Calcent Capsule

Calcent is a kinase inhibitor indicated for the treatment of adult patients with:

• Mantle cell lymphoma (MCL) who have received at least one prior therapy
• This indication is approved under accelerated approval based on overall response rate Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models.

The recommended dose of Acalabrutinib is 100 mg taken orally approximately every twelve hours until disease progression or unacceptable toxicity. Advise patients to swallow capsule whole with water. Advise patients not to open, break or chew the capsules. Acalabrutinib may be taken with or without food. If a dose of Acalabrutinib is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra capsules of Acalabrutinib should not be taken to make up for a missed dose.

Recommended Dose Modifications for Adverse Reactions: Dosage of Acalabrutinib can be reduced up to 100 mg daily for the toxicity has resolved to Grade 1 or baseline level. If the adverse reaction occurrence more than four times Acalabrutinib can be Discontinue.

Effect of CYP3A Inhibitors on Calcent: Co-administration with a strong CYP3A inhibitor (200 mg Iitraconazole once daily for 5 days) increased the Calcent Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects. Physiologically based pharmacokinetic (PBPK) simulations with Calcent and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased Calcent Cmax and AUC increased by 2- to almost 3-fold.

Effect of CYP3A Inducers on Calcent: Co-administration with a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased Calcent Cmax by 68% and AUC by 77% in healthy subjects.

Gastric Acid Reducing Agents: Calcent solubility decreases with increasing pH. Co-administration with an antacid (1 g calcium carbonate) decreased Calcent AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days) decreased Calcent AUC by 43%.

In Vitro Studies-
Metabolic Pathways: Calcent is a weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, and CYP2D6. The active metabolite (ACP-5862) is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6 and CYP3A4/5. Calcent is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; the active metabolite (ACP-5862) weakly induces CYP3A4. Based on in vitro data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations.

Drug Transporter Systems: Calcent is a substrate of P-glycoprotein (P-gp) and BCRP. Calcent is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1, and OATP1B3. Calcent does not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3 at clinically relevant concentrations. Calcent may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP.

Most common adverse reactions (incidence ≥30%) were: anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain.

Pregnancy: Based on findings in animals, Acalabrutinib may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of Acalabrutinib to pregnant rabbits during organogenesis resulted in reduced fetal growth at maternal exposures (AUC) approximately 4 times exposures in patients at the recommended dose of 100 mg twice daily. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 2-4% and 15-20%, respectively.

Lactation: No data are available regarding the presence of Acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in a breastfed child from Acalabrutinib, advise lactating women not to breastfeed while taking Acalabrutinib and for at least 2 weeks after the final dose.

Hemorrhage: Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with Calcent monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis have been reported in 2% of patients. Overall, bleeding events including bruising and petechiae of any grade occurred in approximately 50% of patients with hematological malignancies. The mechanism for the bleeding events is not well understood. Calcent may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding Calcent for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infection: Serious infections (bacterial, viral or fungal), including fatal events and opportunistic infections have occurred in the combined safety database of 612 patients with hematologic malignancies treated with Calcent monotherapy. Consider prophylaxis in patients who are at increased risk for opportunistic infections. Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocaln leukoencephalopathy (PML) have occurred. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Cytopenias: In the combined safety database of 612 patients with hematologic malignancies, patients treated with Calcent monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%) and thrombocytopenia (8%) based on laboratory measurements. In the Calcent clinical Trial LY-004, patients’ complete blood counts were assessed monthly during treatment.

Second Primary Malignancies: Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with Calcent monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.

Atrial Fibrillation and Flutter: In the combined safety database of 612 patients with hematologic malignancies treated with Calcent monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

Renal Impairment: Calcent undergoes minimal renal elimination. Based on population PK analysis, no clinically relevant PK difference was observed in 368 patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). Calcent PK has not been evaluated in patients with severe renal impairment (eGFR <29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis.

Hepatic Impairment: Calcent is metabolized in the liver. In a hepatic impairment study, compared to subjects with normal liver function (n=6), Calcent exposure (AUC) was increased by less than two-fold in subjects with mild (n=6) (Child-Pugh A) and moderate (n=6) (Child-Pugh B) hepatic impairment, respectively. Based on a population PK analysis, no clinically relevant PK difference was observed 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) relative to subjects with normal (n=527) hepatic function (total bilirubin and AST within ULN). Calcent 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 Calcent in pediatric patients have not been established.

Geriatric Use:  Eighty (64.5%) of the 124 MCL patients in clinical trials of Calcent 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 observed between patients ≥ 65 years and younger.

Tyrosine Kinase Inhibitor

Do not store above 30⁰C. Keep away from light and out of the reach of children.