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NILOTINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nilotinib is a selective tyrosine kinase inhibitor that binds to and stabilizes the inactive conformation of the kinase domain of Abl protein.

Specific Substances

    1) Nilotinibum
    2) Tasigna(R)
    3) AMN-107
    4) CAS 641571-10-0
    1.2.1) MOLECULAR FORMULA
    1) C28-H22-F3-N7-O-HCL-H2O (Prod Info TASIGNA(R) oral capsules, 2007)

Available Forms Sources

    A) FORMS
    1) Nilotinib is available as 200 mg light yellow opaque hard gelatin capsules, with a red axial imprint code of NVR/TKI (Prod Info TASIGNA(R) oral capsules, 2007).
    B) USES
    1) Nilotinib is FDA-approved for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients refractory to prior therapy, including imatinib (Prod Info TASIGNA(R) oral capsules, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) The most common adverse effects, following therapeutic administration of nilotinib, include rash, pruritus, nausea, vomiting, diarrhea, constipation, fatigue, and headache. Myelosuppression, including anemia, neutropenia, and thrombocytopenia, and QT interval prolongation have also been reported.
    B) WITH POISONING/EXPOSURE
    1) There is no overdose information available for nilotinib at the time of this review. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects, including myelosuppression, and QTc prolongation with the potential for ventricular dysrhythmias.
    0.2.3) VITAL SIGNS
    A) Pyrexia was reported with nilotinib therapy during clinical trials.
    B) WITH THERAPEUTIC USE
    1) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, pyrexia was reported in 14% of 318 chronic-phase and 24% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Pyrexia was one of the most common serious adverse reactions reported among the accelerated-phase patients (Prod Info TASIGNA(R) oral capsules, 2007).
    0.2.20) REPRODUCTIVE
    A) Nilotinib is classified as FDA pregnancy category D. A case report described a successful pregnancy after nilotinib use during the first trimester. In animals, abortion and decreased gestation weight occurred at doses associated with maternal toxicity. Embryo-fetal toxicity (increased resorption and post-implantation loss), and minor skeletal anomalies have been also reported in animal studies.

Laboratory Monitoring

    A) Monitor serial CBC with differential and platelet counts. Monitor serum electrolytes including calcium and phosphorus, and serum aminotransferase and bilirubin concentrations after significant overdose.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) MYELOSUPPRESSION: Filgrastim 5 mcg/kg/day subcutaneously or sargramostim 250 mcg/m(2)/day intravenously over 4 hours may be useful for severe or febrile neutropenia. Packed red cell and/or platelet transfusion may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage.
    C) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).

Range Of Toxicity

    A) There is no overdose information available for nilotinib at the time of this review.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) The most common adverse effects, following therapeutic administration of nilotinib, include rash, pruritus, nausea, vomiting, diarrhea, constipation, fatigue, and headache. Myelosuppression, including anemia, neutropenia, and thrombocytopenia, and QT interval prolongation have also been reported.
    B) WITH POISONING/EXPOSURE
    1) There is no overdose information available for nilotinib at the time of this review. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects, including myelosuppression, and QTc prolongation with the potential for ventricular dysrhythmias.

Vital Signs

    3.3.1) SUMMARY
    A) Pyrexia was reported with nilotinib therapy during clinical trials.
    B) WITH THERAPEUTIC USE
    1) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, pyrexia was reported in 14% of 318 chronic-phase and 24% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Pyrexia was one of the most common serious adverse reactions reported among the accelerated-phase patients (Prod Info TASIGNA(R) oral capsules, 2007).

