival

Disease progression or death (%) 134 (26%) 231 (44%)

Median, months (95% CI) NE (NE, NE) 22.08 (18.46, 32.92)

Hazard ratio (95% CI)b 0.484 (0.391, 0.600)p-valuec <0.0001a This is based on the pre-specified interim analysis with a median follow-up time of 22 months.b Hazard ratio is from stratified proportional hazards model. Hazard ratio < 1 favours active treatment.c p-value is from the log-rank test stratified by Gleason score at diagnosis (≤ 7 vs. > 7), Region (NA/EU vs. Other Countries)and Prior docetaxel use (Yes vs. No).d Median follow-up time of 44 months.e This p-value is nominal instead of being used for formal statistical testing.

NE=Not Estimable

A statistically significant improvement in OS and rPFS was demonstrated in patients randomised toreceive Erleada compared with patients randomised to receive placebo in the primary analysis. Anupdated OS analysis was conducted at the time of final study analysis when 405 deaths were observedwith a median follow-up of 44 months. Results from this updated analysis were consistent with thosefrom the pre-specified interim analysis. The improvement in OS was demonstrated even though 39%of patients in the placebo arm crossed over to receive Erleada, with a median treatment of 15 monthson Erleada crossover.

Consistent improvement in rPFS was observed across patient subgroups including high- or low-volume disease, metastasis stage at diagnosis (M0 or M1), prior docetaxel use (yes or no), age (< 65,≥ 65, or ≥ 75 years old), baseline PSA above median (yes or no), and number of bone lesions (≤ 10 or> 10).

Consistent improvement in OS was observed across patient subgroups including high- or low-volumedisease, metastasis stage at diagnosis (M0 or M1), and Gleason score at diagnosis (≤ 7 vs. > 7).

Figure 1: Kaplan-Meier plot of updated overall survival (OS); Intent-to-treat mHSPCpopulation (TITAN)

Figure 2: Kaplan-Meier plot of radiographic progression-free survival (rPFS); Intent-to-treatmHSPC population (TITAN)

Treatment with Erleada statistically significantly delayed the initiation of cytotoxic chemotherapy(HR = 0.391, CI = 0.274, 0.558; p < 0.0001), resulting in a 61% reduction of risk for subjects in thetreatment arm compared to the placebo arm.

SPARTAN: Non-Metastatic Castration Resistant Prostate Cancer (nmCRPC)

A total of 1207 subjects with NM-CRPC were randomised 2:1 to receive either apalutamide orally at adose of 240 mg once daily in combination with androgen deprivation therapy (ADT) (medicalcastration or prior surgical castration) or placebo with ADT in a multicentre, double-blind, clinicalstudy (Study ARN-509-003). Subjects enrolled had a Prostate Specific Antigen (PSA) Doubling Time(PSADT) ≤ 10 months, considered to be at high risk of imminent metastatic disease and prostatecancer-specific death. All subjects who were not surgically castrated received ADT continuouslythroughout the study. PSA results were blinded and were not used for treatment discontinuation.

Subjects randomised to either arm were to continue treatment until disease progression defined byblinded central imaging review (BICR), initiation of new treatment, unacceptable toxicity orwithdrawal.

The following patient demographics and baseline disease characteristics were balanced between thetreatment arms. The median age was 74 years (range 48-97) and 26% of subjects were 80 years of ageor older. The racial distribution was 66% Caucasian, 5.6% Black, 12% Asian, and 0.2% Other.

Seventy-seven percent (77%) of subjects in both treatment arms had prior surgery or radiotherapy ofthe prostate. A majority of subjects had a Gleason score of 7 or higher (81%). Fifteen percent (15%) ofsubjects had < 2 cm pelvic lymph nodes at study entry. Seventy-three percent (73%) of subjectsreceived prior treatment with a first generation anti-androgen; 69% of subjects received bicalutamideand 10% of subjects received flutamide. All subjects enrolled were confirmed to be non-metastatic byblinded central imaging review and had an Eastern Cooperative Oncology Group Performance Status(ECOG PS) performance status score of 0 or 1 at study entry.

