Consumer medicine information

Nubeqa

Darolutamide

BRAND INFORMATION

Brand name

Nubeqa

Active ingredient

Darolutamide

Schedule

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Nubeqa. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Nubeqa against the benefits your doctor expects it will have for you.

If you have any concerns about taking this medicine, ask your doctor or health care professional.

Keep this leaflet. You may need to read it again.

WHAT NUBEQA IS USED FOR

Nubeqa contains the active substance darolutamide. It is used to treat prostate cancer that has not spread to other parts of the body. Nubeqa belongs to a group of medicines called androgen receptor inhibitors. It works by blocking the activity of male sex hormones called androgens, such as testosterone leading to inhibition of growth and division of prostate cancer cells. By blocking these hormones, darolutamide stops prostate cancer cells from growing and dividing.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

BEFORE YOU TAKE NUBEQA

When you must not take Nubeqa

If you are not sure whether you should take this medicine, talk to your doctor or health care professional.

You must not take Nubeqa if:

you have an allergy to darolutamide (the active ingredient) or any of the ingredients listed at the end of this leaflet
the packaging is torn or shows signs of tampering
the expiry date printed on the pack after “EXP” has passed
You are intending to father a child. Use a highly effective method of contraception during and for 3 months after treatment with Nubeqa to prevent pregnancy.

Nubeqa is not for use in women. Do not take Nubeqa if you are pregnant, are breast-feeding or may be potentially pregnant.

If you are having sex with a pregnant woman you are advised to use a condom during and for 3 months after treatment with Nubeqa to protect the unborn baby.

The safety and efficacy in children and adolescents under 18 years of age have not been studied.

Before you start to take it

This medicine could possibly have an effect on male fertility.

Tell your doctor or health care professional. If you are intending to have children and you have questions about birth control before taking Nubeqa.

If you are not sure whether you should start using this medicine, talk to your Doctor or health care professional.

If you have not told your doctor about any of the above, tell your doctor or health care professional before you take Nubeqa.

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription or even over-the-counter medicines, such as vitamins, dietary supplements or herbal medicines.

The following medicines may influence the effect of Nubeqa, or Nubeqa may influence the effect of these medicines:

rifampicin – typically used to treat bacterial infections
carbamazepine, phenobarbital – typically used to treat epilepsy
St. John's Wort – typically used to treat symptoms of slightly low mood and mild anxiety
rosuvastatin, fluvastatin, atorvastatin – typically used to treat high cholesterol
methotrexate – typically used to treat severe joint inflammation, severe cases of the skin disease psoriasis, and cancers
sulfasalazine – typically used to treat inflammatory bowel disease

The dose of other medicines that you are taking may need to be changed.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket, naturopath or health food shop

HOW TO TAKE NUBEQA

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

The recommended dose is two tablets two times a day. This is also the maximum daily dose.

How to take it

Swallow the tablets whole, take them with food.

Your doctor may also prescribe other medicines while you are taking Nubeqa.

Dose reduction

Your doctor may need to reduce your dose to one tablet two times daily or may decide to interrupt your treatment if necessary.

No dose adjustment is necessary if you have mildly impaired liver function.

No dosage adjustment is necessary if you have mildly or moderately impaired kidney function.

If you forget to take Nubeqa

Take your missed dose as soon as you remember prior to the next scheduled dose. Do not take a double dose to make up for a forgotten tablet.

If you take too much (overdose)

Continue the treatment with the next dose as scheduled.

If you think you or anybody else has taken too much Nubeqa, contact your doctor, pharmacist or the Poisons Information Centre who will advise you what to do.

You can contact the Poisons Information Centre by dialing:

Australia: 13 11 26
New Zealand: 0800 POISON or 0800 764 766.

If you stop taking Nubeqa

Do not stop taking this medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

WHILE YOU ARE TAKING NUBEQA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Nubeqa.

If you are having sex with a woman of childbearing age you are advised to use a highly effective method of contraception during and for 3 months after treatment with Nubeqa to prevent pregnancy.

If you are having sex with a pregnant woman you are advised to use a condom during and for 3 months after treatment with Nubeqa to protect the unborn baby.

