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INLURIYO tablets contain imlunestrant, an estrogen receptor antagonist. The chemical name for imlunestrant tosylate is (5R)-5-(4-(2-(3-(flouromethyl)azetidin-1-yl)ethoxy)phenyl)-8-(trifluoromethyl)-5H-(1)benzopyrano(4,3-c)quinolin-2-ol, tosylate salt (1:1). Imlunestrant tosylate is a white to practically white to yellow powder with the empirical formula C29H24F4N2O3.C7H8O3S and a molecular weight 696.71 g/mol. The aqueous solubility of imlunestrant tosylate is slightly soluble at low pH, insoluble at neutral pH, and sparingly soluble at high pH. The chemical structure of imlunestrant tosylate is shown below:
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INLURIYO are tablets for oral administration. Each INLURIYO tablet is available as capsule-shaped, film-coated tablet that contains 200 mg imlunestrant (equivalent to 265.66 mg imlunestrant tosylate). The tablet contains the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, and microcrystalline cellulose. The tablets are coated using a common white coating, which consists of polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
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.
The safety of INLURIYO was evaluated in 651 patients with ER+, HER2- locally advanced or metastatic breast cancer previously treated with endocrine therapy with or without a prior CDK4/6 inhibitor in EMBER-3 [see Clinical Studies (14.1)]. Patients received INLURIYO 400 mg orally, once daily (n=327), or standard of care (n=324) consisting of either fulvestrant (n=292) or exemestane (n=32). Among patients who were treated with INLURIYO, the median duration of exposure was 5.6 months (range: 0.2 to 28.6 months) in EMBER-3.
Serious adverse reactions occurred in 10% of patients who received INLURIYO. Serious adverse reactions in > 1% of patients included pleural effusion (1.2%). Fatal adverse reactions occurred in 1.8% of patients who received INLURIYO, including cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock, and upper gastrointestinal hemorrhage (each 0.3%).
Permanent treatment discontinuation of INLURIYO due to an adverse reaction occurred in 4.6% of patients. Adverse reactions which resulted in permanent discontinuation of INLURIYO included increased alanine aminotransferase (0.9%), abdominal pain, fatigue, fractured sacrum, hepatotoxicity, neuropathy peripheral, and pyrexia (each 0.3%).
Dosage interruption of INLURIYO due to an adverse reaction occurred in 10% of patients. Adverse reactions which required dosage interruption in >0.5% were vomiting (1.5%); increased aspartate aminotransferase and COVID-19 (each 0.9%); and increased alanine aminotransferase, anemia, diarrhea, decreased neutrophil count, and pyrexia (each 0.6%).
Dose reductions of INLURIYO due to an adverse reaction occurred in 2.4% of patients. Adverse reactions which required dose reductions were increased aspartate aminotransferase (0.6%); and increased alanine aminotransferase, anemia, fatigue, interstitial lung disease, nausea, neutropenia, and vomiting (each 0.3%).
The most common (≥10%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, musculoskeletal pain, calcium decreased, neutrophils decreased, AST increased, fatigue, diarrhea, ALT increased, triglycerides increased, nausea, platelets decreased, constipation, cholesterol increased, and abdominal pain.
Table 3 summarizes the adverse reactions in EMBER-3.
Table 3: Adverse Reactions (≥10%) in Patients Who Received INLURIYO in EMBER-3
| Adverse Reactiona | INLURIYO N=327 |
Fulvestrant or Exemestane N=324 |
||
| All Grades % | Grades 3 or 4 % | All Grades % | Grades 3 or 4 % | |
| Musculoskeletal Disorders | ||||
| Musculoskeletal Pain | 30 | 3.7 | 29 | 1.9 |
| General Disorders and Administration Site Conditions | ||||
| Fatigueb | 23 | 0.3 | 14 | 0.6 |
| Gastrointestinal Disorders | ||||
| Diarrhea | 22 | 0.6 | 12 | 0.0 |
| Nausea | 17 | 0.3 | 13 | 0.0 |
| Constipation | 10 | 0 | 6 | 0.3 |
| Abdominal painb | 10 | 0.3 | 6 | 0.6 |
|
a Adverse reactions were graded using NCI CTCAE version 5.0. b Includes other related terms |
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Clinically relevant adverse reactions (<10%) in patients who received INLURIYO included: vomiting (9%), headache (9%), cough (9%), decreased appetite (8%), hot flush (7%), pruritus (3.7%), dyspepsia (2.8%), and stomatitis (2.4%).
Table 4 summarizes the laboratory abnormalities in EMBER-3.
