4.1. Therapeutic indications

NUBEQA is indicated for the treatment of adult men with

- non‑metastatic castration resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease (see section 5.1).

- metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (see section 5.1).

- metastatic hormone‑sensitive prostate cancer (mHSPC) in combination with docetaxel (see section 5.1).

4.2. Posology and method of administration

Treatment should be initiated and supervised by a specialist physician experienced in treatment of prostate cancer.

Posology

The recommended dose is 600 mg darolutamide (two tablets of 300 mg) taken twice daily, equivalent to a total daily dose of 1200 mg (see section 5.2).

Darolutamide should be continued until disease progression or unacceptable toxicity.

Medical castration with a luteinising hormone‑releasing hormone (LHRH) analogue should be continued during treatment of patients not surgically castrated.

metastatic hormone‑sensitive prostate cancer (mHSPC)

When used in combination with docetaxel in mHSPC patients (see section 5.1). The first of 6 cycles of docetaxel should be administered within 6 weeks after the start of darolutamide treatment. The recommendation in the product information of docetaxel should be followed. Treatment with darolutamide should be continued until disease progression or unacceptable toxicity even if a cycle of docetaxel is delayed, interrupted, or discontinued.

Missed dose

If a dose is missed, the dose should be taken as soon as the patient remembers prior to the next scheduled dose. The patient should not take two doses together to make up for a missed dose.

Dose modification

If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction related to darolutamide (see sections 4.4 and 4.8), dosing should be withheld or reduced to 300 mg twice daily until symptoms improve. Treatment may then be resumed at a dose of 600 mg twice daily.

Dose reduction below 300 mg twice daily is not recommended, because efficacy has not been established.

Special populations

Elderly

No dose adjustment is necessary in elderly patients (see section 5.2).

Renal impairment

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

For patients with severe renal impairment (eGFR 15‑29 mL/min/1.73 m2) not receiving haemodialysis, the recommended starting dose is 300 mg twice daily (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment.

The available data on darolutamide pharmacokinetics in moderate hepatic impairment is limited. Darolutamide has not been studied in patients with severe hepatic impairment.

For patients with moderate and severe hepatic impairment (Child‑Pugh Classes B and C), the recommended starting dose is 300 mg twice daily (see sections 4.4 and 5.2.).

Paediatric population

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

Method of administration

NUBEQA is for oral use.

The tablets should be taken whole with food (see section 5.2).

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

Ischaemic heart disease

Ischaemic heart disease, including fatal cases, occurred in patients receiving NUBEQA in the clinical studies ARAMIS and ARASENS (see section 4.8). Monitor for signs and symptoms of ischaemic heart disease. Optimise management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidaemia. Discontinue NUBEQA for Grade 3-4 ischaemic heart disease.

Seizure

Seizure occurred in patients receiving NUBEQA in the clinical studies ARAMIS and ARASENS (see section 4.8). It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.

Hepatotoxicity

Cases of idiosyncratic drug-induced liver injury (DILI) with increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) to ≥5 and ≥20 x upper limit of normal (ULN) have been reported in darolutamide. Time to onset ranged from 1 month to 12 months after initiation of darolutamide. Cases with concomitant bilirubin elevation ≥2x ULN were uncommonly reported. Idiosyncratic DILI has been reported in clinical trials and post-marketing setting. Positive dechallenge and rechallenge for darolutamide have been reported in patients. Liver function test abnormalities were reversible upon NUBEQA discontinuation. In case of liver function test abnormalities suggestive of idiosyncratic drug-induced liver injury, permanently discontinue darolutamide.

Renal impairment

The available data in patients with severe renal impairment are limited.

As exposure might be increased those patients should be closely monitored for adverse reactions (see sections 4.2 and 5.2).

Hepatic impairment

The available data in patients with moderate hepatic impairment are limited, and darolutamide has not been studied in patients with severe hepatic impairment.

As exposure might be increased those patients should be closely monitored for adverse reactions (see sections 4.2 and 5.2).

Recent cardiovascular disease

Patients with clinically significant cardiovascular disease in the past 6 months including stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, and symptomatic congestive heart failure were excluded from the clinical studies. Therefore, the safety of darolutamide in these patients has not been established.