Things you must not do

Do not take Nubeqa to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

SIDE EFFECTS

Tell your doctor as soon as possible if you do not feel well while you are taking Nubeqa and ask any questions you may have.

All medicines can have side effects Nubeqa helps most people, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

fatigue (tiredness)
rash
pain in extremity (pain in arms and legs)

Common side effects that may show up in blood tests:

neutrophil count decreased (reduced number of a white blood cell type called neutrophils)
bilirubin increased (high blood levels of bilirubin, a substance produced by the liver)
aspartate transaminase increased (high blood levels of aspartate transaminase, a substance produced by the liver)

Tell your doctor if you notice anything else that is making you feel unwell.

NUBEQA will not affect the ability to drive or use machines.

Other side effects not listed above may also occur in some people.

AFTER TAKING NUBEQA

Storage

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, on each blister pack and on the bottle label after EXP. The expiry date refers to the last day of that month.

Bottle: Once the bottle is opened the medicine is stable for 3 months. Keep the bottle tightly closed after first opening.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

The film-coated tablets are white to off-white, oval with a length of 16 mm and a width of 8 mm. They are marked with “300” on one side, and “BAYER” on the other side.

Ingredients

Active ingredient:

darolutamide

Inactive ingredients:

calcium hydrogen phosphate dihydrate
croscarmellose sodium
hypromellose
lactose monohydrate
macrogol 3350
magnesium stearate
povidone
titanium dioxide

Supplier

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Australian registration number

Blister AUST R 316417

Bottle AUST R 317242

Date of preparation

16 July 2020

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered Trademark of the Bayer Group, Germany.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Nubeqa

Active ingredient

Darolutamide

Schedule

1 Name of Medicine

Darolutamide.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 300 mg of darolutamide.

Excipients with known effect.

Contains sugars as lactose.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off-white, oval, film-coated tablets with a length of 16 mm and a width of 8 mm, marked with "300" on one side, and "BAYER" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Nubeqa is indicated for the treatment of patients with:
non-metastatic castration resistant prostate cancer (nmCRPC);
metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel.

4.2 Dose and Method of Administration

Method of administration.

For oral use.

Dosage regimen.

nmCRPC and mHSPC.

The recommended dose is 600 mg (two film-coated tablets of 300 mg) darolutamide taken twice daily, equivalent to a total daily dose of 1200 mg.
The tablets should be taken whole with food (see Section 5.2 Pharmacokinetic Properties).
Nubeqa should be continued until disease progression or unacceptable toxicity.
Patients receiving Nubeqa should also receive a luteinizing hormone-releasing hormone (LHRH) analog concurrently or should have had bilateral orchiectomy.
If a dose of Nubeqa 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.

mHSPC.

mHSPC patients should start Nubeqa in combination with docetaxel (see Section 5.1 Pharmacodynamic Properties). The first of 6 cycles of docetaxel should be administered within 6 weeks after the start of Nubeqa treatment. The recommended dosage of docetaxel for prostate cancer is 75 mg/m² administered as a one-hour infusion every three weeks. Treatment with Nubeqa should be continued until disease progression or unacceptable toxicity even if a cycle of docetaxel is delayed, interrupted, or discontinued.

Dose modification.

If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction related to Nubeqa, dosing should be withheld or reduced to 300 mg twice daily until symptoms improve (see Section 4.4 Special Warnings and Precautions for Use). Then treatment may be resumed at a dose of 600 mg twice daily.
Dose reduction below 300 mg twice daily is not recommended. The maximum efficacious daily dose is the recommended dose of 600 mg twice daily (see Section 5.2 Pharmacokinetic Properties).

Additional information on special populations.

Paediatric patients.

The safety and efficacy of Nubeqa in children and adolescents below 18 years of age have not been established.

Elderly.

In clinical studies, no clinically relevant differences in safety or efficacy were observed between elderly patients aged 65-74 years, 75-84 years or ≥ 85 years and younger patients (aged < 65 years). No dose adjustment is necessary in elderly patients (also see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

No dose adjustment is necessary for patients with mild hepatic impairment.
The recommended dose for patients with moderate hepatic impairment (Child-Pugh B) is 300 mg twice daily.
The effect of severe hepatic impairment (Child-Pugh C) on darolutamide pharmacokinetics is unknown.

