By: Amal Abdulghani Assistant Clinical Pharmacist

1. King Faisal Specialist Hospital & Research Center - Jeddah Pharmacy & Therapeutic Committee Drug Evaluation By: Amal Abdulghani Assistant Clinical Pharmacist

2. Overview • Generic Name: Nilotinib • Proprietary Name: Tasigna ® • Therapeutic Class: Antineoplastic Agent. Tyrosine Kinase Inhibitor.

3. Registration • Registered/approved in: • USA • Europe • KSA • Requested By: Dr. Mohammed Kelta.

4. Indications • FDA Labeled Indications: 1) Accelerated phase chronic myeloid leukemia, Resistant or intolerant to imatinib. 2) Chronic phase chronic myeloid leukemia, Resistant or intolerant to imatinib.

5. Pharmacology & Mechanism of Action • Nilotinib monohydrochloride, a selective tyrosine kinase inhibitor, binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. • Bcr-Abl is the oncogenic tyrosine kinase expressed by Philadelphia chromosome-positive (Ph+) stem cells, directly involved in the pathogenesis of chronic myeloid leukemia (CML). • Nilotinib inhibits the autophosphorylation of Bcr-Abl, PDGFR, and c-Kit, thereby reducing the tumor size. • It has also demonstrated activity in the case of CML resistance to treatment with imatinib .

6. How Supplied Tasigna® Oral Capsule: 200 MG

7. Pharmacokinetics • Absorption Oral: rapid, reach peak concentration in 3 hours. Effect of food: (Oral), increase AUC by 82%. • Metabolism oxidation and hydroxylation Hepatic; CYP3A4.

8. Pharmacokinetics • Excretion Fecal: 93%. • Elimination Half Life Adults: approximately 17 hours.

9. Dosing & Administration • a)Adult • Accelerated phase chronic myeloid leukemia, Resistant or intolerant to imatinib: 400 mg ORALLY every 12 hours until disease progression or unacceptable toxicity. • Chronic phase chronic myeloid leukemia, Resistant or intolerant to imatinib: 400 mg ORALLY every 12 hours until disease progression or unacceptable toxicity.

10. Dosing & Administration b) Pediatric Safety and efficacy not established in pediatric patients.

11. Monitoring • Chemistry panels periodically, including phosphorous, sodium, magnesium, potassium, and calcium levels • Complete blood counts every 2 weeks for the first 2 months of therapy, then monthly thereafter . • EKG for QTc at baseline, seven days following therapy initiation, following any dose adjustment, and periodically thereafter . • Liver function tests periodically, bilirubin, AST/ALT, and alkaline phosphatase . • Serum lipase levels periodically, especially in patients with a history of pancreatitis

12. Administration •  Oral • swallow capsules whole with water • take on an empty stomach at least 2 hr after food and at least 1 hr before food

13. Adverse Reactions • Common: • Cardiovascular: Peripheral edema (11% ) • Dermatologic: Dry skin (1% to 12% ), Pruritus (20% to 29% ), Rash (28% to 33% ) • Endocrine metabolic: Hyperglycemia, Grades 3 or 4 (4% to 11% ), Hypophosphatemia, Grades 3 or 4 (10% ) • Gastrointestinal: Constipation (18% to 21% ), Diarrhea (19% to 22% ), Increased serum lipase level, Grade 3 or 4 (8% to 17% ), Nausea (18% to 31% ), Vomiting (10% to 21% ) • Musculoskeletal: Arthralgia (16% to 18% ), Bone pain (11% to 13% ), Myalgia (14% ), Pain in limb (13% to 16% ), Spasm, Muscle (11% to 14% ) • Neurologic: Asthenia (12% to 14% ), Headache (21% to 31% ) • Psychiatric: Fatigue (16% to 28% ) • Respiratory: Cough (13% to 17% ), Dyspnea (8% to 11% ), Nasopharyngitis (11% to 16% )

