Darolutamide

L02B - Hormone antagonists and related agents ATC L02BB06 Small molecule approved 2019 Oral Natural product

JFDA label: Nubeqa film coated tablets

Mechanism of Action

Antagonist of Androgen receptor — Androgen Receptor antagonist

Target	Action	Gene / class
Androgen receptor efficacy	ANTAGONIST	AR

Indications

Approved

Neoplasms — neoplasm
Prostatic Neoplasms — prostate carcinoma
Prostatic Neoplasms, Castration-Resistant — prostate cancer

Off-label

Breast Neoplasms
Granulosa Cell Tumor
Salivary Gland Neoplasms

Contraindications

Source: openFDA

None. None. ( 4 ) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (10)

Common And Heart Failure · Arrhythmias · Ischemic Heart Disease · Of Patients Who Received Nubeqa Included Arrhythmia · Treated With Nubeqa Included Ischemic Heart Disease

Uncommon And Myocardial Infarction · Cardiac Arrest · Cardiac Failure · Myocardial Infarction · Tients Who Received Nubeqa Included Cardiac Failure

Vascular disorders (4)

Common Hemorrhage

Uncommon And Hypertension · Hypertension · Patients Who Received Nubeqa Included Hypertension

Nervous system disorders (3)

Common And Spinal Cord Compression

Uncommon Craniocerebral Injury · Seizures

Hepatobiliary disorders (1)

Uncommon And Drug-Induced Liver Injury

Blood and lymphatic system disorders (2)

Common And Febrile Neutropenia · Nubeqa With Docetaxel Included Febrile Neutropenia

Gastrointestinal disorders (2)

Uncommon And Nausea · Diarrhea

Skin and subcutaneous tissue disorders (3)

Common And Rash · Ed In Permanent Discontinuation Of Nubeqa Were Rash

Uncommon Rash

Musculoskeletal and connective tissue disorders (2)

Common Musculoskeletal Pain · O Received Nubeqa With Docetaxel Included Fractures

Infections and infestations (5)

Common Of Patients Who Received Nubeqa Included Pneumonia · Patients Included Sepsis · Pneumonia · Urinary Tract Infection

Uncommon And Pneumonia

Investigations (7)

Common And Increased Ast · Increased Alt · Increased Ast · Iring Dosage Reduction Of Nubeqa Were Increased Alt · Neutrophil Count Decreased · Ng Dosage Interruption Of Nubeqa Were Increased Ast

Uncommon Iring Dosage Reduction Of Nubeqa Were Increased Ast

General disorders and administration site conditions (5)

Uncommon And Death · And Sudden Death · General Physical Health Deterioration · On In Patients Treated With Nubeqa Included Fatigue · Patients Who Received Nubeqa Included Death

Respiratory, thoracic and mediastinal disorders (1)

Uncommon And Pulmonary Embolism

Dosing

Source: openFDA

Recommended Dosage : NUBEQA 600 mg (two 300 mg tablets) administered orally twice daily. Swallow tablets whole. Take NUBEQA with food. ( 2.1 ) For patients with mCSPC treated with NUBEQA in combination with docetaxel, administer the first cycle of docetaxel within 6 weeks after the start of NUBEQA treatment. ( 2.1 ) Patients should also receive a gonadotropin-releasing hormone (GnRH) agonist or antagonist concurrently or have had bilateral orchiectomy. ( 2.1 ) 2.1 Recommended Dosage The recommended dose of NUBEQA is 600 mg (two 300 mg tablets) taken orally, twice daily, with food [see Clinical Pharmacology (12.3) ]. Continue treatment until disease progression or unacceptable toxicity occurs. Patients receiving NUBEQA should also receive a gonadotropin-releasing hormone (GnRH) agonist or antagonist concurrently or have had a bilateral orchiectomy. When used in combination with docetaxel for mCSPC, administer the first of 6 cycles of docetaxel within 6 weeks after the start of NUBEQA treatment. Refer to docetaxel prescribing information for additional dosing information, including dosage modifications. Treatment with NUBEQA may be continued until disease progression or unacceptable toxicity, even if a cycle of docetaxel is delayed, interrupted, or discontinued [see Dosage and Administration (2.2) ] . Advise patients to swallow tablets whole with food, 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 or an intolerable adverse reaction, withhold NUBEQA or reduce dosage to 300 mg twice daily until symptoms improve. NUBEQA may be resumed at a dose of 600 mg twice daily, when adverse reaction returns to baseline [see Adverse Reactions (6.1) ]. Dosage reduction below 300 mg twice daily is not recommended. For patients who experience ischemic heart disease or seizure, additional dose modifications may be required [ see Warnings and Precautions (5.1 and 5.2) ]. 2.3 Recommended Dosage in Patients with Severe Renal Impairment For patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m 2 ) 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) ] .