Patients with renal impairment.

No dose adjustment is necessary for patients with mild and moderate renal impairment.
The recommended dose for patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m²) is 300 mg twice daily.
The pharmacokinetics of darolutamide has not been studied in patients with end stage renal disease receiving dialysis (eGFR < 15 mL/min/1.73 m²).

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.

4.4 Special Warnings and Precautions for Use

Cardiovascular.

The safety of darolutamide has not been characterised in patients with recent (within 6 months) cardiovascular events, including uncontrolled hypertension, stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, and NYHA class III or IV congestive heart failure, as these patients were excluded from the pivotal study (ARAMIS).
Ischemic heart disease, including fatal cases, occurred in patients receiving Nubeqa.
In a randomised study of patients with nmCRPC (ARAMIS), ischaemic heart disease occurred in 3.2% of patients receiving Nubeqa and 2.5% receiving placebo, including Grade 3-4 events in 1.7% and 0.4%, respectively. Ischaemic events led to death in 0.3% of patients receiving Nubeqa and 0.2% receiving placebo.
In a randomised study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 2.9% of patients receiving Nubeqa with docetaxel and 2% receiving placebo with docetaxel. This included Grade 3-4 events in 1.3% and 1.1%, respectively. Ischaemic events led to death in 0.3% of patients receiving Nubeqa with docetaxel and 0.1% receiving placebo with docetaxel.
Patients should be monitored for signs and symptoms of ischemic heart disease. Optimise management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidaemia.

Seizure.

Seizure occurred in patients receiving Nubeqa. Patients with a history of seizure were permitted to enrol in the clinical trials. However, all seizure events in patients receiving Nubeqa occurred in patients without prior history of seizure. In clinical trials, none of the patients permanently discontinued therapy due to seizure.
In a randomised study of patients with nmCRPC, seizure (grade 1-2) occurred in 0.2% of patients receiving Nubeqa or placebo. Seizure occurred 261 and 456 days after initiation of Nubeqa.
In a randomised study of patients with mHSPC, seizure occurred in 0.6% of patients receiving Nubeqa + docetaxel, including one grade 3 event, and 0.2% of patients receiving placebo + docetaxel. Seizure occurred 38 to 340 days after initiation of Nubeqa.

Hepatotoxicity.

Cases of idiosyncratic drug induced liver injury (DILI) consisting of Grade ≥ 3 increases in ALT and/or AST, including with concomitant bilirubin ≥ 2x ULN, have been reported with Nubeqa (see Section 4.8 Adverse Effects (Undesirable Effects), Laboratory test abnormalities). Time to onset ranged approximately from 1 month up to 12 months after initiation of Nubeqa. Liver function test abnormalities were reversible upon Nubeqa discontinuation. Monitor ALT and AST as per routine clinical practice. In case of liver function test abnormalities suggestive of idiosyncratic DILI, permanently discontinue Nubeqa.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Additional information on special populations, Patients with renal impairment.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Additional information on special populations, Elderly.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Additional information on special populations, Paediatric patients.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicinal products on darolutamide.

CYP3A4 and P-gp inducers.

Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp).
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 [AUC _(0-72)] and a decrease of 52% in C_max of darolutamide.
Concomitant use of darolutamide with combined strong CYP3A4 inducers and P-gp inducers (e.g. carbamazepine, phenobarbital, St. John's wort) should be avoided (as this decreases darolutamide exposure) 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.

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 Pharmacodynamic Properties, Clinical trials).

CYP3A4, P-gp and BCRP inhibitors.

Darolutamide is a substrate of CYP3A4, P-gp and breast cancer resistance protein (BCRP).
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 [AUC _(0-72)] and a 1.4-fold increase of C_max of darolutamide.
Consider alternative therapies that do not strongly inhibit CYP3A4 and/or P-gp activity and thus may increase darolutamide exposure. In situations where satisfactory therapeutic alternatives do not exist, patients should be closely monitored for darolutamide related adverse events.

