Notafol - Capsule Ibrutinib - 140mg 1 Capsule(s) / Capsule Genvio Pharma Ltd. Indication: Ibrutinib, is a kinase inhibitor indicated for the treatment of patients with: • Mantle cell lymphoma (MCL), who have received at least one prior therapy Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. • Chronic lymphocytic leukemia (CLL), who have received at least one prior therapy • Chronic lymphocytic leukemia with 17p deletion • Waldenström’s macroglobulinemia (WM) Administration: Administer once daily at approximately the same time each day. Capsules should be taken orally with a glass of water. The capsules should not be opened, broke, or chewed. Adult Dose: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Waldenström Macroglobulinemia 420 mg taken orally once daily (three 140 mg capsules once daily) Mantle Cell Lymphoma 560 mg taken orally once daily (four 140 mg capsules once daily) Hepatic impairment Mild (Child Pugh class A): 140 mg PO qDay Moderate-to-severe (Child Pugh Classes B and C): Avoid use Child Dose: Safety and efficacy not established Contraindication: Hypersensitivity. Concomitant use w/ St. John's wort-containing prep. Mode of Action: Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms 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. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro. Precaution: • Hemorrhage: Should be monitored for bleeding • Infections: Patients should be monitored for fever and infections and evaluated promptly • Cytopenias: Complete blood counts should be checked monthly • Atrial Fibrillation: Patients should be monitored for atrial fibrillation • Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas • Tumor Lysis Syndrome (TLS): Patients should be monitored at risk for TLS (e.g. high tumor burden) • Embryo-Fetal Toxicity: Can cause fetal harm. Women should be advised of the potential risk to a fetus and to avoid pregnancy while taking the drug Side Effect: >10% (MCL) Increased serum creatinine, 1.5 x ULN (67%) Platelets decreased, all grades (57%) Diarrhea (51%) Hemorrhage (48%) Neutrophils decreased, all grades (47%) Hemoglobin decreased, all grades (41%) Fatigue (41%) Musculoskeletal pain (37%) Peripheral edema (35%) URI infection (34%) Nausea (31%) Bruising (30%) Neutropenia, grades 3 or 4 (29%) Dyspnea (27%) Constipation (25%) Rash (25%) Abdominal pain (24%) Vomiting (23%) Decreased appetite (221%) Cough (19%) Pyrexia (18%) Stomatitis (17%) Thrombocytopenia, grades 3 or 4 (17%) UTI infection (14%) Pneumonia (14%) Skin infections (14%) Asthenia (14%) Muscle spasms (14%) Dizziness (14%) Sinusitis (13%) Headache (13%) Dehydration (12%) Dyspepsia (11%) Petechiae (11%)... Interaction: Increased exposure w/ medicinal products that strongly or moderately inhibit CYP3A4. Avoid grapefruit & Seville oranges as these contain moderate inhibitors of CYP3A4. Decreased exposure w/ drugs increasing stomach pH (eg, PPIs). To minimize the potential GI tract interaction, oral narrow therapeutic range, P-gp or BCRP substrates eg, digoxin or methotrexate should be taken at least 6 hr before or after treatment.