Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bayer AG, 51368, Leverkusen, Germany
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).
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).
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).
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.
In case of liver function test abnormalities suggestive of idiosyncratic drug-induced liver injury, permanently discontinue treatment with darolutamide (see section 4.8).
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).
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.
NUBEQA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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.
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.
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.
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).
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.
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.
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.
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).
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).
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).
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.
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.
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.
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).
NUBEQA has no or negligible influence on the ability to drive and use machines.
The most frequently observed adverse reactions in patients with
For additional safety information when darolutamide is administered in combination, refer to the product information of the individual medicinal products.
The adverse reactions observed in patients with nmCRPC 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.
Adverse reactions are classified according to System Organ Class. They 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 the ARAMIS studya:
| System organ class (MedDRA) | Very common | Common |
|---|---|---|
| Cardiac disorders | Ischaemic heart diseaseb Heart failurec | |
| Skin and subcutaneous tissue disorders | Rashd | |
| Musculoskeletal and connective tissue disorders | Pain in extremity Musculoskeletal pain Fractures | |
| General disorders and administration site conditions | Fatigue/asthenic conditionse | |
| Investigationsf | Neutrophil count decreased Blood bilirubin increased AST increased |
a The median duration of exposure was 14.8 months (range: 0.0 to 44.3 months) in patients treated with darolutamide and 11.0 months (range: 0.1 to 40.5 months) in patients treated with placebo.
b 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.
c Includes cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiogenic shock.
d Includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, dermatitis.
e Includes fatigue and asthenia, lethargy and malaise.
f Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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 studya,b:
| System organ class (MedDRA) | Very common | Common |
|---|---|---|
| Vascular disorders | Hypertensionc | |
| Skin and subcutaneous tissue disorders | Rashd,e | |
| Musculoskeletal and connective tissue disorders | Fractures | |
| Reproductive system and breast disorders | Gynaecomastia | |
| Investigationsf | Neutrophil count decreased Blood bilirubin increased ALT increased AST increased |
a The median duration of exposure was 41.0 months (range: 0.1 to 56.5 months) in patients treated with darolutamide+docetaxel and 16.7 months (range: 0.3 to 55.8 months) in patients treated with placebo+docetaxel.
b Adverse reactions incidences may not be attributable to darolutamide alone but may contain contributions from other medicinal products used in combination.
c Includes hypertension, blood pressure increased, hypertensive emergency.
d Includes rash, drug eruption, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, erythema, dermatitis.
e The incidence was highest during the first 6 months of treatment.
f Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The incidence is based on values reported as laboratory abnormalities.
Cases of idiosyncratic drug-induced liver injury with grade 3 and 4 increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) to ≥5 and ≥20 x upper limit of normal (ULN) have been reported with darolutamide treatment including increased transaminases along with a simultaneous increase in total bilirubin to ≥2 x ULN. Time to onset ranged from 1 month to 12 months after initiation of darolutamide. In many cases the ALT and AST elevations were reversible upon darolutamide discontinuation. For specific recommendations, see section 4.4.
Fatigue/asthenic conditions were reported in 15.8% of patients treated with darolutamide and in 11.4% of patients treated with placebo. Events with worst grade of 3 were reported in 0.6% of patients treated with darolutamide and in 1.1% of patients treated with placebo. Fatigue (not including asthenia, lethargy or malaise) occurred in the majority of patients (12.1% of patients treated with darolutamide and 8.7% of patients treated with placebo).
Fractures occurred in 4.2% of patients treated with darolutamide and in 3.6% of patients treated with placebo.
Ischaemic heart disease occurred in 3.2% of patients treated with darolutamide and in 2.5% of patients treated with placebo. Grade 5 events occurred in 0.3% of patients treated with darolutamide and 0.2% of patients treated with placebo. Heart failure occurred in 1.9% of patients treated with darolutamide and in 0.9% of patients treated with placebo.
Neutrophil count decreased was reported as a laboratory abnormality in 19.6% of patients treated with darolutamide and in 9.4% of patients treated with placebo. The median time to nadir was 256 days. The laboratory tests abnormalities manifested predominantly as grade 1 or 2 intensity. Neutrophil count decreased of grade 3 and 4 was reported in 3.5% and 0.5% of patients, respectively. Only one patient permanently discontinued darolutamide due to neutropenia. Neutropenia was either transient or reversible (88% of patients) and were not associated with any clinically relevant signs or symptoms.
Bilirubin increased was reported as a laboratory abnormality in 16.4% of patients treated with darolutamide and in 6.9% of patients treated with placebo. The episodes were predominantly of grade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. Bilirubin increased of grade 3 was reported in 0.1% of patients treated with darolutamide and in 0% of patients treated with placebo. In the darolutamide arm, the mean time to first onset of increased bilirubin was 153 days, and the mean duration of the first episode was 182 days. No patients were discontinued from treatment due to increase in bilirubin.
AST increased was reported as a laboratory abnormality in 22.5% of patients treated with darolutamide and in 13.6% of patients treated with placebo. The episodes were predominantly of grade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. AST increased of grade 3 was reported in 0.5% of patients treated with darolutamide and in 0.2% of patients treated with placebo. In the darolutamide arm, the mean time to first onset of increased AST was 258 days, and the mean duration of the first episode was 118 days. No patients were discontinued from treatment due to increase in AST.
In the ARASENS study hypertension was reported in 13.8% of patients treated with darolutamide+docetaxel and 9.4% of patients treated with placebo+docetaxel.
Grade 3 hypertension was reported in 6.4% of patients treated with darolutamide+docetaxel compared to 3.5% of patients treated with placebo+docetaxel. One patient had grade 4 hypertension in each treatment arm.
One case was reported as grade 5 hypertension with grade 5 arteriosclerosis in the darolutamide+docetaxel arm. This patient had a long-standing history of hypertension and smoking and the case occurred more than 3 years after starting darolutamide treatment. Events of hypertension were reported more commonly in patients with no medical history of hypertension in both treatment arms.
Fractures occurred in 7.5% of patients treated with darolutamide+docetaxel and in 5.1% of patients treated with placebo+docetaxel.
Neutrophil count decreased was reported as a laboratory abnormality in 50.6% of patients treated with darolutamide+docetaxel and in 45.5% of patients treated with placebo+docetaxel. Grade 3 and 4 neutrophil count decreased was reported in 34.4% of patients treated with darolutamide+docetaxel and in 31.4% of patients treated with placebo+docetaxel. In both treatment arms, the incidences of neutrophil count decreased and neutropenia were highest during the first months of treatment, after which the incidence and severity of the events decreased.
Bilirubin increased 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 events were predominantly of grade 1 or 2 intensity. Grade 3 and 4 bilirubin increased was reported in 0.5% of patients treated with darolutamide+docetaxel and in 0.3% of patients treated with placebo+docetaxel.
Alanine aminotransferase (ALT) increased was reported as a laboratory abnormality in 42.3% of patients treated with darolutamide+docetaxel and in 38.0% of patients treated with placebo+docetaxel. Aspartate aminotransferase (AST) increased was reported as a laboratory abnormality in 43.9% of patients treated with darolutamide+docetaxel and in 39.3% of patients treated with placebo+docetaxel. ALT and AST elevations were predominantly of grade 1 intensity. Grade 3 and 4 ALT increased was reported in 3.7% of patients treated with darolutamide+docetaxel and in 3.0% of patients treated with placebo+docetaxel. Grade 3 and 4 AST increased was reported in 3.6% of patients treated with darolutamide+docetaxel and in 2.3% of patients treated with placebo+docetaxel.
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 national reporting system listed in Appendix V.
Not applicable.
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