March 22, 2018, with PAP

On March 22, 2018, the Food and Drug Administration approved nilotinib (TASIGNA®, Novartis Pharmaceuticals Corporation) for pediatric patients 1 year of age or older with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy.

Approval was based on results in 69 pediatric patients with Ph+ CML-CP from two open-label, single-arm, multi-center trials: CAMN107A2120 (NCT01077544) in pediatric patients with Ph+ CML-CP resistant or intolerant to imatinib or dasatinib (n=11) and CAMN107A2203 (NCT01844765) in pediatric patients with Ph+ CML-CP resistant or intolerant to imatinib or dasatinib (n=33) and newly diagnosed Ph+ CML-CP (n=25). In both trials, patients received nilotinib 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (maximum single dose of 400 mg) in 28-day treatment cycles. The median time on treatment was 13.8 months (range: 0.7 to 30.9 months).

In patients with resistant or intolerant Ph+ CML-CP, the major molecular response rate (MMR; BCR-ABL/ABL ≤0.1% IS) was 40.9% (18/44, 95% CI: 26.3%, 56.8%) at 12 cycles. In patients with newly diagnosed Ph+ CML-CP, the MMR rate was 60.0% (15/25, 95% CI: 38.7%, 78.9%) at 12 cycles. In patients with resistant or intolerant CML, the cumulative MMR rate was 47.7% (21/44) by cycle 12. In patients with newly diagnosed CML, the cumulative MMR rate was 64.0% (16/25) by cycle 12.

Among patients with resistant or intolerant CML, 4.5% of patients achieved BCR-ABL/ABL ≤0.0032% IS (MR4.5) by the cut-off date. Among patients with newly diagnosed CML, the percentage who achieved MR4.5 was 28.0%.

The safety profile in pediatric patients is similar to the known safety profile in adults with Ph+ CML-CP. Common adverse reactions (greater than 20%) were hyperbilirubinemia, thrombocytopenia, rash, neutropenia, lymphopenia, alanine aminotransferase (ALT) increased, headache, anemia, pyrexia, nausea, upper respiratory tract infection, aspartate aminotransferase increased, and vomiting. The most common grade 3/4 adverse reactions were ALT increased and hyperbilirubinemia. Increase in QTcF greater than 30 msec from baseline was observed in 17 patients (25%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline.

The recommended pediatric dose is 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (maximum single dose of 400 mg).

Full prescribing information is available at:

FDA granted this application priority review and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist’s Applications to Practice

Nilotinib for Pediatric Patients with Newly Diagnosed or Resistant or Intolerant Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase

Author: Kala Rorabaugh, PharmD BCPPS
West Virginia University Medicine Children’s Hospital
Morgantown, WV

What is the potential role for nilotinib in the treatment of pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP)?1-9

  • Chronic myeloid leukemia (CML) in pediatric patients is relatively rare, with increasing incidence as age increases, reaching a peak incidence of 1.2 per million children per year in adolescence.
  • A Children’s Oncology Group (COG) study found that imatinib was effective in children with newly diagnosed CML, resulting in 72% of patients achieving complete cytogenetic response. Up to 20% of patients failed initial therapy with imatinib.
    • In adult patients, in a major open-label cross-over study comparing imatinib to interferon alfa plus cytarabine, 15.9% of patients discontinued imatinib therapy because of “unsatisfactory therapeutic effect.”
      • The cumulative rate of major cytogenetic response to imatinib was 89%.
    • A phase 2 open-label nonrandomized prospective trial of pediatric patients with newly diagnosed or imatinib-resistant or -intolerant CML-CP, imatinib-resistant or -intolerant CML in accelerated or blast phase, and Ph+ acute lymphoblastic leukemia reviewed the safety and efficacy of dasatinib.
      • Complete cytogenetic response was 76% at 12 months in pediatric patients with imatinib-resistant CML-CP and 92% in the newly diagnosed CML-CP patients.
      • Twenty-nine patients in the CML-CP group (n = 113) were imatinib-resistant or -intolerant.
    • A phase 3 study comparing dasatinib to imatinib in treatment-naive CML-CP adult patients has also been conducted.
      • Complete cytogenetic response at 3 months in patients on dasatinib and imatinib was 94% and 92%, respectively.
      • Treatment failure, defined as lack of hematologic response or progression of disease, occurred in 11% of dasatinib patients and in 14% of imatinib patients.
  • In vitro, nilotinib has shown activity against imatinib-resistant leukemic cells, as well as imatinib-sensitive leukemic cells, through a different inhibition mechanism of the tyrosine kinase domain of the BCR-ABL gene on the Philadelphia chromosome.
  • Protocol CAMN107A2120, partnering with COG, studied nilotinib in pediatric patients with Ph+ CML-CP resistant or intolerant to imatinib or dasatinib (n = 44), as well as those newly diagnosed with Ph+ CML-CP (n = 25).
    • Patients resistant or intolerant to other tyrosine kinase inhibitors (TKIs) showed a major molecular response rate (MMR) of 40.9% (18/44, 95% confidence interval [CI]: 26.3%, 56.8%).
      • Gore et al. reported an MMR at 12 months of 41% in pediatric patients resistant or intolerant to imatinib who were taking dasatinib.8
    • Newly diagnosed patients had an MMR of 60% (15/25, 95% CI: 38.7%, 78.9%).
      • Gore et al. reported an MMR of 52% in pediatric patients with newly diagnosed CML-CP who were taking dasatinib.8
  • Pediatric patients with Ph+ CML-CP either resistant or intolerant to imatinib or dasatinib now have another treatment option in nilotinib.
    • In patients with imatinib-resistant Ph+ CML-CP, dasatinib and nilotinib have similar safety and efficacy profiles. Decisions about which TKI to use as a second-line therapy should be based upon the significance of differences in dosing, potential adverse effects, and drug-drug interactions to the individual patient.