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.
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 C_max of rosuvastatin.
This indicates that co-administration of Nubeqa may increase the plasma concentrations of other concomitant BCRP, OATP1B1, or OATP1B3 substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin).
Avoid concomitant use with BCRP substrates where possible.
If used together, the related monitoring advice and recommendations in the product information of the BCRP, OATP1B1, or OATP1B3 substrates should be followed.

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 Pharmacodynamic Properties, Clinical trials).

P-gp substrates.

Co-administration of darolutamide together with the sensitive P-gp substrate dabigatran etexilate did not reveal any increase in exposure (AUC and C_max) of dabigatran.
This indicates that Nubeqa may be given concomitantly with P-gp substrates without a clinically relevant drug-drug interaction.

CYP substrates.

Darolutamide is a weak inducer of CYP3A4. 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 C_max of midazolam by 29% and 32%, respectively.
Darolutamide did not inhibit the metabolism of selected CYP substrates in vitro at clinically relevant concentrations.
This indicates that Nubeqa may be given concomitantly with CYP substrates (e.g. warfarin, L-thyroxine, omeprazole) without a clinically relevant drug-drug interaction.

Substrates for other transporters.

In vitro data indicate darolutamide administration may inhibit OAT3, MATE1, MATE2K and intestinal MRP2. Darolutamide did not inhibit the transporters, BSEP, OAT1, OCTs, OATP2B1 and NTCP at clinically relevant concentrations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of Nubeqa on fertility.
In repeated dose toxicity studies in rats and dogs, atrophy and hypospermia in the male reproductive system were observed, which is consistent with the pharmacological activity of darolutamide.
(Category D)

Pregnancy and breast-feeding.

Nubeqa is contraindicated in women who are or may become pregnant. Based on its mechanism of action, Nubeqa may cause foetal harm when administered during pregnancy. There are no data available with the use of Nubeqa during pregnancy in humans. It is not known whether darolutamide or its metabolites are present in semen. 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. Patients having sex with pregnant women should use a condom during and for three months after the last dose of Nubeqa.

Women of childbearing potential/contraception in males and females.

Nubeqa may be harmful to a developing foetus. Patients having sex with female partners of reproductive potential should use a condom along with another highly effective contraceptive method during treatment and for three months after the last dose of Nubeqa.
Nubeqa is not indicated in women. Nubeqa is not to be used in women who are, or may be, pregnant or breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

There is no evidence that Nubeqa will affect the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

Summary of the safety profile.

nmCRPC (ARAMIS).

The safety profile of Nubeqa in nmCRPC is based on data from 1508 patients of whom 954 received at least one dose of Nubeqa in the ARAMIS study.
The most frequently observed adverse drug reaction (≥ 10%) in patients with nmCRPC receiving Nubeqa is fatigue.
Serious adverse events occurred in 25% of patients receiving Nubeqa and in 20% of patients receiving placebo. 3.9% of patients receiving Nubeqa and 3.2% of patients receiving placebo died from adverse events, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for Nubeqa.
Permanent discontinuation due to adverse events occurred in 9% of patients receiving Nubeqa or placebo. The most frequent adverse events requiring permanent discontinuation in patients who received Nubeqa included cardiac failure (0.4%), and death (0.4%).
Dosage interruptions due to adverse events occurred in 13% of patients treated with Nubeqa. The most frequent adverse events requiring dosage interruption in patients who received Nubeqa included hypertension (0.6%), diarrhoea (0.5%), and pneumonia (0.5%).
Dosage reductions due to adverse events occurred in 6% of patients treated with Nubeqa. The most frequent adverse events requiring dosage reduction in patients treated with Nubeqa included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%).

mHSPC (ARASENS).

