Notafol Capsule

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.

Mantle Cell Lymphoma and Marginal Zone Lymphoma: The recommended dose of Ibrutinib for MCL and MZL is 560 mg (four 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenstrom Macroglobulinemia (WM): The recommended dose of Ibrutinib for CLL/SLL and WM is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity. The recommended dose of Ibrutinib for CLL/SLL when used in combination with bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

Administer Ibrutinib orally once daily at approximately the same time each day.
Swallow the capsules whole with water. Do not open, break, or chew the capsules.

CYP3A Inhibitors: Co-administration with strong and moderate CYP3A inhibitors should be avoided. If a moderate CYP3A inhibitor must be used, Notafol dose should be reduced 

CYP3A Inducers: Co-administration with strong CYP3A inducers should be avoided

Hypersensitivity to the active substance or to any of the excipients.

The following adverse reactions are discussed in more detail in other sections of the labeling: Hemorrhage, Infections, Cytopenias, Atrial Fibrillation, Hypertension, Second Primary Malignancies and Tumor Lysis Syndrome. Additional Important Adverse Reactions: Diarrhea, Visual Disturbance.

Pregnancy: Ibrutinib, a kinase inhibitor, can cause fetal harm based on findings from animal studies. In animal reproduction studies, administration of Ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including malformations. If Ibrutinib is used during pregnancy or if the patient becomes pregnant while taking Ibrutinib, the patient should be apprised of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

Lactation: There is no information regarding the presence of Ibrutinib or its metabolites in human milk, the effects on the breast fed infant, or the effects on milk production.

Pediatric Use: The safety and effectiveness of Notafol in pediatric patients has not been established.

Geriatric Use: Of the 905 patients in clinical studies of Notafol, 62% were ≥ 65 years of age, while 21% were ≥75 years of age. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades) and Grade 3 or higher pneumonia occurred more frequently among older patients treated with Notafol.

Hepatic Impairment: Notafol is metabolized in the liver. In a hepatic impairment study, data showed an increase in Notafol exposure. The safety of Notafol has not been evaluated in cancer patients with mild to severe hepatic impairment by Child-Pugh criteria. Monitor patients for signs of Notafol toxicity and follow dose modification guidance as needed. It is not recommended to administer Notafol to patients with moderate or severe hepatic impairment.

There is no specific experience in the management of Notafol over dose in patients. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.

Targeted Cancer Therapy

Store in a dry place below 30°C, protect from light. Keep out of the reach of children.