Table 4: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received INLURIYO in EMBER-3
| Lab Abnormalitya |
INLURIYOb |
Fulvestrant or Exemestaneb | ||
| All Grades % |
Grades 3 or 4 % |
All Grades % |
Grades 3 or 4 % |
|
| Hematology | ||||
| Hemoglobin decreased | 30 | 1.2 | 35 | 3.4 |
| Neutrophils decreased | 26 | 4 | 29 | 4.7 |
| Platelets decreased | 16 | 1.8 | 14 | 1.3 |
| Chemistry | ||||
| Calcium decreased | 26 | 0 | 19 | 0.6 |
| Aspartate aminotransferase increased | 25 | 1.9 | 27 | 2.3 |
| Alanine aminotransferase increased | 21 | 1.3 | 23 | 1.0 |
| Triglycerides increased | 21 | 0 | 22 | 1.2 |
| Cholesterol increased | 10 | 0 | 12 | 0 |
|
a Graded according to NCI CTCAE version 5 b The denominator used to calculate the rate varied from 252 to 325 based on the number of patients with a baseline value and at least one post-treatment value. |
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Avoid concomitant use of INLURIYO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce the dosage of INLURIYO [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
Imlunestrant is a CYP3A substrate. Concomitant use of a strong CYP3A inhibitor increases imlunestrant exposure [see Clinical Pharmacology (12.3)], which may increase the risk of INLURIYO-associated adverse reactions.
Avoid concomitant use of INLURIYO with strong CYP3A inducers. If concomitant use cannot be avoided, increase the dosage of INLURIYO [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
Imlunestrant is a CYP3A substrate. Concomitant use of a strong CYP3A inducer decreases imlunestrant exposure [see Clinical Pharmacology (12.3)], which may reduce effectiveness of INLURIYO.
Avoid concomitant use unless otherwise recommended in the Prescribing Information for P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions.
Imlunestrant inhibits both P-gp and BCRP. Imlunestrant increases exposure of P-gp and BCRP substrates, which may increase the risk of adverse reactions related to these substrates [see Clinical Pharmacology (12.3)].
Included as part of the PRECAUTIONS section.
Based on findings in animals and its mechanism of action, INLURIYO can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of imlunestrant to pregnant rats during the period of organogenesis led to embryo-fetal mortality and structural abnormalities at maternal exposures that were below the human exposure at the recommended dose based on AUC.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
Carcinogenicity studies have not been conducted with imlunestrant.
Imlunestrant was not mutagenic in the bacterial reverse mutation (Ames) assay. Imlunestrant was clastogenic in an in vitro human lymphocyte micronucleus assay. Imlunestrant was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA breaks in the liver and duodenum comet assays.
Fertility studies with imlunestrant in animals have not been conducted. In repeat-dose toxicity studies up to 6 months in rats and 3 months in cynomolgus monkeys, oral administration of imlunestrant resulted in follicular cysts in the ovary and atrophy in the vagina, cervix, and uterus at doses ≥ 10 mg/kg/day in rats (≥ 4 times the human AUC at the recommended dose) and ≥ 15 mg/kg/day in cynomolgus monkeys (≥1 times the human AUC at the recommended dose). Decreased sperm and cellular debris in the epididymis and spermatid retention in the testis were observed in male rats at ≥10 mg/kg/day. The effects of imlunestrant on male and female reproductive organs were reversible in rats following a 3- month recovery period. Reversibility was not assessed in cynomolgus monkeys.
In a 6-month repeat-dose toxicity study, oral administration of imlunestrant to rats resulted in epithelial hyperplasia in the urinary bladder, granulosa cell hyperplasia in the ovary, and hyperplasia in the mammary gland at doses ≥ 10 mg/kg/day (≥ 4 times the human AUC at the recommended dose). These effects, except urinary bladder effects, were reversible after a 3-month recovery period.
NO information provided
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Imlunestrant is an estrogen receptor (ER) antagonist that binds to ERα. In vitro, imlunestrant induced degradation of ERα, leading to inhibition of ER-dependent gene transcription and cellular proliferation in ER+ breast cancer cells. Imlunestrant demonstrated in vitro and in vivo anti-tumor activity in ER+ breast cancer xenograft models, including models with ESR1 mutations.
Imlunestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.
At 2 times the mean maximum concentration observed with the approved recommended dose, a mean increase in the QTc interval >20 msec was not observed.
Imlunestrant pharmacokinetics were observed at steady state at the approved recommended dosage and are presented as mean (%CV) unless otherwise specified. The maximum concentration (Cmax) of imlunestrant is 141 ng/mL (45%) and the area under the concentration-time curve (AUC) is 2,400 ng*h/mL (46%). Imlunestrant Cmax and AUC increase in a dose proportional manner over a dosage range of 200 mg to 1,200 mg (0.5 to 3 times the approved recommended dosage) once daily. Steady-state is reached in approximately 6 days and the accumulation is 2.3-fold based on AUC.