The safety profile of Nubeqa in mHSPC is based on data from 1302 patients of whom 652 received at least one dose of Nubeqa in the ARASENS study.
The most frequently observed adverse drug reaction (≥ 10%) in patients with mHSPC receiving Nubeqa in combination with docetaxel were constipation (23%), decreased appetite (19%), rash (19%) and hypertension (14%).
The most frequently observed adverse events (≥ 20%) in patients receiving Nubeqa + docetaxel were alopecia (40.5%), fatigue (33.1%), anaemia (27.8%), arthralgia (27.3%), oedema peripheral (26.5%), neutrophil count decreased (26.1%), diarrhoea (25.6%), white blood cell count decreased (23.8%), and constipation (22.5%). Serious adverse events occurred in 44.8% of patients receiving Nubeqa + docetaxel and in 42.3% of patients receiving placebo + docetaxel. Serious adverse events in ≥ 2% of patients who received Nubeqa + docetaxel included febrile neutropenia (6.1%), neutrophil count decreased (2.8%), and pneumonia (2.5%). Overall, 4.1% of patients receiving Nubeqa + docetaxel and 4.0% receiving placebo + docetaxel died from adverse events. Deaths reported in ≥ 2 patients in the Nubeqa + docetaxel arm included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%).
Permanent discontinuation of study drug due to adverse events occurred in 13.5% of patients who received Nubeqa + docetaxel and 10.6% of patients who received placebo + docetaxel. The most frequent adverse events requiring discontinuation in patients who received Nubeqa + docetaxel included rash (1.1%), aspartate aminotransferase (AST) increased (0.9%), and alanine aminotransferase (ALT) increased (0.8%).
Dose interruption of study drug due to adverse events occurred in 22.9% of patients treated with Nubeqa + docetaxel and in 15.7% of patients who received placebo + docetaxel. The most frequent adverse events requiring dosage interruption in patients who received Nubeqa + docetaxel included ALT increased (3.2%), AST increased (3.1%), and febrile neutropenia (2.1%).
Dose reductions of study drug due to adverse events occurred in 8.7% of patients treated with Nubeqa + docetaxel and in 4.3% of patients who received placebo + docetaxel. The most frequent adverse events requiring dosage reduction in patients treated with Nubeqa + docetaxel included ALT increased (2.8%), and AST increased (2.5%).

Tabulated list of adverse reactions.

The adverse drug reactions observed in patients with nmCRPC treated with Nubeqa are listed in Table 1, Table 2, and Table 4. The adverse drug reactions observed in patients with mHSPC treated with Nubeqa in combination with docetaxel are listed in Table 3 and Table 5.
They are classified according to System Organ Class (MedDRA). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Adverse drug 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.
Within each frequency group, adverse drug reactions are presented in order of decreasing seriousness.

nmCRPC (ARAMIS).

See Tables 1 and 2.

Cardiovascular.

Ischaemic heart disease occurred in 3.2% of patients treated with Nubeqa and in 2.5% of patients treated with placebo. Grade 3 or 4 reactions occurred in 1.7% of patients treated with Nubeqa and 0.4% of patients treated with placebo. Heart failure occurred in 1.9% of patients treated with Nubeqa and in 0.9% of patients treated with placebo. Grade 3 or 4 reactions occurred only in the Nubeqa arm in 0.5% of patients.

mHSPC (ARASENS).

See Table 3.

Laboratory test abnormalities.

Liver function tests.

Cases of idiosyncratic drug-induced liver injury with increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) to ≥ 5x and ≥ 20x upper limit of normal (ULN), including with concomitant bilirubin elevation ≥ 2x ULN, have been reported in patients treated with Nubeqa (see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).

nmCRPC (ARAMIS).

See Table 4.

mHSPC (ARASENS).

See Table 5.

4.9 Overdose

For general advice on overdose management, contact the Poisons Information Centre, telephone number 13 11 26 (Australia) or the National Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).
The highest dose of Nubeqa 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 Pharmacokinetic Properties) 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, Nubeqa treatment can be continued with the next dose as scheduled.
There is no specific antidote for Nubeqa and symptoms of overdose are not established.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anti-androgens ATC code: L02BB06.

Mechanism of action.

