4.1. Therapeutic indications

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) in combination with androgen deprivation therapy (ADT) (see section 5.1).

4.2. Posology and method of administration

Treatment with apalutamide should be initiated and supervised by an appropriate prescriber experienced in the treatment of prostate cancer.

Posology

The recommended dose is 240 mg (four 60 mg tablets) as an oral single daily dose.

Medical castration with gonadotropin releasing hormone analogue (GnRHa) should be continued during 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 normal schedule 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 should be held rather than permanently discontinuing treatment until symptoms improve to ≤ Grade 1 or original grade, then should be resumed at the same dose or a reduced dose (180 mg or 120 mg), if warranted. For the most common adverse reactions, (see section 4.8).

Special populations

Elderly

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

Renal impairment

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 in this patient population (see section 5.2). If treatment is started, patients should be monitored for the adverse reactions listed in section 4.8 and dose reduce as per section 4.2 Posology and method of administration.

Hepatic impairment

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

For patients with severe hepatic impairment (Child Pugh Class C), the recommended dose is 120 mg (two 60 mg tablets) administered orally once daily (see section 5.2).

Paediatric population

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

Method of administration

Oral use.

The tablets should be swallowed whole to ensure that the full intended dose is taken. The tablets should not be crushed or split. The tablets can be taken with or without food.

Taking Erleada with non‑fizzy beverage or soft food

For patients who cannot swallow tablets whole, Erleada can be dispersed in non‑fizzy water and then 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 entire prescribed dose of Erleada in a cup. Do not crush or split the tablets.

2. Add about 20 mL (4 teaspoons) of non‑fizzy water to make sure that the tablets are completely in water.

3. Wait 2 minutes until the tablets are 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 soft foods; orange juice, green tea, applesauce, drinkable yogurt, or additional water and stir the mixture.

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 can also be administered through a nasogastric feeding tube (NG tube) 8 French or greater as follows:

1. Place the entire prescribed dose of Erleada in the barrel of a syringe (use at least a 50 mL syringe) and draw up 20 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 in the syringe or feeding tube.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Seizure

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

In two randomised studies (SPARTAN and TITAN), seizure occurred in 0.6% of patients receiving apalutamide and in 0.2% of patients treated with placebo. These studies excluded patients with a history 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 be evaluated for fracture and fall risk before starting Erleada and should continue to be monitored and managed according to established treatment guidelines and use of bone-targeted agents should be considered.

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 had cardiac/cerebrovascular ischaemic disease risk factors. Patients should be monitored for signs and symptoms of ischaemic heart disease and ischaemic cerebrovascular disorders. Management of risk factors, such as hypertension, diabetes, or dyslipidaemia should be optimised as per standard of care.

Concomitant use with other medicinal products

Apalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products (see section 4.5). A review of concomitant medicinal products should therefore be conducted when apalutamide treatment is initiated. Concomitant use of apalutamide with medicinal products 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 dose adjustments 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 or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted (see section 4.5).

Recent cardiovascular disease

Patients with clinically significant cardiovascular disease in the past 6 months including severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischaemic attacks), or clinically significant ventricular arrhythmias were excluded from the clinical studies. Therefore, the safety of apalutamide in these patients has not been established. If Erleada is prescribed, patients with clinically significant cardiovascular disease should be monitored for risk factors such as hypercholesterolaemia, hypertriglyceridaemia, or other cardio-metabolic disorders (see section 4.8). Patients should be treated, if appropriate, after initiating Erleada for these conditions according to established treatment guidelines.

Androgen deprivation therapy may prolong the QT interval

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5), physicians should assess the benefit-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 be life‑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 these symptoms are observed, Erleada should be withdrawn immediately and patients should seek immediate 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 of acute onset and/or unexplained worsening of pulmonary symptoms, treatment with apalutamide should be interrupted pending further investigation of these symptoms. If ILD is diagnosed, apalutamide should be discontinued and appropriate treatment initiated as necessary (see section 4.8).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per 240 mg dose (4 tablets), that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

The elimination of apalutamide and formation of its active metabolite, N‑desmethyl apalutamide, is mediated by both CYP2C8 and CYP3A4 to a similar extent at steady-state. No clinically meaningful changes in their overall exposure is expected as a result of drug interaction with inhibitors or inducers of CYP2C8 or CYP3A4. Apalutamide is an inducer of enzymes and transporters and may lead to an increase 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. In a drug‑drug interaction study, the Cmax of apalutamide decreased by 21% while AUC increased by 68% 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 active metabolite), Cmax decreased by 21% while AUC increased by 45%. No initial dose adjustment is necessary 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 (see section 4.2). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide.

Medicinal products that inhibit CYP3A4

CYP3A4 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug‑drug interaction study, the Cmax of apalutamide decreased by 22% while AUC was similar following co‑administration of Erleada as a 240 mg single dose with itraconazole (strong CYP3A4 inhibitor). 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 of apalutamide.