What role can the pharmacist play in the management of patients on nilotinib?1,6

  • Pharmacists can make an impact by managing the doses used in pediatric patients taking nilotinib.
    • Protocols CAMN107A2120 and CAMN107A2203 dosed nilotinib at 230 mg/m2 twice daily, rounded to the nearest 50 mg (maximum dose: 400 mg).
  • Dose reductions may be required for myelosuppression and other toxicities such as elevated serum lipase or amylase, elevated bilirubin, and elevated hepatic transaminases.
  • Nilotinib is a CYP3A4 substrate; concomitant use with CYP3A4 inhibitors and inducers may increase and decrease serum concentrations, respectively.
  • The concomitant use of proton pump inhibitors (PPIs) can decrease serum concentrations of nilotinib. Use of PPIs with nilotinib is not recommended; instead a histamine-2 receptor antagonist (H2RA) or antacid may be used.
  • QTc-prolonging medications should also be avoided with nilotinib, because this medication can prolong the QTc interval.
  • Tumor lysis syndrome may occur in patients with imatinib-resistant or -intolerant CML.
  • Because nilotinib is an oral medication, pharmacists may assist patients with acquisition through specialty pharmacies.
  • Administration:
    • Nilotinib should be administered in doses as close to 12 hours apart as possible, on an empty stomach (1 hour before or 2 hours after eating).
      • For patients who are unable to swallow whole capsules, the capsule may be opened, dispersed into 5 ml of applesauce, and administered within 15 minutes. Do not save the nilotinib-applesauce mixture for administration later.
    • Dasatinib is administered once daily, without regard to food. It cannot be administered with acid-suppressing drugs other than antacids, separated by 2 hours before and after. If patients are unable to discontinue therapy with a PPI or an H2RA, nilotinib may be preferred.
    • Imatinib is administered once or twice daily in children, ideally with food. Imatinib does not have drug-drug interactions with acid-suppressing agents.

Clinical Pearls1

  • In patients requiring acid suppression, the following recommendations showed no effect on serum concentrations of nilotinib.
    • An H2RA should be administered 10 hours prior to or 2 hours after a dose of nilotinib.
    • An antacid should be administered 2 hours prior to or 2 hours after a dose of nilotinib.
  • In patients with an absolute neutrophil count (ANC) less than 1 x 109/L or a platelet count less than 50 x 109/L, nilotinib should be withheld. Lab results should be reevaluated in 2 weeks, and if the ANC and platelet count remain low at 2 weeks, the dose may be reduced to 230 mg/m2 once daily.


  1. Tasigna [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2018. Accessed March 29, 2018.
  2. Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation: September 2017. Accessed March 29, 2018.
  3. Sprycel [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; October 2010. Accessed March 29, 2018.
  4. Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program; 2010:368-376.
  5. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of BCR-ABL, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005;11(13):4941-4947.
  6. FDA approves nilotinib for pediatric patients with newly diagnosed or resistant/intolerant Ph+ CML in chronic phase. (March 22, 2018). Retrieved March 29, 2018, from
  7. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017; 376(10):917–927.
  8. Gore L, Kearns PR, de Martino ML, et al. Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase: results from a phase II trial. J Clin Oncol. 2018;36(13):1330-1338.
  9. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333-2340.