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASOPHARYNGITIS - In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, nasopharyngitis was reported in 16% of 318 chronic-phase and 11% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) In clinical trials of patients with chronic myeloid leukemia (CML) receiving nilotinib, prolonged QT interval was reported in 1% to 10% of patients. QT prolongation may result in Torsade de pointes, which may lead to syncope, seizure, and/or death (Prod Info TASIGNA(R) oral capsules, 2007).
    b) The corrected QT interval by Fridericia's formula (QTcF) increased by 5 to 15 milliseconds in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119) (Kantarjian et al, 2006).
    B) DEAD - SUDDEN DEATH
    1) WITH THERAPEUTIC USE
    a) In an ongoing study of patients receiving nilotinib, sudden death was reported in 5 of 867 (0.6%) patients, with similar results reported in the expanded access program. Ventricular repolarization abnormalities are believed to have contributed to some of the deaths due to the relatively early occurrence in relation to drug initiation (Prod Info TASIGNA(R) oral capsules, 2007).
    C) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, peripheral edema was reported in 11% of 318 chronic-phase and 11% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. No Grade 3 or 4 cases of peripheral edema were reported (Prod Info TASIGNA(R) oral capsules, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, dyspnea was reported in 11% of 318 chronic-phase and 8% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, cough was reported in 17% of 318 chronic-phase and 13% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, fatigue was reported in 28% of 318 chronic-phase and 16% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Fatigue was one of the most common adverse reactions reported among the chronic-phase patients (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Fatigue occurred in 6% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). All cases were grade 1 or 2 (Kantarjian et al, 2006).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, headache was reported in 31% of 318 chronic-phase and 21% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Headache was one of the most common adverse reactions reported in the chronic-phase patient group (Prod Info TASIGNA(R) oral capsules, 2007).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, asthenia was reported in 14% of 318 chronic-phase and 12% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, nausea and vomiting were reported in 31% and 21%, respectively, of 318 chronic-phase and 18% and 10%, respectively, of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Nausea, vomiting, or both occurred in 8% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). All cases were grade 1 or 2 (Kantarjian et al, 2006).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, constipation was reported in 21% of 318 chronic-phase and 18% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Constipation was one of the most common adverse reactions (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Constipation occurred in 8% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). All cases were grade 1 or 2 (Kantarjian et al, 2006).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, abdominal pain was reported in 11% of 318 chronic-phase and 13% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, diarrhea was reported in 22% (Grade 3 or 4, 3%) of 318 chronic-phase and 19% (Grade 3 or 4, 2%) of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Diarrhea was one of the most common adverse reactions reported in the chronic-phase patient group (Prod Info TASIGNA(R) oral capsules, 2007).
    E) HIGH LIPASE LEVEL IN SERUM
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, elevated lipase (Grades 3 or 4) was reported in 15% of 318 chronic-phase and 17% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Grade 3 or 4 increases in serum lipase occurred in 8% of patients with various phases of chronic myeloid leukemia (CML) who received nilotinib in phase II, open-label clinical trials (LeCoutre et al, 2006; Kantarjian et al, 2006a).
    c) Increased lipase levels occurred in 5% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). All cases were grade 3 or 4 (Kantarjian et al, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, elevated total bilirubin (Grades 3 or 4) was reported in 9% of 318 chronic-phase and 10% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Increases in total or conjugated bilirubin levels occurred in 8% (grade 3 or 4, 3%) of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119), while increases in unconjugated bilirubin levels occurred in 6% (grade 3 or 4, 4%). Increases in unconjugated bilirubin levels did not coincide with increases in levels of aminotransferase or increased hemolysis. Hyperbilirubinemia was dose-related, most often occurred during the first week of nilotinib therapy, and typically resolved spontaneously with continued administration. In addition, hyperbilirubinemia was frequently observed in patients with Gilbert's syndrome (7 of 14) as compared to those patients without Gilbert's syndrome (10 of 97) (Kantarjian et al, 2006).
