Source: FDA, National Drug Code (US) Revision Year: 2019
None.
The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1)].
Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of NUBEQA [see Use in Specific Populations (8.1, 8.3)].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ARAMIS, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had non-metastatic, castration-resistant prostate cancer (nmCRPC). In this study, patients received either NUBEQA at a dose of 600 mg, or a placebo, twice a day. All patients in the ARAMIS study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 14.8 months (range: 0 to 44.3 months) in patients who received NUBEQA.
Overall, serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia and hematuria. Overall 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, 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 reactions occurred in 9% of patients receiving NUBEQA or placebo. The most frequent adverse reactions requiring permanent discontinuation in patients who received NUBEQA included cardiac failure (0.4%), and death (0.4%).
Dosage interruptions due to adverse reactions occurred in 13% of patients treated with NUBEQA. The most frequent adverse reactions requiring dosage interruption in patients who received NUBEQA included hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%).
Dosage reductions due to adverse reactions occurred in 6% of patients treated with NUBEQA. The most frequent adverse reactions requiring dosage reduction in patients treated with NUBEQA included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%).
Table 1 shows adverse reactions in ARAMIS reported in the NUBEQA arm with a ≥2% absolute increase in frequency compared to placebo. Table 2 shows laboratory test abnormalities related to NUBEQA treatment and reported more frequently in NUBEQA-treated patients compared to placebo-treated patients in the ARAMIS study.
Table 1. Adverse Reactions in ARAMIS:
| Adverse Reaction* | NUBEQA (n=954) | Placebo (n=554) | ||
|---|---|---|---|---|
| All Grades % | Grades ≥3 % | All Grades % | Grade ≥3 % | |
| Fatigue† | 16 | 0.6 | 11 | 1.1 |
| Pain in extremity | 6 | 0 | 3 | 0.2 |
| Rash | 3 | 0.1 | 1 | 0 |
* Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
† Includes fatigue and asthenia
Additionally, clinically significant adverse reactions occurring in 2% or more of patients treated with NUBEQA included ischemic heart disease (4.0% versus 3.4% on placebo) and heart failure (2.1% versus 0.9% on placebo).
Table 2. Laboratory Test Abnormalities in ARAMIS:
| Laboratory Abnormality | NUBEQA (N=954)* | Placebo (N=554)* | ||
|---|---|---|---|---|
| All Grades† % | Grade 3-4† % | All Grades† % | Grade 3-4† % | |
| Neutrophil count decreased | 20 | 4 | 9 | 0.6 |
| AST increased | 23 | 0.5 | 14 | 0.2 |
| Bilirubin increased | 16 | 0.1 | 7 | 0 |
* The denominator used to calculate the rate varied based on the number of patients with a baseline value and at least one post-treatment value.
† Common Terminology Criteria for Adverse Events (CTCAE) version 4 .03.
Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide exposure which may decrease NUBEQA activity [see Clinical Pharmacology (12.3)]. Avoid concomitant use of NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers.
Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure [see Clinical Pharmacology (12.3)] which may increase the risk of NUBEQA adverse reactions. Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed [see Dosage and Administration (2.2)].
NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and Cmax of BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of BCRP substrate-related toxicities.
Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug. Consult the approved product labeling of the BCRP substrate when used concomitantly with NUBEQA.
The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy [see Clinical Pharmacology (12.1)]. Animal embryo-fetal developmental toxicology studies were not conducted with darolutamide. There are no human data on the use of NUBEQA in pregnant females.
The safety and efficacy of NUBEQA have not been established in females. There are no data on the presence of darolutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production.
Based on the mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of NUBEQA [see Use in Specific Populations (8.1)].
Based on animal studies, NUBEQA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].
Safety and effectiveness of NUBEQA in pediatric patients have not been established.
Of the 954 patients who received NUBEQA in ARAMIS, 88% of patients were 65 years and over, and 49% were 75 years and over. No overall differences in safety or efficacy were observed between these patients and younger patients.
Patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m² who are not receiving hemodialysis have a higher exposure to NUBEQA and reduction of the dose is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. No dose reduction is needed for patients with mild or moderate renal impairment (eGFR 30-89 mL/min/1.73 m²). The effect of end stage renal disease (eGFR ≤15 mL/min/1.73 m² on darolutamide pharmacokinetics is unknown.
Patients with moderate hepatic impairment (Child-Pugh Class B) have a higher exposure to NUBEQA and reduction of the dose is recommended [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. No dose reduction is needed for patients with mild hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on darolutamide pharmacokinetics is unknown.
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