If NUBEQA is prescribed, patients with clinically significant cardiovascular disease should be treated for these conditions according to established guidelines.

Concomitant use with other medicinal products

Use of strong CYP3A4 and P‑gp inducers during treatment with darolutamide may decrease the plasma concentration of darolutamide and is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product with less potential to induce CYP3A4 or P‑gp should be considered (see section 4.5).

Patients should be monitored for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates as co‑administration with darolutamide may increase the plasma concentrations of these substrates.

Co‑administration with rosuvastatin should be avoided unless there is no therapeutic alternative (see section 4.5).

Androgen deprivation therapy (ADT) may prolong the QT interval

In patients with a history of 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 NUBEQA.

Information about excipients

NUBEQA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

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

Effects of other medicinal products on darolutamide

CYP3A4 and P‑gp inducers

Darolutamide is a substrate of CYP3A4 and P‑glycoprotein (P‑gp).

Use of strong and moderate CYP3A4 inducers and P‑gp inducers (e.g. carbamazepine, phenobarbital, St. John's Wort, phenytoin, and rifampicin) during treatment with darolutamide is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product, with no or weak potential to induce CYP3A4 or P‑gp should be considered.

Repeated administration of rifampicin (600 mg), a strong CYP3A4 and a P‑gp inducer, with a single dose of darolutamide (600 mg) together with food, resulted in a decrease of 72% in mean exposure (AUC0‑72) and a decrease of 52% in Cmax of darolutamide.

CYP3A4, P‑gp and BCRP inhibitors

Darolutamide is a substrate of CYP3A4, P‑gp and breast cancer resistance protein (BCRP).

No clinically relevant drug‑drug interaction is expected in case of CYP3A4, P‑gp or BCRP inhibitor administration. Darolutamide may be given concomitantly with CYP3A4, P‑gp or BCRP inhibitors. Concomitant use of darolutamide with a combined P‑gp and strong CYP3A4 inhibitor increases darolutamide exposure which may increase the risk of darolutamide adverse reactions. It is recommended to monitor patients more frequently for darolutamide adverse reactions and modify darolutamide dose as needed.

Administration of itraconazole (200 mg twice daily on day 1 and once daily on the following 7 days), a strong CYP3A4, P‑gp and BCRP inhibitor, with a single dose of darolutamide (600 mg on day 5 together with food) resulted in a 1.7‑fold increase in mean exposure (AUC0‑72) and a 1.4‑fold increase of Cmax of darolutamide.

UGT1A9 inhibitors

Darolutamide is a substrate of UGT1A9.

No clinically relevant drug‑drug interaction is expected in case of UGT1A9 inhibitor administration.

Darolutamide may be given concomitantly with UGT1A9 inhibitors.

A population pharmacokinetic analysis showed that co-administration of UGT1A9 inhibitors with darolutamide resulted in a 1.2‑fold increase in exposure (AUC0-72) of darolutamide.

Docetaxel

Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of darolutamide in mHSPC patients (see section 5.1).

Effects of darolutamide on other medicinal products

BCRP, OATP1B1 and OATP1B3 substrates

Darolutamide is an inhibitor of breast cancer resistance protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3.

Co‑administration of rosuvastatin should be avoided unless there is no therapeutic alternative. Selection of an alternative concomitant medicinal product with less potential to inhibit BCRP, OATP1B1 and OATP1B3 should be considered.

Administration of darolutamide (600 mg twice daily for 5 days) prior to co‑administration of a single dose of rosuvastatin (5 mg) together with food resulted in approximately 5‑fold increase in mean exposure (AUC) and Cmax of rosuvastatin.

Co‑administration of darolutamide with other BCRP substrates should be avoided where possible.

Co‑administration of darolutamide may increase the plasma concentrations of other concomitant BCRP, OATP1B1 and OATP1B3 substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin, pitavastatin). Therefore, it is recommended to monitor patients for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates. In addition, the related recommendation in the product information of these substrates should be followed when co‑administered with darolutamide.