Medicinal products that induce CYP3A4 or CYP2C8

The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Based on the drug-drug interaction study results with strong CYP3A4 inhibitor or strong CYP2C8 inhibitor, CYP3A4 or CYP2C8 inducers are not expected to have clinically relevant effects on the pharmacokinetics of apalutamide and the active moieties therefore no dose adjustment is necessary 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 and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead 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 weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N‑desmethyl apalutamide do not affect 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. When substrates of CYP2B6 (e.g., efavirenz) are administered with Erleada, monitoring for an adverse reaction and evaluation for loss of efficacy of the substrate should be performed and dose adjustment of 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 apalutamide with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (CYP3A4 substrate), 85% decrease in the AUC of omeprazole (CYP2C19 substrate), and 46% decrease in the AUC of S‑warfarin (CYP2C9 substrate). Apalutamide did not cause clinically meaningful changes in exposure to the CYP2C8 substrate. Concomitant use of Erleada with medicinal products that are primarily metabolised by CYP3A4 (e.g., darunavir, felodipine, midazolam, simvastatin), CYP2C19 (e.g., diazepam, omeprazole), or CYP2C9 (e.g., warfarin, phenytoin) can result in lower exposure to these medicinal products. Substitution for these medicinal products is recommended when possible or evaluation for loss of efficacy should be performed if the medicinal product 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 be induced 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) can result in lower exposure to these medicinal products. When substrates of UGT are co‑administered with Erleada, evaluation for loss of efficacy of the substrate should be performed and dose adjustment of 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 resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. A drug‑drug interaction study using a cocktail approach showed that co‑administration of apalutamide with single oral 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 no impact 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 the substrate should be performed and dose adjustment of the substrate may be required to maintain optimal 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 metabolite cannot be excluded. No in vitro inhibition of organic anion transporter 1 (OAT1) was observed.

GnRH Analogue

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

Medicinal products which prolong the QT interval

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Erleada with 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).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Contraception in males and females

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

Pregnancy

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

Breast‑feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions observed during clinical studies and/or in post‑marketing experience are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (frequency cannot be estimated from the available data).

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

Table 1: Adverse reactions

System Organ Class

Adverse reaction and frequency

Blood and lymphatic system disorders

common: neutropenia

not known: agranulocytosis

Endocrine disorders

common: hypothyroidisma

Metabolism and nutrition disorders

very common: decreased appetite

common: hypercholesterolaemia, hypertriglyceridaemia

Nervous system disorders

common: dysgeusia, ischaemic cerebrovascular disordersb

uncommon: seizurec (see section 4.4), restless legs syndrome

Cardiac disorders

common: ischaemic heart diseased

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

Vascular disorders

very common: hot flush, hypertension

Respiratory, thoracic and mediastinal disorders

not known: interstitial lung diseasee

Gastrointestinal disorders

very common: diarrhoea

Skin and subcutaneous tissue disorders

very common: skin rashf

common: pruritus, alopecia

uncommon: lichenoid eruption

not known: drug reaction with eosinophilia and systemic symptoms (DRESS)e, Stevens‑Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)e

Musculoskeletal and connective tissue disorders

very common: fractureg, arthralgia

common: muscle spasm

General disorders and administration site conditions

very common: fatigue

Investigations

very common: weight decreased

Injury, poisoning and procedural complications

very common: fall

a Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroxine decreased, autoimmune thyroiditis, thyroxine free decreased, tri‑iodothyronine decreased

b Includes transient ischaemic attack, cerebrovascular accident, cerebrovascular disorder, ischaemic stroke, carotid arteriosclerosis, carotid artery stenosis, hemiparesis, lacunar infarction, lacunar stroke, thrombotic cerebral infarction, vascular encephalopathy, cerebellar infarction, cerebral infarction, and cerebral ischaemia

c Includes tongue biting

d Includes angina pectoris, angina unstable, myocardial infarction, acute myocardial infarction, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, arteriosclerosis coronary artery, cardiac stress test abnormal, troponin increased, myocardial ischaemia

e See section 4.4

f 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 limb fracture, 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.

Description of selected adverse reactions

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 treated with apalutamide. Grade 3 skin rashes (defined as covering > 30% body surface area [BSA]) were reported 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 of rash with a median of 78 days to resolution. Medicinal products utilised included topical corticosteroids, oral anti-histamines, and 19% of patients received systemic corticosteroids. Among patients with skin rash, dose interruption occurred in 28% and dose reduction occurred in 14% (see section 4.2). Skin rash recurred in 59% of patients who had dose interruption. Skin rash led to apalutamide 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 and 6.5% of patients treated with placebo. Half of the patients experienced a fall within 7 days before the fracture event in both treatment groups. Falls were reported for 15.6% of patients treated with apalutamide 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 with apalutamide 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 from ischaemic heart disease (see section 4.4).

In the SPARTAN study, with a median exposure of 32.9 months for apalutamide and 11.5 months for placebo, ischaemic cerebrovascular disorders occurred in 4% of patients treated with apalutamide and 1% of patients treated with placebo (see above). In the TITAN study, ischaemic cerebrovascular disorders 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 no patients treated with placebo died from an ischaemic cerebrovascular disorder (see section 4.4).

Hypothyroidism

Hypothyroidism was reported for 8% of patients treated with apalutamide and 2% of patients treated with placebo based on assessments of thyroid‑stimulating hormone (TSH) every 4 months. There were no grade 3 or 4 adverse events. Hypothyroidism occurred in 30% of patients already receiving thyroid replacement therapy in the apalutamide arm and in 3% of patients in the placebo arm. In patients not receiving thyroid replacement therapy, hypothyroidism occurred in 7% of patients treated with apalutamide and in 2% of patients treated with placebo. Thyroid replacement therapy, when clinically indicated, should be initiated or dose‑adjusted (see section 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known specific antidote for apalutamide overdose. In the event of an overdose, Erleada should be stopped and general supportive measures should be undertaken until clinical toxicity has been 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.