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:

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
 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.

23. Multicenter, international, single-arm, open-label trial. Length
Study 1
Type
Multicenter, international, single-arm, open-label trial.
Length
Median duration of treatment of 202 days N
119
Date Published
February 2008
Journal
Journal of the American Society of Hematology
Title
Nilotinib, a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib- resistant or –intolerant accelerated-phase chronic myelogenous leukemia.
Methods
All patients were initially treated with nilotinib 400 mg orally twice daily -600 mg twice daily was permitted.
Treatment continued until the patient experienced disease progression, toxicity, withdrew consent..
The primary efficacy variable was the rate of hematological response (HR)

24. Results
An HR was observed in 56 patients (74%, 95% confidence interval (CI) , 38%-56%).
Major cytogenic response (MCyR) was observed in 35 patients (29%, 95% CI21%-39%).
Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%).
Nonhematological adverse events were mostly mild to moderate.
Severe peripheral edema and pleural effusions were not observed.
The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%).
Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients.

25. The New England Journal of Medicine
Study 2
Type
The study was designed to evaluate the safety and tolerability of nilotinib. Patients were successively assigned to one of nine dose cohorts, ranging from 50 to 1200 mg once daily and from 400 to 600 mg twice daily.
Length
from May 25, 2004, to May 4, 2005 N
119
Date Published
2006
Journal
The New England Journal of Medicine
Title
Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALL
Methods
In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily.

26. Results
Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes.
Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response;
of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response;
11 of 12 patients with the chronic phase had a complete hematologic remission.
nilotinib may have a limited role in patients with Ph-positive ALL.

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.