P‑gp substrates

No clinically relevant drug‑drug interaction is expected in case of P‑gp substrate administration. Darolutamide may be given concomitantly with P‑gp substrates (e.g. digoxin, verapamil or nifedipine). Co‑administration of darolutamide together with the sensitive P‑gp substrate dabigatran etexilate did not reveal any increase in exposure (AUC and Cmax) of dabigatran.

CYP3A4 substrates

Darolutamide is a mild inducer of CYP3A4.

No clinically relevant drug‑drug interaction is expected in case of CYP substrate administration. Darolutamide may be given concomitantly with CYP substrates (e.g. warfarin, L‑thyroxine, omeprazole).

Administration of darolutamide (600 mg twice daily for 9 days) prior to co‑administration of a single dose of the sensitive CYP3A4 substrate midazolam (1 mg) together with food, decreased the mean exposure (AUC) and Cmax of midazolam by 29% and 32%, respectively.

Darolutamide did not inhibit the metabolism of selected CYP substrates in vitro at clinically relevant concentrations.

Docetaxel

Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of docetaxel in mHSPC patients (see section 5.1).

Medicinal products that prolong the QT interval

Since androgen deprivation treatment may prolong the QT interval, the co‑administration with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes should be carefully evaluated. These include medicinal products such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, and antipsychotics (e.g. haloperidol).

4.6. Fertility, pregnancy and lactation

This medicinal product is not indicated in women of childbearing potential. It is not to be used in women who are, or may be, pregnant or breast‑feeding (see sections 4.1 and 4.3).

Women of childbearing potential / contraception in males and females

It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a woman of childbearing potential, a highly effective contraceptive method (<1% failure rate per year) should be used during and for 1 week after completion of treatment with NUBEQA to prevent pregnancy.

Pregnancy

Based on its mechanism of action, darolutamide may cause foetal harm. No non‑clinical reproductive toxicity studies have been conducted (see section 5.3).

It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a pregnant woman, a condom should be used during and for 1 week after completion of treatment with NUBEQA. Exposure of the foetus to an androgen receptor inhibitor through seminal transfer to the pregnant woman has to be avoided, as this could affect development of the foetus.

Breast‑feeding

It is unknown whether darolutamide or its metabolites are excreted in human milk. No studies in animals have been conducted to evaluate the excretion of darolutamide or its metabolites into milk (see section 5.3). A risk to the breast‑fed child cannot be excluded.

Fertility

There are no human data on the effect of darolutamide on fertility.

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

4.7. Effects on ability to drive and use machines

NUBEQA has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

nmCRPC and mHSPC

In a pooled analysis of ARAMIS and ARANOTE, the most common adverse reactions in patients receiving darolutamide was fatigue/asthenic conditions (13.7%). The most common serious adverse reactions were ischaemic heart disease (1.9%), cardiac arrhythmias (1.8%), pneumonia (1.5%), urinary retention (1.3%), urinary tract infection (1.1%) and fractures (1.0%). Discontinuation of darolutamide due to adverse reactions occurred in 8.0% of patients. The most common adverse reactions leading to discontinuation were heart failure (0.4%) and ischemic heart disease (0.4%). Dose interruptions of darolutamide due to adverse reactions occurred in 12.9% of patients. The most common adverse reactions leading to dose interruption were hypertension (0.7%), ischaemic heart disease (0.6%), cardiac arrhythmias (0.6%), rash (0.6%), AST increased (0.6%), and pneumonia (0.6%). Dose reductions of darolutamide due to adverse reactions occurred in 3.4% of the patients. The most common adverse reaction leading to dose reduction was fatigue (0.6%).

mHSPC in combination with docetaxel

The most common adverse reactions in patients receiving darolutamide in combination with docetaxel were rash (17.3%) alanine aminotransferase (ALT) increased (15.8%), aspartate aminotransferase (AST) increased (14.0%) and hypertension (13.8%). The most common serious adverse reactions in patients receiving darolutamide in combination with docetaxel were febrile neutropenia (6.1%), neutrophil count decreased (2.8%) and pneumonia (2.5%). Discontinuation of darolutamide due to adverse reactions occurred in 13.7% of patients. The most common adverse reactions leading to discontinuation were rash (1.1%), AST increased (0.9%) and ALT increased (0.8%). Dose interruptions of darolutamide due to adverse reactions occurred in 22.9% of patients. The most common adverse reactions leading to dose interruption were ALT increased (3.2%), AST increased (3.1%) and febrile neutropenia (2.1%). Dose reductions of darolutamide due to adverse reactions occurred in 8.7% of the patients. The most common adverse reactions leading to dose reduction were ALT increased (2.8%) and AST increased (2.5%).