14. Adverse Reactions • Serious • Cardiovascular: Sudden death (0.6% ), Prolonged QT interval (1% to 10% ) • Endocrine metabolic: Hypokalemia, Grades 3 or 4 (1% to 5% ), Hyponatremia, Grades 3 or 4 (3% ) • Hematologic: Anemia, Grade 3 or 4 (7% to 23% ), Febrile neutropenia (1% to 10% ), Neutropenia, Grade 3 or 4 (18% to 37% ), Thrombocytopenia, Grade 3 or 4 (24% to 37% ) • Hepatic: ALT (SGPT) level raised, Grade 3 or 4 (2% to 6% ), AST/SGOT level raised, Grade 3 or 4 (1% ), Hyperbilirubinemia, Grade 3 or 4 (9% to 10% ) • Neurologic: Intracranial hemorrhage (0.1% to 1% ) • Respiratory: Pneumonia (0.1% to 1% )

15. Contraindications • hypokalemia; may increase risk of QT prolongation and Torsades de points which can lead to syncope, seizure, and/or death • hypomagnesemia; may increase risk of QT prolongation and Torsades de points which can lead to syncope, seizure, and/or death • long QT syndrome; may increase the risk of Torsades de points which can lead to syncope, seizure, and/or death

16. Precautions • concomitant administration with food; increases bioavailability and systemic exposure of nilotinib by as much as 82% • concomitant use with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, voriconazole, grapefruit juice) or other agents which cause QT prolongation; may increase risk of QT prolongation which can lead to syncope, seizure, and/or death • electrolyte abnormalities; nilotinib may cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia

17. Precautions • QT prolongation; nilotinib may prolong ventricular repolarization resulting in Torsades de points which can lead to syncope, seizure, and/or death • lactose deficiency (severe), galactose intolerance, or glucose-galactose malabsorption; nilotinib capsules contain lactose • myelosuppression; nilotinib may cause severe grade 3/4 thrombocytopenia, neutropenia, and anemia • hepatic impairment; risk of hepatotoxicity (increased levels of bilirubin, AST/ALT, and alkaline phosphatase) and increased risk of QT prolongation

18. Chronic myeloid leukemia (CML) • Chronic myeloid leukemia (CML) accounts for approximately 15% of all leukemias. • CML can be classified into three disease phases: chronic phase (CP), accelerated phase (AP) and blast phase (BP).

19. Chronic myeloid leukemia (CML) • Characterized by the formation of the Philadelphia chromosome and oncogenic signaling by the resulting Bcr-Abl fusion protein. Understanding the molecular basis of CML has led to the development of highly effective targeted therapies that block Bcr-Abl tyrosine kinase activity.

20. Tyrosine Kinase Inhibitors (TKIs) • The availability of tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, which inhibit the molecular processes driving CML, has revolutionized the management and outlook in CML.

21. Imatinib • The current first-line therapy for CML • However, patients may develop imatinib resistance, which is often due to BCR-ABL mutations.

22. Nilotinib • With the availability of second generation tyrosine kinase inhibitors, an effective therapeutic option other than stem cell transplantation is available following imatinib failure. • Nilotinib, a recently approved analogue of imatinib, has demonstrated encouraging treatment responses in patients with imatinib-resistant CML.

27. Study Results Figure 1. Total Steady-State Serum Levels of Nilotinib, According to the Daily Dose.

28. Conclusion • Nilotinib is a novel oral inhibitor of Bcr-Abl that has recently been approved in the USA and Europe for patients with imatinib-resistant or -intolerant CML. • Nilotinib was rationally designed to bind to Bcr-Abl with a better topographic fit than imatinib, resulting in greater potency and less likelihood of resistance

29. Conclusion • With greater experience and availability of TKIs, and greater understanding of the molecular pathology of CML, the potential to tailor treatment for individual patients has become a realistic goal. • Future CML treatment may involve combination strategies. • Overall, targeted agents have significantly improved the prognosis of patients diagnosed with CML.