1 INDICATIONS AND USAGE
NUBEQA is indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC).
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dose of NUBEQA is 600 mg (two 300 mg film-coated tablets) taken orally, twice daily, equivalent to a
total daily dose of 1200 mg. Swallow tablets whole with food[see Clinical Pharmacology (12.3)].
Patients receiving NUBEQA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or
should have had a bilateral orchiectomy.
Advise patients to take any missed dose as soon as they remember prior to the next scheduled dose, and not to take two
doses together to make up for a missed dose.
2.2 Dosage Modification
If a patient experiences a greater than or equal to Grade 3 toxicity or an intolerable adverse reaction, withhold dosing or
reduce to 300 mg twice daily until symptoms improve. Then the treatment may be resumed at a dose of 600 mg twice
daily.
Dose reduction below 300 mg twice daily is not recommended.
2.3 Recommended Dosage in Patients with Severe Renal Impairment
For patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m2 ) not receiving hemodialysis, the recommended
dose of NUBEQA is 300 mg twice daily[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.4 Recommended Dosage in Patients with Moderate Hepatic Impairment
For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dose of NUBEQA is 300 mg
twice daily[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
Tablets (300 mg): white to off-white oval film-coated tablets marked with “300” on one side and “Bayer” on the other.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
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)].
6 ADVERSE REACTIONS
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.
Reference ID: 4469847 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.
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on NUBEQA
Combined P-gp and Strong or Moderate CYP3A4 Inducer
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.
Reference ID: 4469847Combined P-gp and Strong CYP3A4 Inhibitors
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)].
7.2 Effects of NUBEQA on Other Drugs
Breast Cancer Resistance Protein (BCRP) Substrates
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.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
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.
8.2 Lactation
Risk Summary
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.
8.3 Females and Males of Reproductive Potential
Contraception
Males
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)].
Infertility
Males
Based on animal studies, NUBEQA may impair fertility in males of reproductive potential[see Nonclinical Toxicology
(13.1)].
8.4 Pediatric Use
Safety and effectiveness of NUBEQA in pediatric patients have not been established.
8.5 Geriatric Use
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.
8.6 Renal Impairment
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.
Reference ID: 4469847 8.7 Hepatic Impairment
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.
10 OVERDOSAGE
There is no known specific antidote for darolutamide overdose. 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 and the absence of evidence for acute toxicity, an intake of a higher than
recommended dose of darolutamide is not expected to lead to systemic toxicity in patients with intact hepatic and renal
function[see Clinical Pharmacology (12.3)].
In the event of intake of a higher than recommended dose in patients with severe renal impairment or moderate hepatic
impairment, if there is suspicion of toxicity, interrupt NUBEQA treatment and undertake general supportive measures
until clinical toxicity has been diminished or resolved. If there is no suspicion of toxicity, NUBEQA treatment can be
continued with the next dose as scheduled.
11 DESCRIPTION
NUBEQA is an androgen receptor inhibitor. The chemical name is N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1
yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.
The molecular weight is 398.85 and the molecular formula is C19H19Cl N6O2. The structural formula is:
Darolutamide is an optically active with a specific rotation value [α]20 D= 72.2 o *mL/(dm*g), white to greyish- or
yellowish white crystalline powder, that is soluble in tetrahydrofuran, but practically insoluble in aqueous medium.
Darolutamide has a pKa of 11.75.
NUBEQA (darolutamide) is supplied as film-coated tablets containing 300 mg of darolutamide for oral use. The inactive
ingredients of the tablet are: calcium hydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium
stearate, povidone K 30, hypromellose 15 cP, macrogol 3350, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear
translocation, and AR-mediated transcription. A major metabolite, keto-darolutamide, exhibited similarin vitroactivity to
darolutamide. In addition, darolutamide functioned as a progesterone receptor (PR) antagonistin vitro(approximately 1%
activity compared to AR). Darolutamide decreased prostate cancer cell proliferationin vitroand tumor volume in mouse
xenograft models of prostate cancer.
12.2 Pharmacodynamics
Darolutamide exposure at 600 mg twice daily results in PSA mean reduction of more than 90% from baseline.
Cardiac Electrophysiology
The effect of darolutamide (600 mg twice daily) on the QTc interval was evaluated in a subgroup of 500 patients in the
ARAMIS study. No large mean increase in QTc (i.e., > 20 ms) was detected.