Tabulated list of adverse reactions

The adverse reactions observed in patients with nmCRPC and mHSPC treated with darolutamide are listed in Table 1. The adverse reactions observed in patients with mHSPC treated with darolutamide in combination with docetaxel are listed in Table 2. They are classified according to System Organ Class.

Adverse reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: 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); not known (cannot be estimated from the available data).

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

Table 1: Adverse reactions reported in nmCRPC and mHSPC patients treated with darolutamide in ARAMIS and ARANOTE studies

System organ class(MedDRA)

Very common

Common

Cardiac disorders

Ischaemic heart diseasea

Heart failureb

Skin and subcutaneous tissue disorders

Rashc

Musculoskeletal and connective tissue disorders

Pain in extremity

Fractures

General disorders and administration site conditions

Fatigue/asthenic conditionsd

Investigationse

Neutrophil count decreased

Blood bilirubin increased

ALT increased

AST increased

Anaemia

a Includes arteriosclerosis coronary artery, coronary artery disease, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, acute myocardial infarction, angina pectoris, angina unstable, myocardial infarction, myocardial ischaemia.

b Includes cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiogenic shock, heart failure with preserved ejection fraction.

c Includes rash, rash macular, rash maculo‑papular, rash papular, rash pustular, erythema, dermatitis.

d Includes fatigue and asthenia, lethargy and malaise..

e Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The incidence is based on values reported as laboratory abnormalities.

Table 2: Adverse reactions reported in mHSPC patients treated with darolutamide in combination with docetaxel in the ARASENS study (with a ≥2% increase compared to placebo with docetaxel)a

System organ class(MedDRA)

Very common

Vascular disorders

Hypertensionb

Skin and subcutaneous tissue disorders

Rashc, d

Investigationse

Blood bilirubin increased

ALT increased

AST increased

a Adverse reactions incidences may not be attributable to darolutamide alone but may contain contributions from other medicinal products used in combination.

b Includes hypertension, blood pressure increased, hypertensive emergency.

c Includes rash, rash maculopapular, drug eruption, rash pruritic, rash erythematous, rash macular, rash papular, rash follicular, rash pustular, rash vesicular, erythema, dermatitis.

d The incidence was highest during the first 6 months of treatment.

e Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The incidence is based on values reported as laboratory abnormalities.

Description of selected adverse reactions

Fatigue

nmCRPC and mHSPC

Fatigue/asthenic conditions were reported in 13.7% of patients treated with darolutamide and in 11.7% of patients treated with placebo. Events with worst Grade of 3 were reported in 0.4% of patients treated with darolutamide and in 0.9% of patients treated with placebo. Fatigue (not including asthenia, lethargy or malaise) occurred in the majority of patients (10.0% of patients treated with darolutamide and 8.5% of patients treated with placebo). The median time to onset of first fatigue event was 2.2 months in patients treated with darolutamide. Serious events of fatigue were reported in <0.1% of patients treated with darolutamide. Dose reduction of darolutamide due to fatigue was reported in 0.6% of patients. Discontinuation of darolutamide due to fatigue was reported in 0.2% of patients.