    c) Grade 3 or 4 elevations in bilirubin occurred in 6% of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who received nilotinib in a phase II, open-label clinical trial (n=34) (Ottmann et al, 2006).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, elevated ALT (Grades 3 or 4) was reported in 4% of 318 chronic-phase and 2% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Grade 3 or 4 elevations in ALT occurred in 6% of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who received nilotinib in a phase II, open-label clinical trial (n=34) (Ottmann et al, 2006).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, Grade 3 or 4 neutropenia was reported in 28% of 318 chronic-phase and 37% (Grade 3, 12%; Grade 4, 25%) of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Neutropenia was one of the most common serious adverse reactions in both chronic-phase and accelerated-phase patients (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Grade 3 or 4 neutropenia occurred in 18% to 27% of patients with various phases of chronic myeloid leukemia (CML) and 6% of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who received nilotinib in phase II, open-label clinical trials (LeCoutre et al, 2006; Kantarjian et al, 2006a; Giles et al, 2006; Ottmann et al, 2006).
    c) Neutropenia occurred in 14% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). The majority (13%) of cases were grade 3 or 4. Neutropenia appeared to be dose-related (Kantarjian et al, 2006).
    d) In clinical trials of patients with chronic myeloid leukemia (CML) receiving nilotinib, febrile neutropenia was reported in 1% to 10% of patients and was one of the most common serious adverse reactions reported among the accelerated-phase patients (Prod Info TASIGNA(R) oral capsules, 2007).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, Grade 3 or 4 thrombocytopenia was reported in 28% (Grade 3, 11%; Grade 4, 17%) of 318 chronic-phase and 37% (Grade 3, 7%; Grade 4, 30%) of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Thrombocytopenia was one of the most common serious adverse reactions in both chronic-phase and accelerated-phase patients (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Grade 3 or 4 thrombocytopenia occurred in 24% to 33% of patients with various phases of chronic myeloid leukemia (CML) and 9% of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who received nilotinib in phase II, open-label clinical trials (LeCoutre et al, 2006; Kantarjian et al, 2006a; Giles et al, 2006; Ottmann et al, 2006).
    c) Thrombocytopenia occurred in 21% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). The majority (20%) of cases were grade 3 or 4. Thrombocytopenia appeared to be dose-related (Kantarjian et al, 2006).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, Grade 3 or 4 anemia was reported in 8% of 318 chronic-phase and 23% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Anemia was usually reversible with temporary discontinuation or dose reduction of nilotinib (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Grade 3 or 4 anemia occurred in 7% to 16% of patients with various phases of chronic myeloid leukemia (CML) who received nilotinib in phase II, open-label clinical trials (LeCoutre et al, 2006; Kantarjian et al, 2006a; Giles et al, 2006; Ottmann et al, 2006).
    c) Anemia occurred in 9% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). The majority (6%) of cases were grade 3 or 4 (Kantarjian et al, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, rash was reported in 33% of 318 chronic-phase and 28% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Rash was one of the most common adverse reactions reported (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Rash occurred in 22% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). The majority (20%) of cases were grade 1 or 2 (Kantarjian et al, 2006).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, pruritus was reported in 29% of 318 chronic-phase and 20% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively. Pruritus was one of the most common adverse reactions (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Pruritus occurred in 17% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). The majority (15%) of cases were grade 1 or 2 (Kantarjian et al, 2006).
    C) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) In clinical trials of patients with chronic myeloid leukemia (CML) receiving nilotinib, dry skin was reported in 1% to 10% of patients (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Dry skin occurred in 12% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). All cases were grade 1 or 2 (Kantarjian et al, 2006).
    D) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials of patients with chronic myeloid leukemia (CML) receiving nilotinib, alopecia was reported in 1% to 10% of patients (Prod Info TASIGNA(R) oral capsules, 2007).
    b) Alopecia occurred in 6% of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who received nilotinib in a phase I, dose-escalation trial (n=119). All cases were grade 1 or 2 (Kantarjian et al, 2006).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, arthralgia was reported in 18% of 318 chronic-phase and 16% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, myalgia was reported in 14% of 318 chronic-phase and 14% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    b) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, muscle spasm was reported in 11% of 318 chronic-phase and 14% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    C) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, extremity pain was reported in 13% of 318 chronic-phase and 16% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    D) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, bone pain was reported in 11% of 318 chronic-phase and 13% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).