Darolutamide is a non-steroidal androgen receptor antagonist with a flexible polar-substituted pyrazole structure that binds with nanomolar affinity directly to the receptor ligand binding domain to retain antagonistic activity against the androgen receptor (AR).
Darolutamide competitively inhibits androgen binding, androgen receptor nuclear translocation and AR mediated transcription.
Darolutamide had significant in vivo anti-tumour efficacy (decreased tumour cell proliferation) leading to decreased tumour volume in xenograft models of prostate cancer implemented in mice, including the castration-resistant model VCaP which overexpresses the AR.

Pharmacodynamic effects.

Patients receiving darolutamide in the ARAMIS study demonstrated a significantly higher confirmed PSA response rate (defined as a ≥ 50% reduction from baseline), compared with patients receiving placebo, 84% versus 7.9% (difference = 76.1%, p < 0.000001).
Patients receiving darolutamide + docetaxel in the ARASENS study had a significantly higher PSA response rate (defined as a ≥ 50% reduction from baseline) at 12 months after randomisation compared with patients receiving placebo + docetaxel, 89.6% versus 80.4% (difference = 9.2, p < 0.0001).
No prolongation of the mean QTcF interval (i.e. greater than 10 ms) was observed after oral administration of 600 mg darolutamide twice daily compared to placebo in a subgroup of 500 patients in the phase III study (ARAMIS).

Clinical trials.

Non-metastatic castration resistant prostate cancer (nmCRPC).

The efficacy and safety of Nubeqa was assessed in a randomised, double-blind, placebo-controlled multicentre phase III study (ARAMIS) in patients with non-metastatic castration resistant prostate cancer with a prostate-specific antigen doubling time (PSADT) of ≤ 10 months. In total, 1509 patients were randomised 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554).
Patients with presence of pelvic lymph nodes < 2 cm in short axis below the aortic bifurcation were allowed to enter the study. Absence or presence of metastasis was assessed by independent central radiological review. Included in these analyses were 89 patients that were retrospectively identified with metastasis at baseline. Randomisation was stratified by PSADT (≤ 6 months or > 6 months) and use of osteoclast-targeted therapy at study entry (yes or no).
The following patient demographics and disease characteristics were balanced between treatment arms. The median age was 74 years (range 48-95) and 9% of patients were 85 years of age or older. The racial distribution was 79% White, 13% Asian, and 3% Black. A majority of patients had a Gleason score of 7 or higher at diagnosis (73%). The median PSADT was 4.5 months. Nine percent (9%) of patients had prior orchiectomy, 25% of patients had prior prostatectomy and 50% of patients had at least one prior radiotherapy. Seventy-six percent (76%) of patients received more than one prior antihormonal treatment. Most patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 (69%) at study entry. Patients with a medical history of seizure were allowed to enter the study, and 12 patients (0.21%) were enrolled in the darolutamide arm.
Treatment with Nubeqa continued until radiographic disease progression as assessed by conventional imaging (CT, MRI, Tc99m bone scan) by blinded central review, unacceptable toxicity, or withdrawal.
The primary efficacy endpoint was metastasis free survival (MFS). Secondary endpoints were overall survival (OS), time to pain progression, time to initiation of first cytotoxic chemotherapy for prostate cancer, and time to first symptomatic skeletal events (defined as occurrence of any of the following: external beam radiotherapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, spinal cord compression, or tumour-related orthopaedic surgical intervention).
Treatment with Nubeqa resulted in a statistically significant improvement in MFS compared to placebo with a p-value of < 0.000001 and a hazard ratio (HR) of 0.413 (see Table 6 and Figure 1).
MFS results were consistent across patient subgroups regardless of PSADT, prior use of bone-targeting agents or loco-regional disease. Additional subgroups with consistent MFS results included PSA at baseline, Gleason score at diagnosis, age, geographical region, ECOG PS at baseline, race, and number of prior hormonal therapies.
After the primary analysis of MFS, patients receiving placebo were offered treatment with open-label Nubeqa (cross-over option) once the study was unblinded. Among the 554 patients randomised to placebo, 170 (31%) crossed over to receive Nubeqa treatment. The OS analysis was not adjusted for confounding effects of cross-over.
At the time of the final analysis, treatment with Nubeqa resulted in a statistically significant improvement in overall survival compared to placebo (HR = 0.685, p = 0.003048, median was not reached in either arm, see Table 6 and Figure 2.
Treatment with Nubeqa also resulted in statistically significant delays in time to pain progression (HR = 0.647, p = 0.000008), time to initiation of first cytotoxic chemotherapy (HR = 0.579, p = 0.000044) and time to first symptomatic skeletal event (HR = 0.484, p = 0.005294) compared to placebo, see Table 6.
All analyses were performed in the full analysis set.