Rash

nmCRPC and mHSPC

Rash occurred in 3.4% of patients treated with darolutamide and in 1.7% of patients treated with placebo. The events were predominantly of Grade 1 or 2. Grade 3 rash was reported in 0.4% of patients treated with darolutamide and in 0% of patients treated with placebo. The median time to onset of the first rash event was 3.7 months in patients treated with darolutamide. No serious events of rash were reported in either treatment arm. Dose reduction of darolutamide due to rash was reported in 0.3% of patients. Discontinuation of darolutamide due to rash was reported in 0.1% of patients.

mHSPC treated in combination with docetaxel

Rash occurred in 17.3% of patients treated with darolutamide+docetaxel and in 13.7% of patients treated with placebo+docetaxel. The events were predominantly Grade 1 or 2. Grade 3 and 4 rash was reported in 1.4% of patients treated with darolutamide+docetaxel and in 0.2% of patients treated with placebo+docetaxel. The median time to onset of the first rash event was 1.4 months in patients treated with darolutamide+docetaxel. Serious events of rash were reported in 0.2% of patients in both treatment arms. Dose reduction of darolutamide due to rash was reported in 0.5% of patients. Dose interruption of darolutamide due to rash was reported in 1.4% of patients. Discontinuation of darolutamide due to rash was reported in 1.1% of patients. The incidence of rash was highest during the first 6 months of study treatment in both treatment arms and decreased thereafter.

Hypertension

mHSPC treated in combination with docetaxel

Hypertension was reported in 13.8% of patients treated with darolutamide+docetaxel and 9.7% of patients treated with placebo+docetaxel. Grade 3 and 4 hypertension was reported in 6.6% of patients treated with darolutamide+docetaxel and 3.6% of patients treated with placebo+docetaxel. In patients receiving darolutamide+docetaxel, the median time to onset of the first hypertension event was 9.6 months. Discontinuation of darolutamide due to hypertension was reported in 0.2% of patients. There were no dose reductions of darolutamide due to hypertension. Intracranial haemorrhage events were reported in 3 patients with a history of hypertension.

Fractures

nmCRPC and mHSPC

Non-pathological fractures occurred in 4.1% of patients treated with darolutamide and in 3.2% of patients treated with placebo. Non-pathological fractures with worst Grade of 3 were reported in 1.1% of patients treated with darolutamide and in 0.8% of patients treated with placebo. Serious events of non-pathological fractures were reported in 0.1% of patients treated with darolutamide and 0.8% of patients treated with placebo. The median time to onset of non-pathological fractures was 10.6 months in patients treated with darolutamide. Discontinuation of darolutamide due to non-pathological fractures was reported in 0.1% of patients. There were no dose reductions of darolutamide due to non-pathological fractures. Pathological fractures were reported in 0.4% of patients treated with darolutamide and in 0.5% of patients treated with placebo. Bone health agents were used in 13.2% and 13.4% of patients treated with darolutamide and placebo, respectively.

mHSPC treated in combination with docetaxel

Non-pathological fractures occurred in 7.7% of patients treated with darolutamide+docetaxel and in 5.1% of patients treated with placebo+docetaxel. Non-pathological fractures with worst Grade of 3 were reported in 1.5% and 2.3% of patients, respectively. Serious events of non-pathological fractures were reported in 1.4% of patients treated with darolutamide+docetaxel and 1.5% of patients treated with placebo+docetaxel. The median time to onset of non-pathological fractures was 18.2 months in patients treated with darolutamide+docetaxel. There were no dose reductions or discontinuations of darolutamide due to non-pathological fractures. Pathological fractures were reported in 1.1% of patients treated with darolutamide+docetaxel and in 0.5% of patients treated with placebo+docetaxel. Bone health agents were used in 23.3% and 21.5% of patients treated with darolutamide+docetaxel and placebo+docetaxel, respectively.

Ischaemic heart disease and heart failure

nmCRPC and mHSPC

Ischaemic heart disease occurred in 3.4% of patients treated with darolutamide and in 2.2% of patients treated with placebo. Grade 3 and 4 ischaemic heart disease occurred in 1.4% and 0.3% of patients, respectively. Grade 5 (fatal) events occurred in 0.4% of patients in both treatment arms. Serious events of ischaemic heart disease were reported in 1.9% of patients treated with darolutamide and 1.2% of patients treated with placebo. The median time to onset of the first ischaemic heart disease event was 10.2 months in patients treated with darolutamide. Discontinuation of darolutamide due to ischaemic heart disease was reported in 0.4% of patients. There were no dose reductions of darolutamide due to ischaemic heart disease.