    b) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, back pain was reported in 10% of 318 chronic-phase and 12% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) In a single, open-label, multicenter clinical trial of 438 chronic myeloid leukemia (CML) patients, hyperglycemia (Grades 3 or 4) was reported in 11% of 318 chronic-phase and 4% of 120 accelerated-phase patients receiving nilotinib (median dose 797 mg/day) over a median duration of 245 and 138 days, respectively (Prod Info TASIGNA(R) oral capsules, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Nilotinib is classified as FDA pregnancy category D. A case report described a successful pregnancy after nilotinib use during the first trimester. In animals, abortion and decreased gestation weight occurred at doses associated with maternal toxicity. Embryo-fetal toxicity (increased resorption and post-implantation loss), and minor skeletal anomalies have been also reported in animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In rats, embryo-fetal toxicity, including increased resorption and post-implantation loss, occurred at doses of 30 mg/kg/day or higher, and a decrease in viable fetuses occurred at a dose of 100 mg/kg/day. In rabbits, embryo-fetal toxicity was evident at oral doses of 300 mg/kg/day. Embryo-fetal effects included increased resorption and minor skeletal abnormalities. Nilotinib is not considered to be teratogenic (Prod Info TASIGNA(R) oral capsules, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Nilotinib is classified by the manufacturer as FDA pregnancy category D (Prod Info TASIGNA(R) oral capsules, 2009).
    B) LACK OF EFFECT
    1) A case report described a successful pregnancy in a 30-year-old woman with Philadelphia-positive chronic myeloid leukemia (CML) after nilotinib exposure during the first trimester of her second pregnancy. CML was diagnosed at 16 weeks during her first pregnancy. After delivering a healthy baby, imatinib was initiated; however, the drug was permanently discontinued due to hepatotoxicity. One year later as a participant in a phase II trial, the patient was initiated on oral nilotinib 400 mg twice daily. She experienced grade 1 hepatotoxicity and grade 3 myelotoxicity after 1 week resulting in a dose reduction. Her nilotinib dose was 200 mg twice daily when she became pregnant with her second child. After being advised of the potential fetotoxicity of nilotinib treatment, the patient desired to continue the pregnancy. Therefore, nilotinib was immediately discontinued. At gestational week 33, a healthy baby was delivered, breast-fed for 2 months, and remained healthy with normal development at 5 months of age. Molecular, cytogenic and hematologic response were lost after the patient delivered. As a result, she was initiated on dasatinib 100 mg/day and is now in complete hematologic remission (Conchon et al, 2009).
    C) ANIMAL STUDIES
    1) In studies in pregnant rats, maternal and embryo-fetal toxicity were evident at oral doses of 100 mg/kg/day, which resulted in approximately 5.7-fold the exposure (AUC) in patients at the recommended human dose. Decreases occurred in gestation weight, gravid uterine weight, net weight gain, food consumption and viable fetuses. Increased resorption and post-implantation loss occurred at lower doses (30 mg/kg/day or higher; 2 times the human exposure). In pregnant rabbits, maternal and embryo-fetal toxicity were evident at oral doses of 300 mg/kg/day (approximately one-half the human exposure (AUC)). Maternal effects included mortality, abortion, and decreased gestation weights and food consumption. Embryo-fetal effects included increased resorption and minor skeletal abnormalities. Nilotinib is not considered to be teratogenic (Prod Info TASIGNA(R) oral capsules, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lactation studies with nilotinib have not been conducted in humans, and it is not known whether it is excreted into human milk (Prod Info TASIGNA(R) oral capsules, 2009).
    B) ANIMAL STUDIES
    1) Nilotinib was excreted into the milk of lactating rats in one study (Prod Info TASIGNA(R) oral capsules, 2009).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) The effect of nilotinib on human fertility is not known (Prod Info TASIGNA(R) oral capsules, 2009).
    B) ANIMAL STUDIES
    1) In a study of male and female rats and female rabbits, there were no effects on mating or fertility at doses up to 180 mg/kg (approximately 4- to 7-fold the recommended human dose based on AUC) or 300 mg/kg (approximately one-half the recommended human dose), respectively. In a study of male and female rats, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested following nilotinib exposure at oral doses of 20 to 180 mg/kg/day (approximately 1- to 6.6-fold the recommended human dose) during the premating and mating periods, following mating, and continuing on nilotinib through gestation day 6 (Prod Info TASIGNA(R) oral capsules, 2009).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) RATS: There was no evidence of carcinogenicity when rats were administered oral nilotinib at doses of 5, 15, and 40 mg/kg/day in a 2-year carcinogenicity study. The highest dose tested was approximately 2- to 3-fold the human exposure at a nilotinib dose of 400 mg twice daily (based on AUC). In a 26-week carcinogenicity study, nilotinib at doses up to 300 mg/kg/day resulted in an increase in papillomas in females and papillomas and combined papillomas and carcinomas in males. The no observed adverse effect level (NOAEL) for skin neoplastic lesions was 100 mg/kg/day (Prod Info TASIGNA(R) oral capsules, 2015).