Imlunestrant absolute oral bioavailability after a single oral 400 mg dose is 10% (32%). Imlunestrant median (min, max) time to maximum plasma concentration (Tmax) is 4 (2, 8) hours.
Imlunestrant AUC increased 2-fold and Cmax increased 3.6-fold following administration with a low-fat meal (approximately 475 calories with 13% fat, 16% protein, and 71% carbohydrates). The effect of high-fat meal (approximately 800-1,000 calories with 500-600 calories from fat) on imlunestrant exposures is unknown.
The apparent (oral) volume of distribution is 8,120 L (69%). Imlunestrant protein binding is >99% and is not concentration dependent.
Imlunestrant elimination half-life is 30 hours with an estimated apparent clearance of 166 L/h (51%).
Metabolism
Imlunestrant is metabolized by sulfation, CYP3A4, and direct glucuronidation (UGT1A1, 1A3, 1A8, 1A9, 1A10).
Excretion
After a single dose of radiolabeled imlunestrant 400 mg to healthy subjects, 97% of the dose was recovered in feces (62% unchanged) and 0.3% in urine.
No clinically significant differences in the pharmacokinetics of imlunestrant based on age (28 to 95 years), race (64% White, 23% Asian, and 5% Black or African American), ethnicity (74% non-Hispanic/Latino, 17% Hispanic/Latino), body weight (36 to 145 kg), mild to moderate (eGFR 30 to 89 mL/min, estimated by CKD-EPI equation) renal impairment, or UGT1A1 genetic polymorphisms (e.g., UGT1A1*1/*28 or UGT1A1*28/*28). The effect of severe (eGFR 15 to 29 mL/min) renal impairment and renal impairment requiring dialysis on imlunestrant pharmacokinetics is unknown.
Patients with Hepatic Impairment
Imlunestrant AUC increased 2.2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.1-fold in subjects with severe hepatic impairment (Child-Pugh C). No clinically significant differences in the pharmacokinetics of imlunestrant were observed in subjects with mild hepatic impairment (Child-Pugh A).
Clinical Studies
Strong CYP3A Inhibitors: Imlunestrant AUC increased 2.1-fold and Cmax increased 1.9-fold following concomitant use of itraconazole (strong CYP3A inhibitor) for multiple days.
Strong CYP3A Inducers: Imlunestrant AUC decreased by 42% and Cmax decreased by 29% following concomitant use of carbamazepine (strong CYP3A inducer) for multiple days.
P-gp Substrates: Digoxin (P-gp substrate) AUC increased 1.4-fold and Cmax increased 1.6-fold following concomitant use of imlunestrant.
BCRP Substrates: Rosuvastatin (BCRP substrate) AUC increased 1.5-fold and Cmax increased 1.6-fold following concomitant use with imlunestrant.
Other Drugs: No clinically significant differences in the pharmacokinetics of imlunestrant were observed when used concomitantly with omeprazole (gastric acid-reducing agent) or quinidine (P-gp inhibitor).
No clinically significant differences in the pharmacokinetics of midazolam (CYP3A substrate), repaglinide (CYP2C8 substrate), omeprazole (CYP2C19 substrate), or dextromethorphan (CYP2D6 substrate) were observed when used concomitantly with imlunestrant.
In Vitro Studies
CYP Enzymes: Imlunestrant is an inhibitor of CYP2B6 and CYP2C9 but is not an inhibitor of CYP1A2. Imlunestrant is not an inducer of CYP1A2, CYP2B6, or CYP2C9.
Transporter Systems: Imlunestrant is not a substrate of BCRP, OCT1, OATP1B1, or OATP1B3.
Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients that hypercholesterolemia and hypertriglyceridemia may occur while taking INLURIYO. Inform patients that lipid profile monitoring will be performed prior to starting and periodically while taking INLURIYO [see Adverse Reactions (6.1)].
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose [see Use in Specific Populations (8.3)].
Advise women not to breastfeed during treatment with INLURIYO and for 1 week after the last dose [see Use in Specific Populations (8.2)].
Advise males and females of reproductive potential that INLURIYO may impair fertility [see Use in Specific Populations (8.3)].
Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over the counter drugs, and herbal products [see Drug Interactions (7.1, 7.2)].
Instruct patients to take INLURIYO at approximately the same time each day and to swallow the tablet(s) whole. Tablets should not be chewed, crushed, or split prior to swallowing [see Dosage and Administration (2.1)].
Advise patients to take INLURIYO without food, either 2 hours before food or 1 hour after food [see Dosage and Administration (2.1)].
Instruct patient that if a dose of INLURIYO is missed by more than 6 hours or vomiting occurs, skip the dose and take the next dose the following day at its regularly scheduled time [see Dosage and Administration (2.1)].