Metastatic hormone sensitive prostate cancer (mHSPC).

The efficacy and safety of Nubeqa in combination with docetaxel was assessed in a multicentre, double-blind, placebo-controlled phase III study (ARASENS) in patients with mHSPC. In total, 1306 patients were randomised (1:1) to receive 600 mg darolutamide orally twice daily (n = 651) or matching placebo (n = 655), concomitantly with 75 mg/m² of docetaxel, for 6 cycles. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral orchiectomy. Patients should receive ADT (LHRH agonist/ antagonists or orchiectomy) as standard therapy started ≤ 12 weeks before Nubeqa and docetaxel (if combined with a first-generation anti-androgen, such as bicalutamide, flutamide, nilutamide, or cyproterone acetate, it must be stopped before treatment). For those receiving LHRH agonists, treatment in combination with a first-generation anti-androgen for at least 4 weeks prior to commencing Nubeqa and docetaxel was recommended.
Treatment with Nubeqa or placebo continued until symptomatic progressive disease, change of antineoplastic therapy, unacceptable toxicity, death, or withdrawal.
Presence of metastasis was assessed by independent central radiological review. Patients with regional lymph node involvement only (M0) were excluded from the study. Randomisation was stratified by extent of disease (non-regional lymph nodes metastases only (M1a), bone metastases with or without lymph node metastases (M1b) or visceral metastases with or without lymph node metastases or with or without bone metastases (M1c)) and by alkaline phosphatase level (< or ≥ upper limit of normal) at study entry.
The following patient demographics and disease characteristics were balanced between treatment arms. The median age was 67 years (range 41-89) and 17% of patients were 75 years of age or older. The racial distribution was 52% White, 36% Asian, and 4% Black. A majority of patients had a Gleason score of 8 or higher at diagnosis (78%). Seventy-one percent (71%) of patients had an ECOG PS score of 0 and 29% of patients had an ECOG PS score of 1. There were 86.1% of patients with de novo and 12.9% with recurrent disease. At study entry, 3% of patients had M1a, 79.5% had M1b and 17.5% had M1c; alkaline phosphatase was < ULN in 44.5% of patients and ≥ ULN in 55.5% of patients; median PSA level at baseline was 30.3 microgram/L and 24.2 microgram/L for Nubeqa vs placebo group, respectively. Patients with a medical history of seizure were allowed to enter the study, and 4 patients (0.6%) were enrolled in the Nubeqa + docetaxel arm and 2 patients (0.3%) in the placebo + docetaxel arm.
The primary efficacy endpoint was overall survival (OS). Secondary endpoints evaluated in hierarchical order were time to castration-resistant prostate cancer, time to pain progression, symptomatic skeletal event free survival (SSE-FS), time to first symptomatic skeletal event (SSE), time to initiation of subsequent antineoplastic therapy, time to worsening of disease-related physical symptoms, and time to initiation of opioid use for ≥ 7 consecutive days.
A statistically significant improvement in OS with a 32.5% reduction in risk of death (HR = 0.675, p < 0.0001) was observed in the Nubeqa + docetaxel arm compared to the placebo + docetaxel arm (see Table 7 and Figure 3). OS results were consistent across all patient subgroups, including stratification subgroups (extent of disease and alkaline phosphatase level).
The following secondary efficacy endpoints showed a statistically significant advantage in favour of Nubeqa + docetaxel: time to castration-resistant prostate cancer (HR = 0.357, p < 0.0001), time to pain progression (HR = 0.792, p = 0.0058), symptomatic skeletal event free survival (HR=0.609, p < 0.0001), time to first symptomatic skeletal event (HR = 0.712, p = 0.0081), and time to initiation of subsequent antineoplastic chemotherapy (HR = 0.388, p < 0.0001), see Table 7.
For the time to castration-resistant prostate cancer endpoint, although PSA progression represented the majority of events in both treatment arms, the proportion of radiological progression events in the absence of PSA progression was higher in the darolutamide + docetaxel arm.