Metastasis-free survival (MFS) was the primary endpoint, defined as the time from randomisation tothe time of first evidence of BICR-confirmed bone or soft tissue distant metastasis or death due to anycause, whichever occurred first. Treatment with Erleada significantly improved MFS. Erleadadecreased the relative risk of distant metastasis or death by 70% compared to placebo (HR = 0.30;95% CI: 0.24, 0.36; p < 0.0001). The median MFS for Erleada was 41 months and was 16 months forplacebo (see Figure 3). Consistent improvement in MFS with Erleada was observed for allpre-specified subgroups, including age, race, region of the world, nodal status, prior number ofhormonal therapies, baseline PSA, PSA doubling time, baseline ECOG status and use of bone-sparingagents.

Figure 3: Kaplan-Meier metastasis-free survival (MFS) curve in Study ARN-509-003

Taking account of all data, subjects treated with Erleada and ADT showed significant improvementover those treated with ADT alone for the following secondary endpoints of time to metastasis(HR = 0.28; 95% CI: 0.23, 0.34; p < 0.0001), progression-free survival (PFS) (HR = 0.30; 95% CI:0.25, 0.36; p < 0.0001); time to symptomatic progression (HR = 0.57; 95% CI: 0.44, 0.73; p < 0.0001);overall survival (OS) (HR = 0.78; 95% CI: 0.64, 0.96; p = 0.0161) and time to initiation of cytotoxicchemotherapy (HR = 0.63; 95% CI: 0.49, 0.81; p = 0.0002).

Time to symptomatic progression was defined as time from randomisation to development of askeletal related event, pain/symptoms requiring initiation of a new systemic anti-cancer therapy, orloco-regional tumour progression requiring radiation/surgery. While the overall number of events wassmall, the difference between the two arms was sufficiently large to reach statistical significance.

Treatment with Erleada decreased the risk of symptomatic progression by 43% compared with placebo(HR = 0.567; 95% CI: 0.443, 0.725; p < 0.0001). The median time to symptomatic progression wasnot reached in either treatment group.

With median follow-up time of 52.0 months, results showed that treatment with Erleada significantlydecreased the risk of death by 22% compared with placebo (HR = 0.784; 95% CI: 0.643, 0.956;2-sided p = 0.0161). The median OS was 73.9 months for the Erleada arm and 59.9 months for theplacebo arm. The pre-specified alpha boundary (p ≤ 0.046) was crossed and statistical significancewas achieved. This improvement was demonstrated even though 19% of patients in the placebo armreceived Erleada as subsequent therapy.

Figure 4: Kaplan-Meier overall survival (OS) curve in Study ARN-509-003 at final analysis

Treatment with Erleada significantly decreased the risk of initiating cytotoxic chemotherapy by 37%compared with placebo (HR = 0.629; 95% CI: 0.489, 0.808; p = 0.0002) demonstrating statisticallysignificant improvement for Erleada versus placebo. The median time to the initiation of cytotoxicchemotherapy was not reached for either treatment arm.

PFS-2, defined as the time to death or disease progression by PSA, radiographic, or symptomaticprogression on or after first subsequent therapy was longer for subjects treated with Erleada comparedto those treated with placebo. Results demonstrated a 44% reduction in risk of PFS-2 with Erleadaversus placebo (HR = 0.565, 95% CI: 0.471, 0.677; p < 0.0001).

There were no detrimental effects to overall health-related quality of life with the addition of Erleadato ADT and a small but not clinically meaningful difference in change from baseline in favour of

Erleada observed in the analysis of the Functional Assessment of Cancer Therapy-Prostate (FACT-P)total score and subscales.

The European Medicines Agency has waived the obligation to submit the results of studies with

Erleada in all subsets of the paediatric population in advanced prostate cancer. See section 4.2 forinformation on paediatric use.

Following repeat once-daily dosing, apalutamide exposure (Cmax and area under the concentrationcurve [AUC]) increased in a dose-proportional manner across the dose range of 30 to 480 mg.

Following administration of 240 mg once daily, apalutamide steady state was achieved after 4 weeksand the mean accumulation ratio was approximately 5-fold relative to a single dose. At steady-state,mean (CV%) Cmax and AUC values for apalutamide were 6 µg/mL (28%) and 100 µg.h/mL (32%),respectively. Daily fluctuations in apalutamide plasma concentrations were low, with meanpeak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeatdosing, likely due to induction of apalutamide’s own metabolism.

