Calcent 100

Acalabrutinib is a small-molecule inhibitor of BTK. The medicine and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, and this stops the enzyme from working. BTK is a signaling molecule in the B cell antigen receptor (BCR) pathway and in the cytokine receptor pathways. In B cells, BTK signaling switches on the pathways needed for B-cell proliferation, trafficking, chemotaxis and adhesion.

In nonclinical studies, acalabrutinib blocked BTK-mediated activation of the downstream signaling proteins CD86 and CD69. It also inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models.

Pregnancy: Animal findings suggest that Acalabrutinib may cause fetal harm if a pregnant woman takes it. There are no data in pregnant women to show what the risk is. In animal studies, pregnant rabbits given Acalabrutinib during organogenesis had reduced fetal growth. This happened at maternal exposures (AUC) about 4 times the exposure seen in patients taking the recommended dose of 100 mg twice daily. Pregnant women should be told about the potential risk to the fetus. The background risk of major birth defects and miscarriage for the people this medicine is meant for is unknown. Every pregnancy carries a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation: No data are available on whether Acalabrutinib or its active metabolite passes into human milk, what effect it has on a breastfed child, or what effect it has on milk production. Both Acalabrutinib and its active metabolite were found in the milk of lactating rats. Because a breastfed child could have adverse reactions from Acalabrutinib, women who are breastfeeding should be advised not to breastfeed while taking it and for at least 2 weeks after the final dose.

Renal Impairment: Acalabrutinib is cleared by the kidneys only to a minimal extent. A population PK analysis included 368 patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, estimated by MDRD, the modification of diet in renal disease equation), and no clinically relevant PK difference was seen in them. Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR <29 mL/min/1.73m2, MDRD) or in patients whose renal impairment requires dialysis.

Hepatic Impairment: Acalabrutinib is metabolized in the liver. A hepatic impairment study compared subjects with normal liver function (n=6) against those with mild (n=6) (Child-Pugh A) and moderate (n=6) (Child-Pugh B) hepatic impairment. Acalabrutinib exposure (AUC) was increased by less than two-fold in the mild and moderate groups, respectively. A population PK analysis also found no clinically relevant PK difference in subjects with mild (n=41) or moderate (n=3) hepatic impairment (total bilirubin between 1.5 to 3 times the upper limit of normal [ULN] and any AST), when compared with subjects who had normal (n=527) hepatic function (total bilirubin and AST within ULN). Acalabrutinib PK has not been evaluated in patients with severe hepatic impairment (Child-Pugh C or total bilirubin between 3 and 10 times ULN and any AST).

Pediatric Use: The safety and efficacy of Acalabrutinib in pediatric patients have not been established.

Geriatric Use: Of the 124 MCL patients in clinical trials of Acalabrutinib, eighty (64.5%) were 65 years of age or older, and 32 patients (25.8%) were 75 years of age or older. No clinically relevant differences in safety or efficacy were seen between patients ≥ 65 years and younger patients.

Store Acalabrutinib at a temperature not above 30⁰C. Keep it away from light, and keep it out of the reach of children.