Genotoxicity

    A) There was no evidence of mutagenicity with nilotinib in a bacterial mutagenesis (Ames) assay. Nilotinib was not clastogenic in a human lymphocyte chromosome aberration assay and an in vivo rat bone marrow micronucleus assay after 2 oral doses of up to 2000 mg/kg/dose. Nilotinib did not induce DNA damage in a comet assay with L5178Y mouse lymphoma cells (Prod Info TASIGNA(R) oral capsules, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC with differential and platelet counts. Monitor serum electrolytes including calcium and phosphorus, and serum aminotransferase and bilirubin concentrations after significant overdose.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC with differential and platelet counts. Monitor serum electrolytes including calcium and phosphorus, and serum aminotransferase and bilirubin concentrations after significant overdose.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatography with ultraviolet detection was performed for the determination and quantification of nilotinib in human plasma and urine. The limit of detection in plasma and urine, using this method, was 2 ng/mL and 10 ng/mL, respectively. The lower limits of quantification for plasma and urine was 5 ng/mL and 100 ng/mL, respectively (Pursche et al, 2007).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor serial CBC with differential and platelet counts. Monitor serum electrolytes including calcium and phosphorus, and serum aminotransferase and bilirubin concentrations after significant overdose.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In cases of nilotinib overdose, treatment should be symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor hepatic enzymes after significant overdose.
    2) Monitor fluid and electrolyte status after acute overdose and in patients with severe vomiting and/or diarrhea.
    3) Monitor serial CBC with differential and platelet count after significant overdose.
    4) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT interval prolongation.
    C) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    D) TORSADES DE POINTES
    1) Torsades de pointes has not been reported after nilotinib overdose, but is possible because of its QT prolonging properties.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to the high protein binding of nilotinib, hemodialysis is not expected to be an effective method of enhanced elimination (Prod Info TASIGNA(R) oral capsules, 2007).

Range Of Toxicity

Summary

    A) There is no overdose information available for nilotinib at the time of this review.

Therapeutic Dose

    7.2.1) ADULT
    A) PHILADELPHIA CHROMOSOME-POSITIVE CHRONIC MYELOID LEUKEMIA
    1) NEWLY DIAGNOSED, CHRONIC PHASE: Recommended dose is 300 mg orally twice daily(Prod Info TASIGNA(R) oral capsules, 2014).
    2) RESISTANT OR INTOLERANT, CHRONIC AND ACUTE PHASES: Recommended dose is 400 mg orally twice daily (Prod Info TASIGNA(R) oral capsules, 2014).
    3) ADMINISTRATION: Swallow the capsules whole with water (Prod Info TASIGNA(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of nilotinib have not been established in pediatric patients (Prod Info TASIGNA(R) oral capsules, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) 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 (Prod Info TASIGNA(R) oral capsules, 2007).

Physicochemical

Physical Characteristics

    A) Nilotinib is a white to slightly yellowish to slightly greenish yellow powder. Its solubility in aqueous solutions decreases with increasing pH (Prod Info TASIGNA(R) oral capsules, 2007).

Molecular Weight

    A) 565.98 (Prod Info TASIGNA(R) oral capsules, 2007)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    4) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    5) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    6) Conchon M, Sanabani SS, Bendit I, et al: Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study. J Hematol Oncol 2009; 2:42.
    7) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    8) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    9) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    11) Giles F, LeCoutre P, Bhalla K, et al: A phase II study of nilotinib, a novel tyrosine kin ase inhibitor administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who have also failed dasatinib therapy. Blood 2006; 108(N11,1):615A-616A.
    12) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    13) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    14) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    15) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
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    18) Kantarjian HM, Gattermann N, Hochhaus A, et al: A phase II study of nilotinib a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). Blood 2006a; 108(N11,1):615A-615A.
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    20) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    21) LeCoutre P, Bhalla K, Giles F, et al: A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib-resistant and -intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP). Blood 2006; 108(N11,1):53A-53A.
    22) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    23) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    24) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    25) Ottmann O, Kantarjian H, Larson R, et al: A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). Blood 2006; 108(11, Part 1):528A-528A.
    26) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    27) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    28) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    29) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    30) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    31) Product Information: TASIGNA(R) oral capsules, nilotinib oral capsules. Novartis Pharmaceuticals Corporation, East Hanover, NJ;, 2007.
    32) Product Information: TASIGNA(R) oral capsules, nilotinib oral capsules. Novartis Pharmaceuticals Corporation (per FDA), East Hanover, NJ, 2014.
    33) Product Information: TASIGNA(R) oral capsules, nilotinib oral capsules. Novartis Pharmaceuticals Corporation (per manufacturer), East Hanover, NJ, 2015.
    34) Product Information: TASIGNA(R) oral capsules, nilotinib oral capsules. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2009.
    35) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    36) Pursche S, Ottmann OG, Ehninger G, et al: High-performance liquid chromatography method with ultraviolet detection for the quantification of the BCR-ABL inhibitor nilotinib (AMN107) in plasma, urine, culture medium and cell preparations. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852(1-2):208-216.
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    38) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
    39) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    40) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    41) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.