5.2 Pharmacokinetic Properties

Darolutamide consists of two diastereomers [(S,R) darolutamide and (S,S) darolutamide] which interconvert via the main circulating metabolite called keto-darolutamide. In vitro, all three substances show similar pharmacological activity. Darolutamide is poorly soluble in aqueous solvents over a large pH range and generally more soluble in organic solvents.

Absorption.

Following oral administration of 600 mg (2 tablets of 300 mg), peak plasma concentrations of darolutamide of 4.79 mg/L (coefficient of variation: 30.9%) are usually reached around 4 hours after administration. The ratio of the two diastereomers, (S,R) darolutamide to (S,S) darolutamide, changed from a 1:1 ratio in the tablet to an approximately 1:9 ratio in plasma based on AUC_(0-12) data at steady-state. Following oral administration together with food, steady-state is reached after 2-5 days of repeated twice-daily dosing.
The absolute bioavailability compared to an intravenous injection is approximately 30% following oral administration of a Nubeqa tablet containing 300 mg darolutamide under fasted conditions. Bioavailability of darolutamide was enhanced by 2.0- to 2.5-fold when administered with food. A similar increase of exposure was observed for the major metabolite keto-darolutamide.

Distribution.

The apparent volume of distribution of darolutamide after intravenous administration is 119 L indicating that darolutamide is widely distributed throughout the body to both intracellular and extracellular fluid spaces.
Darolutamide is moderately (92%) bound to human plasma proteins without any difference between the two diastereomers. The major metabolite of darolutamide, keto-darolutamide, is highly (99.8%) bound to plasma proteins.
Passage of darolutamide across the blood-brain barrier has not been studied clinically. However, brain exposures to darolutamide in terms of AUC_(0-24) are very low with 4.5% of plasma exposure after single dose in rats and 2-4% after repeated dose in mice. This indicates low passage of darolutamide across the intact blood-brain barrier in rats and mice and a low likelihood that darolutamide crosses the intact blood-brain barrier in humans to a clinically relevant extent.

Metabolism.

The diastereomers (S,R) darolutamide and (S,S) darolutamide are able to interconvert via the metabolite keto-darolutamide with a preference for (S,S) darolutamide.
Following single oral administration of 300 mg ¹⁴C-darolutamide given as an oral solution, keto-darolutamide is the only major metabolite with about 2-fold higher total exposure in plasma compared to darolutamide. Darolutamide and keto-darolutamide accounted together for 87.4% of the ¹⁴C-radioactivity in plasma indicating that all other metabolites are of minor importance.
Darolutamide is metabolized primarily by oxidative metabolism mediated mainly by CYP3A4, as well as by direct glucuronidation mediated preferentially by UGT1A9 and UGT1A1. In addition, mainly the AKR1C3 to a lesser extent AKR1C1 and AKR1D1 aldo-keto reductase isoforms were shown to catalyse the reduction of keto-darolutamide to primarily the S,S-diastereomer.

Excretion.

The effective half-life of darolutamide and keto-darolutamide in plasma of patients is approximately 20 hours. Of the two diastereomers comprising darolutamide, (S,R) darolutamide has a shorter effective half-life of 9 hours compared to (S,S) darolutamide with an effective half-life of 22 hours.
The clearance of darolutamide following intravenous administration was 116 mL/min (CV: 39.7%). A total of 63.4% of drug related material is excreted in the urine (approximately 7% unchanged), 32.4% is excreted in the faeces. More than 95% of the dose was recovered within 7 days after administration.
In the dose range of 100 to 700 mg (after single dose and at steady state), the exposure to the two diastereomers and the major metabolite keto-darolutamide increases linearly in a nearly dose-related manner. Based on a saturated absorption, no further increase in exposure to darolutamide was observed at 900 mg twice daily.