Yulareb Special Precautions

Diarrhea: Severe diarrhea associated with dehydration and infection occurred in patients treated with YULAREB.
Across four clinical trials in 3691 patients, diarrhea occurred in 81% to 90% of patients who received YULAREB.
Grade 3 diarrhea occurred in 8% to 20% of patients receiving YULAREB [see Clinical Studies Experience under Adverse Reactions].
Most patients experienced diarrhea during the first month of YULAREB treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. Across trials, 19% to 26% of patients with diarrhea required a YULAREB dose interruption and 13% to 23% required a dose reduction.
Instruct patients to start antidiarrheal therapy such as loperamide at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up [see Patient Counselling Information]. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue YULAREB until toxicity resolves to ≤Grade 1, and then resume YULAREB at the next lower dose [see Dose Modification under Dosage & Administration].
Neutropenia: Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with YULAREB.
Across four clinical trials in 3691 patients, neutropenia occurred in a 37% to 46% of patients receiving YULAREB. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19% to 32% of patients receiving YULAREB. Across trials, the median time to the first episode of Grade ≥3 neutropenia ranged from 29 days to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 days to 16 days [see Clinical Studies Experience under Adverse Reactions].
Febrile neutropenia has been reported in <1% of patients exposed to YULAREB across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider [see Patient Counselling Information].
Monitor complete blood counts prior to the start of YULAREB therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dose Modification under Dosage & Administration].
Interstitial Lung Disease (ILD) or Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with YULAREB and other CDK4/6 inhibitors. In YULAREB-treated patients in early breast cancer (monarchE, N=2791), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In YULAREB-treated patients in advanced or metastatic breast cancer (N=900) (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of YULAREB-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Postmarketing experience under Adverse Reactions].
Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.
Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue YULAREB in all patients with Grade 3 or 4 ILD or pneumonitis [see Dose Modification under Dosage & Administration].
Hepatotoxicity: Grade ≥3 ALT (2% to 6%) and AST (2% to 3%) were reported in patients receiving YULAREB. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days, and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days.
Monitor liver function tests (LFTs) prior to the start of YULAREB therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or Grade 4, hepatic transaminase elevation [see Dose Modification under Dosage & Administration].
Venous Thromboembolism: Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3, venous thromboembolic events were reported in 2% to 5% of patients treated with YULAREB. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to venous thromboembolism have been reported in patients treated with YULAREB.
YULAREB has not been studied in patients with early breast cancer who had a history of venous thromboembolism. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for early breast cancer patients with any grade venous thromboembolic event and for advanced or metastatic breast cancer patients with a Grade 3 or 4 venous thromboembolic event [see Dose Modification under Dosage & Administration].
Embryo-Fetal Toxicity: Based on findings from animal studies and the mechanism of action, YULAREB can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with YULAREB and for 3 weeks after the last dose [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions].
Renal Impairment: No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown [see Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B).
Reduce the dosing frequency when administering YULAREB to patients with severe hepatic impairment (Child-Pugh C) [see Dose Modification under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of YULAREB have not been established in pediatric patients.
Use in the Elderly: Of the 2791 YULAREB-treated patients in monarchE, 15% were 65 years of age or older and 2.7% were 75 years of age or older.
Of the 900 patients who received YULAREB in MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 2, and 3 were: neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of YULAREB were observed between these patients and younger patients.