NUBEQA

/ Bayer

Treatment should be initiated and supervised by a specialist physician experienced in treatment of prostate cancer.
The recommended dose is 600 mg darolutamide (two tablets of 300 mg) taken twice daily, equivalent to a total daily dose of 1200 mg. 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)
mHSPC patients should start darolutamide in combination with docetaxel 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 unaccepatble 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, 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.

* Non-metastatic castration resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease in combination with ADT treatment
* Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel

Hypersensitivity to the active substance or to any of the excipients.

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.
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.
Hepatic transaminase elevations
In case of hepatic transaminase elevations suggestive of idiosyncratic drug-induced liver injury related to darolutamide, permanently discontinue treatment with darolutamide.
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.
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.
Androgen deprivation therapy 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 this medical product.
See prescribing information for full details

The most frequently observed adverse reactions in patients with
– nmCRPC receiving darolutamide are fatigue/asthenic conditions (15.8%).
– mHSPC receiving darolutamide in combination with docetaxel are rash (16.6%) and hypertension (13.8%).
Adverse reactions reported in patients with nmCRPC
Very common: Fatigue/asthenic conditions, Neutrophil count decreased Blood bilirubin increased AST increased.
Common: Ischemic heart disease, Heart failure, Rash, Pain in extremity musculoskeletal pain Fractures.
Adverse reactions reported in mHSPC patients treated with darolutamide in combination with docetaxel
Very common: Hypertension, Rash, Neutrophil count decreased Blood bilirubin increased
ALT increased AST increased
Common: Fractures, Gynaecomastia
See prescribing information for full details

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.
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.
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.
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.
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).
See prescribing information for full details

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 darolutamide to prevent pregnancy.
Pregnancy: Based on its mechanism of action, darolutamide may cause foetal harm. No non-clinical reproductive toxicity studies have been conducted. 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.
Lactation: It is unknown whether darolutamide or its metabolites are excreted in human milk.
See prescribing information for full details.

Considering the saturable absorption 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