Heart failure occurred in 1.6% of patients treated with darolutamide and in 0.9% of patients treated with placebo. Grade 3 and 4 heart failure occurred in 0.5% and 0.1% of patients, respectively. Grade 5 (fatal) events occurred 0.3% of patients treated with darolutamide and 0.4% of patients treated with placebo. Serious events of heart failure were reported in 0.8% of patients in both treatment arms. The median time to onset of the first heart failure event was 13.9 months in patients treated with darolutamide. There were no dose reductions of darolutamide due to heart failure. Discontinuation of darolutamide due to heart failure was reported in 0.4% of patients.

mHSPC treated in combination with docetaxel

Ischaemic heart disease occurred in 3.2% of patients treated with darolutamide+docetaxel and in 2.0% of patients treated with placebo+docetaxel. Grade 3 and 4 ischaemic heart disease occurred in 1.6% and 1.1% of patients, respectively. Grade 5 (fatal) events occurred in 0.3% of patients treated with darolutamide+docetaxel and 0% of patients treated with placebo+docetaxel. Serious events of ischaemic heart disease were reported in 1.7% of patients treated with darolutamide+docetaxel and 1.1% of patients treated with placebo+docetaxel. The median time to onset of the first ischaemic heart disease event was 11.6 months in patients treated with darolutamide. Discontinuation of darolutamide due to ischaemic heart disease was reported in 0.6% of patients. There were no dose reductions of darolutamide due to ischaemic heart disease.

Neutrophil count decreased

nmCRPC and mHSPC

Neutrophil count decreased was reported as a laboratory abnormality in 17.3% of patients treated with darolutamide and in 7.4% of patients treated with placebo. The median time to nadir was 225 days. The laboratory tests abnormalities manifested predominantly as Grade 1 or 2 intensity. Grade 3 and 4 neutrophil count decreased was reported in 2.6% of patients treated with darolutamide and 0.3% of patients treated with placebo. The median time to first onset of Grade 3 and 4 neutrophil count decreased was 11.3 months in patients treated with darolutamide. Dose reduction of darolutamide due to an adverse event of neutrophil count decreased reported in 0.1% of patients. Only one patient (<0.1%) discontinued darolutamide due to neutropenia. Neutropenia was either transient or reversible (83% of patients) and were not associated with any clinically relevant signs or symptoms.

Blood bilirubin increased

nmCRPC and mHSPC

Bilirubin increased was reported as a laboratory abnormality in 16.1% of patients treated with darolutamide and in 6.1% of patients treated with placebo. The episodes were predominantly of Grade 1 or 2, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. Grade 3 and 4 bilirubin increased was reported in 0.2% of patients treated with darolutamide and in 0% of patients treated with placebo. In patients treated with darolutamide, the mean time to first onset of increased bilirubin was 187 days, and the mean duration of the first episode was 172 days. There were no dose reductions of darolutamide due to the adverse event of increased bilirubin. Discontinuation of darolutamide due to increased bilirubin was reported in <0.1% of patients. Bilirubin levels were either transient or normalized after discontinuation of darolutamide treatment

mHSPC treated in combination with docetaxel

Increased bilirubin was reported as a laboratory abnormality in 19.6% of patients treated with darolutamide+docetaxel and in 10.0% of patients treated with placebo+docetaxel. The episodes were predominantly of Grade 1 or 2. Grade 3 and 4 bilirubin increased was reported as a laboratory abnormality in 0.5% of patients treated with darolutamide+docetaxel and in 0.3% patients treated with placebo+docetaxel. In patients treated with darolutamide+docetaxel, the median time to first onset of any-grade increased bilirubin was 2.9 months and the median time to first onset of Grade 3 and 4 increased bilirubin was 16.5 months. Dose reduction of darolutamide due to an adverse event of bilirubin increased, was reported in 0.3% of patients. No patients discontinued darolutamide due to increase in bilirubin.