At steady-state, the mean (CV%) Cmax and AUC values for the major active metabolite, N-desmethylapalutamide, were 5.9 µg/mL (18%) and 124 µg.h/mL (19%), respectively. N-desmethyl apalutamideis characterised by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of1.27. Mean (CV%) AUC metabolite/parent drug ratio for N-desmethyl apalutamide followingrepeat-dose administration was about 1.3 (21%). Based on systemic exposure, relative potency, andpharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity ofapalutamide.

After oral administration, median time to achieve peak plasma concentration (tmax) was 2 hours (range:1 to 5 hours). Mean absolute oral bioavailability is approximately 100%, indicating that apalutamide iscompletely absorbed after oral administration.

Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat mealresulted in no clinically relevant changes in Cmax and AUC. Median time to reach tmax was delayedabout 2 hours with food (see section 4.2).

Apalutamide is not ionisable under relevant physiological pH condition, therefore acid loweringagents (e.g., proton pump inhibitor, H2-receptor antagonist, antacid) are not expected to affect thesolubility and bioavailability of apalutamide.

In vitro, apalutamide and its N-desmethyl metabolite are substrates for P-gp. Because apalutamide iscompletely absorbed after oral administration, P-gp does not limit the absorption of apalutamide andtherefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.

The mean apparent volume of distribution at steady-state of apalutamide is about 276 L. The volumeof distribution of apalutamide is greater than the volume of total body water, indicative of extensiveextravascular distribution.

Apalutamide and N-desmethyl apalutamide are 96% and 95% bound to plasma proteins, respectively,and mainly bind to serum albumin with no concentration dependency.

Following single oral administration of 14C-labelled apalutamide 240 mg, apalutamide, the activemetabolite, N-desmethyl apalutamide, and an inactive carboxylic acid metabolite accounted for themajority of the 14C-radioactivity in plasma, representing 45%, 44%, and 3%, respectively, of the total14C-AUC.

Metabolism is the main route of elimination of apalutamide. It is metabolised primarily by CYP2C8and CYP3A4 to form N-desmethyl apalutamide. Apalutamide and N-desmethyl apalutamide arefurther metabolised to form the inactive carboxylic acid metabolite by carboxylesterase. Thecontribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and13% following single dose but the level of contribution is expected to change at steady-state due toinduction of CYP3A4 by apalutamide after repeat dose.

Apalutamide, mainly in the form of metabolites, is eliminated primarily via urine. Following a singleoral administration of radiolabelled apalutamide, 89% of the radioactivity was recovered up to 70 dayspost-dose: 65% was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as

N-desmethyl apalutamide) and 24% was recovered in faeces (1.5% of dose as unchanged apalutamideand 2% as N-desmethyl apalutamide).

The apparent oral clearance (CL/F) of apalutamide is 1.3 L/h after single dosing and increases to2.0 L/h at steady-state after once-daily dosing. The mean effective half-life for apalutamide in patientsis about 3 days at steady-state.

In vitro data indicate that apalutamide and its N-desmethyl metabolite are not substrates for BCRP,

OATP1B1 or OATP1B3.

The effects of renal impairment, hepatic impairment, age, race, and other extrinsic factors on thepharmacokinetics of apalutamide are summarised below.

A dedicated renal impairment study for apalutamide has not been conducted. Based on the populationpharmacokinetic analysis using data from clinical studies in subjects with castration-resistant prostatecancer (CRPC) and healthy subjects, no significant difference in systemic apalutamide exposure wasobserved in subjects with pre-existing mild to moderate renal impairment (estimated glomerularfiltration rate [eGFR] between 30 to 89 mL/min/1.73 m2; N=585) compared to subjects with baselinenormal renal function (eGFR ≥ 90 mL/min/1.73 m2; N=372). The potential effect of severe renalimpairment or end stage renal disease (eGFR ≤ 29 mL/min/1.73 m2) have not been established due toinsufficient data.

A dedicated hepatic impairment study compared the systemic exposure of apalutamide and

N- desmethyl apalutamide in subjects with baseline mild hepatic impairment (N=8, Child-Pugh Class

A, mean score = 5.3) or moderate hepatic impairment (N=8, Child-Pugh Class B, mean score = 7.6)versus healthy controls with normal hepatic function (N=8). Following a single oral 240 mg dose ofapalutamide, the geometric mean ratio (GMR) for AUC and Cmax for apalutamide in subjects with mildimpairment was 95% and 102%, respectively, and the GMR for AUC and Cmax of apalutamide insubjects with moderate impairment was 113% and 104%, respectively, compared to healthy controlsubjects. Clinical and pharmacokinetic data for apalutamide are not available for patients with severehepatic impairment (Child-Pugh Class C).

