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King Faisal Specialist Hospital & Research Center - Jeddah. Pharmacy & Therapeutic Committee Drug Evaluation. By: Amal Abdulghani Assistant Clinical Pharmacist. Overview. Generic Name: Nilotinib Proprietary Name: Tasigna ® Therapeutic Class: Antineoplastic Agent.

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slide1

King Faisal Specialist Hospital

& Research Center - Jeddah

Pharmacy & Therapeutic Committee

Drug Evaluation

By:

Amal Abdulghani

Assistant Clinical Pharmacist

overview
Overview
  • Generic Name: Nilotinib
  • Proprietary Name: Tasigna ®
  • Therapeutic Class:

Antineoplastic Agent.

Tyrosine Kinase Inhibitor.

registration
Registration
  • Registered/approved in:
  • USA
  • Europe
  • KSA
  • Requested By:

Dr. Mohammed Kelta.

indications
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.

pharmacology mechanism of action
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 .
how supplied
How Supplied

Tasigna®

Oral Capsule: 200 MG

pharmacokinetics
Pharmacokinetics
  • Absorption

Oral: rapid, reach peak concentration in 3 hours.

Effect of food: (Oral), increase AUC by 82%.

  • Metabolism

oxidation and hydroxylation

Hepatic; CYP3A4.

pharmacokinetics1
Pharmacokinetics
  • Excretion

Fecal: 93%.

  • Elimination Half Life

Adults: approximately 17 hours.

dosing administration
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.

dosing administration1
Dosing & Administration

b) Pediatric

Safety and efficacy not established in pediatric patients.

monitoring
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
administration
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
adverse reactions
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% )
adverse reactions1
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% )
contraindications
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
precautions
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
precautions1
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
chronic myeloid leukemia cml
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).
chronic myeloid leukemia cml1
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.
tyrosine kinase inhibitors tkis
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.
imatinib
Imatinib
  • The current first-line therapy for CML
  • However, patients may develop imatinib resistance, which is often due to BCR-ABL mutations.
nilotinib
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.
study results
Study Results

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

conclusion
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
conclusion1
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.