Reference ID: 4469847 12.3 Pharmacokinetics
Following administration of 600 mg twice daily, darolutamide mean (%CV) steady-state peak plasma concentration (Cmax)
is 4.79 mg/L (30.9%) and area under the plasma concentration-time curve from time 0 to 12 hours (AUC12h) is 52.82
h•µg/mL (33.9%). Steady-state is reached 2–5 days after repeated dosing with food, with an approximate 2-fold
accumulation.
The exposure (Cmax and AUC12) of the darolutamide and the active metabolite keto-darolutamide increase in a nearly
dose-proportional manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved recommended dosage). No
further increase in darolutamide exposure was observed at 900 mg twice daily (1.5 times the approved recommended
dosage).
Absorption
Darolutamide Cmax is reached approximately 4 hours after administration of a single 600 mg oral dose.
The absolute bioavailability is approximately 30% following oral administration of a NUBEQA tablet containing 300 mg
darolutamide under fasted conditions.
Food Effect
Bioavailability of darolutamide increased by 2.0 to 2.5-fold when administered with food. A similar increase of exposure
was observed for the active metabolite keto-darolutamide.
Distribution
The apparent volume of distribution of darolutamide after intravenous administration is 119 L.
Protein binding is 92% for darolutamide and 99.8% for the active metabolite, keto-darolutamide. Serum albumin is the
main binding protein for darolutamide and keto-darolutamide.
Elimination
The effective half-life of darolutamide and keto-darolutamide is approximately 20 hours in patients. The clearance (%CV)
of darolutamide following intravenous administration is 116 mL/min (39.7%).
Metabolism
Darolutamide is primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1. Keto-darolutamide total
exposure in plasma is 1.7-fold higher compared to darolutamide.
Excretion
After a single radiolabeled dose as an oral solution, a total of 63.4% of darolutamide-related material is excreted in the
urine (approximately 7% unchanged) and 32.4% (approximately 30% unchanged) in the feces. More than 95% of the dose
was recovered within 7 days after administration.
Specific Populations
In nmCRPC patients, no clinically significant differences in the pharmacokinetics of darolutamide were observed based
on age (48-95 years), race (White, Japanese, non-Japanese Asian, Black or African American), mild to moderate renal
impairment (eGFR 30–89 mL/min/1.73m2 ), or mild hepatic impairment.
In non-cancer subjects with severe renal impairment (eGFR 15–29 mL/min/1.73 m2 ) not receiving dialysis or with
moderate hepatic impairment (Child-Pugh Class B), NUBEQA exposure increased by about 2.5- and 1.9-fold,
respectively, compared to healthy subjects.
The effect of end-stage renal disease (eGFR <15 mL/min/1.73 m2 ) or severe hepatic impairment (Child-Pugh C) on
darolutamide pharmacokinetics has not been studied.
Drug Interaction Studies
Clinical Studies
Combined P-gp and Strong CYP3A4 Inducers
Concomitant use of rifampicin (a combined P-gp and strong CYP3A4 inducer) decreased mean darolutamide AUC0-72 by
72% and Cmaxby 52%.The decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be in the
range of 36% – 58 %.
Reference ID: 4469847Combined P-gp and Strong CYP3A4 Inhibitors
Itraconazole (a strong combined CYP3A4 and P-gp inhibitor) increased mean darolutamide AUC0-72 by 1.7- and Cmax by
1.4-fold.
CYP3A4 substrates
Concomitant use of darolutamide decreased the mean AUC and Cmax of midazolam (CYP3A4 substrate) by 29% and 32%,
respectively. No clinically significant differences in the pharmacokinetics of midazolam were observed when used
concomitantly with darolutamide.
BCRP Substrates
Concomitant use of darolutamide increased the mean AUC and Cmax of rosuvastatin (BCRP substrate) by approximately
5-fold.
P-gp Substrates
No clinically significant differences in the pharmacokinetics of dabigatran (P-gp substrate) were observed when used
concomitantly with darolutamide.
In Vitro Studies
In vitro, darolutamide inhibits OATP1B1 and OATP1B3. Darolutamide did not inhibit the major CYP enzymes
(CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or transporters (MRP2, BSEP, OATs, OCTs, MATEs,
OATP2B1, and NTCP) at clinically relevant concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies to evaluate the carcinogenic potential of darolutamide have not been conducted.
Darolutamide was clastogenic in anin vitrochromosome aberration assay in human peripheral blood lymphocytes.
Darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in thein
vivocombined bone marrow micronucleus assay and the Comet assay in the liver and duodenum of the rat.
Fertility studies in animals have not been conducted with darolutamide. In repeat-dose toxicity studies in male rats (up to
26 weeks) and dogs (up to 39 weeks), tubular dilatation of testes, hypospermia, and atrophy of seminal vesicles, testes,
prostate gland and epididymides were observed at doses ≥ 100 mg/kg/day in rats (0.6 times the human exposure based on
AUC) and ≥ 50 mg/kg/day in dogs (approximately 1 times the human exposure based on AUC).
14 CLINICAL STUDIES
ARAMIS (NCT02200614) was a multicenter, double-blind, placebo-controlled clinical trial in 1509 patients with non
metastatic castration resistant prostate cancer with a prostate-specific antigen doubling time (PSADT) of ≤ 10 months.
Randomization was stratified by PSADT and use of bone-targeted therapy at study entry. Patients with pelvic lymph
nodes less than 2 cm in short axis below the aortic bifurcation were allowed to enter the study. Patients with a history of
seizures were not excluded. Absence or presence of metastasis was assessed by blinded independent central review
(BICR). PSA results were not blinded and were not used for treatment discontinuation.
Patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo
(n=554). Treatment continued until radiographic disease progression as assessed by CT, MRI, 99mTc bone scan by BICR,
unacceptable toxicity or withdrawal. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently
or had a bilateral orchiectomy.
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 (73%) had a Gleason score of 7 or higher at diagnosis. The median PSADT
was 4.5 months. Forty-two percent of patients in both treatment arms had prior surgery or radiotherapy to the prostate.
Eleven percent of patients had enlarged pelvic lymph nodes less than 2 cm at study entry. Six percent of patients were
retrospectively identified by BICR as having metastases at baseline. Seventy-three percent of patients received prior
treatment with an anti-androgen (bicalutamide or flutamide). All patients had an Eastern Cooperative Oncology Group
Performance Status (ECOG PS) score of 0 or 1 at study entry. There were 12 patients enrolled on the NUBEQA arm with
Reference ID: 4469847 a history of seizure. At baseline, 47% of patients reported no pain on the Brief Pain Inventory-Short Form (a 7-day diary
average of the daily worst pain item).
The major efficacy endpoint was metastasis free survival (MFS), defined as the time from randomization to the time of
first evidence of BICR-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan,
whichever occurred first. Distant metastasis was defined as new bone or soft tissue lesions or enlarged lymph nodes above
the aortic bifurcation. Overall survival (OS) and time to pain progression were additional efficacy endpoints.
The efficacy results for MFS from ARAMIS are summarized in Table 3 and Figure 1. Treatment with NUBEQA resulted
in a statistically significant improvement in MFS compared to placebo. MFS results were consistent across patient
subgroups for PSADT (≤ 6 months or > 6 months) or prior use of bone-targeting agents (yes or no). OS data were not
mature at the time of final MFS analysis (57% of the required number of events). Locoregional-only progression occurred
in 6% of patients overall.
The MFS result was supported by a delay in time to pain progression, defined as at least a 2-point worsening from
baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in patients treated with NUBEQA
as compared to placebo. Pain progression was reported in 28% of all patients on study.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
NUBEQA (darolutamide) 300 mg film-coated tablets are white to off-white, oval shaped tablets, marked with “300” on
one side, and “BAYER” on the other side. NUBEQA 300 mg tablets are available in bottles of 120 tablets.
NDC 50419-395-01
16.2 Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled
Room Temperature].
Keep the bottle tightly closed after first opening.
17 PATIENT COUNSELING INFORMATION
Dosage and Administration
Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain
this treatment during the course of treatment with NUBEQA.
Instruct patients to take their dose of two tablets (twice daily). NUBEQA should be taken with food. Each tablet should be
swallowed whole.
Inform patients that in the event of a missed daily dose of NUBEQA, to take any missed dose, as soon as they remember
prior to the next scheduled dose, and not to take two doses together to make up for a missed dose[see Dosage and
Administration (2.1)].
Reference ID: 4469847 Embryo-Fetal Toxicity
Inform patients that NUBEQA can be harmful to a developing fetus and can cause loss of pregnancy[see Use in Specific
Populations (8.1)].
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 Warnings and Precautions (5.1) and Use in Specific Populations (8.1,8.3)].
Infertility