Warnings & Precautions

Source: openFDA

Warnings & Precautions

Ischemic Heart Disease : Optimize management of cardiovascular risk factors. Monitor for signs and symptoms of coronary artery disease. Discontinue NUBEQA for Grade 3-4 events. ( 5.1 ) Seizure : Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. ( 5.2 ) Embryo-Fetal Toxicity : NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception. ( 5.3 , 8.1 , 8.3 )

Ischemic Heart Disease Ischemic heart disease, including fatal cases,

Ischemic Heart Disease Ischemic heart disease, including fatal cases, occurred in patients receiving NUBEQA. In a pooled analysis of ARAMIS and ARANOTE, ischemic heart disease occurred in 3.4% of patients receiving NUBEQA and 2.2% receiving placebo, including Grade 3-4 events in 1.4% and 0.3%, respectively. Ischemic events led to death in 0.4% of patients receiving NUBEQA and 0.4% receiving placebo. In ARASENS, ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel and 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% and 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel and 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.

Seizure Seizure occurred in patients receiving NUBEQA. In a pooled ana

Seizure Seizure occurred in patients receiving NUBEQA. In a pooled analysis of ARAMIS and ARANOTE, Grade 1-3 seizure occurred in 0.2% of patients receiving NUBEQA. Seizure occurred from 261 to 665 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.8% of patients receiving NUBEQA with docetaxel, including two Grade 3 events. Seizure occurred from 38 to 1754 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.

Embryo-Fetal Toxicity The safety and efficacy of NUBEQA have not been

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) ] .

Chemistry & Properties

Formula	C19H19ClN6O2
Molecular weight	398.85 g/mol
IUPAC name	N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide
CAS	1297538-32-9
PubChem CID	67171867
InChIKey	`BLIJXOOIHRSQRB-PXYINDEMSA-N`
logP	2.67 (XLogP 1.8)
Polar surface area	119.62 Å²
H-bond acceptors / donors	6 / 3
Drug-likeness (QED)	0.59
Lipinski violations	0

SMILES

CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.053 h
Volume of distribution	1.349 L/kg
Protein binding	96.9%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP3A4	Inhibitor	—

Receptor binding (top 1)

Target	Action	Affinity
Androgen receptor (AR)	Antagonist	pIC50 7.6

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OAT1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)Transporter(unspecified) (Inhibitor)BCRP (Substrate)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Apalutamide	major
Berotralstat	major
Carbamazepine	major
Dexamethasone	major
Eluxadoline	major
Enzalutamide	major
Fosphenytoin	major
Grazoprevir	major
Lorlatinib	major
Lumacaftor	major
Phenobarbital	major
Phenytoin	major
Primidone	major
Rifampicin	major
Rifapentine	major
Rosuvastatin	major
St. John's Wort	major
Afatinib	moderate
Alpelisib	moderate
Ambrisentan	moderate
Aminoglutethimide	moderate
Amobarbital	moderate
Armodafinil	moderate
Artesunate	moderate
Atazanavir	moderate
Atorvastatin	moderate
Bexarotene	moderate
Bictegravir	moderate
Binimetinib	moderate
Boceprevir	moderate
Bosentan	moderate
Brigatinib	moderate
Butabarbital	moderate
Butalbital	moderate
Cenobamate	moderate
Cerivastatin	moderate
Cladribine	moderate
Clarithromycin	moderate
Cobicistat	moderate
Conivaptan	moderate

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Nubeqa film coated tablets	Film-Coated Tablet 300 mg	112 tab	The Jordan Drugstore Co	—