Ethnicity and race

Based on population pharmacokinetic analysis, there were no clinically relevant differences inapalutamide pharmacokinetics between White (Caucasian or Hispanic or Latino; N=761), Black (of

African heritage or African American; N=71), Asian (non-Japanese; N=58) and Japanese (N=58).

Population pharmacokinetic analyses showed that age (range: 18 to 94 years) does not have aclinically meaningful influence on the pharmacokinetics of apalutamide.

Apalutamide was negative for genotoxicity in a standard battery of in vitro and in vivo tests.

Apalutamide was not carcinogenic in a 6-month study in the male transgenic (Tg.rasH2) mouse atdoses up to 30 mg/kg per day, which is 1.2 and 0.5 times for apalutamide and N-desmethylapalutamide respectively, the clinical exposure (AUC) at the recommended clinical dose of240 mg/day.

In a 2-year carcinogenicity study in male Sprague-Dawley rats, apalutamide was administered by oralgavage at doses of 5, 15 and 50 mg/kg/day (0.2, 0.7, and 2.5 times the AUC in patients (humanexposure at recommended dose of 240 mg), respectively). Neoplastic findings were noted including anincreased incidence of testicular Leydig cell adenoma and carcinoma at doses greater than or equal to5 mg/kg/day, mammary adenocarcinoma and fibroadenoma at 15 mg/kg/day or 50 mg/kg/day, andthyroid follicular cell adenoma at 50 mg/kg/day. These findings were considered rat-specific andtherefore of limited relevance to humans.

Male fertility is likely to be impaired by treatment with apalutamide based on findings in repeat-dosetoxicology studies which were consistent with the pharmacological activity of apalutamide. Inrepeat-dose toxicity studies in male rats and dogs, atrophy, aspermia/hypospermia, degenerationand/or hyperplasia or hypertrophy in the reproductive system were observed at doses corresponding toexposures approximately equal to the human exposure based on AUC.

In a fertility study in male rats, a decrease in sperm concentration and motility, copulation and fertilityrates (upon pairing with untreated females) along with reduced weights of the secondary sex glandsand epididymis were observed following 4 weeks of dosing at doses corresponding to exposuresapproximately equal to the human exposure based on AUC. Effects on male rats were reversible after8 weeks from the last apalutamide administration.

In a preliminary embryofetal developmental toxicity study in rats, apalutamide caused developmentaltoxicity when administered at oral doses of 25, 50 or 100 mg/kg/day throughout the period oforganogenesis (gestational days 6-20). These doses resulted in systemic exposures approximately 2, 4and 6 times, respectively, on an AUC basis, the exposure in humans at the dose of 240 mg/day.

Findings included non-pregnant females at 100 mg/kg/day and embryofetal lethality (resorptions) atdoses ≥ 50 mg/kg/day, decreased fetal anogenital distance and a misshapen pituitary gland (morerounded shape) at ≥ 25 mg/kg/day. Skeletal variations (unossified phalanges, supernumerary shortthoracolumbar rib(s) and/or abnormalities of the hyoid) were also noted at doses ≥ 25 mg/kg/day,without resulting in an effect on mean fetal weight.

Colloidal anhydrous silica

Croscarmellose sodium

Hypromellose acetate succinate

Magnesium stearate

Microcrystalline cellulose (silicified)

Glycerol monocaprylocaprate

Iron oxide black (E172)

Poly (vinyl alcohol)

Talc

Titanium dioxide (E171)

Macrogol poly (vinyl alcohol) grafted copolymer

Not applicable.

2 years

Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

White high-density polyethylene (HDPE) bottle with a polypropylene (PP) child-resistant closure.

Each bottle contains 30 film-coated tablets and a total of 2 g of silica gel desiccant.

Transparent PVC-PCTFE film blister with an aluminium push-through foil sealed inside achild-resistant wallet pack.

- Each 28-day carton contains 28 film coated tablets in 2 cardboard wallet packs of14 film-coated tablets each.

- Each 30-day carton contains 30 film coated tablets in 3 cardboard wallet packs of10 film-coated tablets each.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/18/1342/004

EU/1/18/1342/005

EU/1/18/1342/006

Date of first authorisation: 14 January 2019

Date of latest renewal: 22 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.