ALT and AST increased

nmCRPC and mHSPC

ALT increased was reported as a laboratory abnormality in 13.3% of patients treated with darolutamide and in 9.7% of patients treated with placebo. AST increased was reported as a laboratory abnormality in 22.0% of patients treated with darolutamide and in 13.4% of patients treated with placebo. The episodes were predominantly Grade 1 or 2, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. Grade 3 or 4 ALT increased was reported in 0.9% of patients treated with darolutamide and in 0.3% of patients treated with placebo. Grade 3 or 4 AST increased was reported in 1.2% of patients treated with darolutamide and in 0.3% of patients treated with placebo. In the patients treated with darolutamide, the mean time to first onset of increased ALT was 253 days, and the mean duration of the first episode was 122 days. In the patients treated with darolutamide, the mean time to first onset of increased AST was 257 days, and the mean duration of the first episode was 121 days. The median time to first onset of Grade 3 or 4 ALT increased was 11.2 months. The median time to first onset of Grade 3 or 4 AST increased was 11.1 months. ALT increased was reported as an adverse event in 3.4% of patients treated with darolutamide and in 2.5% of patients treated with placebo. Grade 3 ALT increased was reported as an adverse event in 0.7% and 0.1% of patients, respectively. AST increased was reported as an adverse event in 4% of patients treated with darolutamide and in 2.3% of patients treated with placebo. Grade 3 AST increased was reported as an adverse event in 0.9% and 0.1% of patients, respectively. Dose reduction of darolutamide due to an adverse event of ALT increased was reported in 0.1% of patients. Dose reduction of darolutamide due to an adverse event of AST increased was reported in 0.3% of patients. One patient (<0.1%) discontinued darolutamide due to Grade 4 ALT increased. Two patients (0.1%) discontinued darolutamide due to Grade 3 AST increased.

mHSPC treated in combination with docetaxel

ALT and AST increased were reported as laboratory abnormalities in 42.3% and 43.9% of patients treated with darolutamide+docetaxel and in 38.0% and 39.3% of patients treated with placebo+docetaxel, respectively. The episodes were predominantly of Grade 1 intensity. Grade 3 and 4 ALT and AST increased were reported as laboratory abnormalities in 3.7% and 3.6% of patients treated with darolutamide+docetaxel and in 3.0% and 2.3% of patients treated with placebo+docetaxel, respectively. In the patients treated with darolutamide+docetaxel, the median time to first onset of Grade 3 and 4 ALT and AST increased was 2.3 months and 8.0 months, respectively. ALT and AST increased were reported as adverse events in 15.8% and 14.0% of patients treated with darolutamide+docetaxel and in 12.9% and 10.5% of patients treated with placebo+docetaxel, respectively. Grade 3 and 4 ALT and AST increased were both reported as adverse events in 2.8% of patients treated with darolutamide+docetaxel and in 1.7% and 1.1% of patients treated with placebo+docetaxel, respectively. Dose reductions of darolutamide due to adverse events of ALT and AST increased were reported in 2.8% and 2.5% of patients, respectively. Discontinuation of darolutamide due to adverse events of ALT and AST increased were reported in 0.8% and 0.9% of patients, respectively.

Seizure

nmCRPC and mHSPC

Seizure occurred in 0.2% of patients treated with darolutamide and 0.2% treated with placebo. All events were of Grade 1 and 2 intensity. Seizure occurred 261 and 456 days after initiation of darolutamide. Serious events of seizure were reported only in patients treated with darolutamide, in 0.2% of patients. There were no dose reductions or discontinuations of darolutamide due to seizure.

mHSPC treated in combination with docetaxel

Seizure occurred in 0.6% of patients treated with darolutamide+docetaxel, including 1 Grade 3 event, and 0.2% of patients treated with placebo+docetaxel. Seizure occurred 38 to 340 days after initiation of darolutamide. Serious events of seizure were reported only in patients treated with darolutamide+docetaxel, in 0.2% of patients. There were no dose reductions or discontinuations of darolutamide due to seizure.

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 https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest dose of darolutamide studied clinically was 900 mg twice daily, equivalent to a total daily dose of 1800 mg. No dose limiting toxicities were observed with this dose.

Considering the saturable absorption (see section 5.2) and the absence of evidence for acute toxicity, an intake of a higher than recommended dose of darolutamide is not expected to lead to toxicity.

In the event of intake of a higher than recommended dose, treatment with darolutamide can be continued with the next dose as scheduled.

There is no specific antidote for darolutamide and symptoms of overdose are not established.