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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


November 9, 2017 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf

On November 9, 2017, the Food and Drug Administration granted regular approval to dasatinib (SPRYCEL®, Bristol-Myers Squibb Co.) for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase​.

Approval was based on data from 97 pediatric patients with chronic phase CML evaluated in two trials—a phase 1, open-label, non-randomized, dose-ranging trial and a phase 2, open-label, non-randomized trial. Fifty-one patients exclusively from the phase 2 trial were newly diagnosed with chronic phase CML and 46 patients (17 from the phase 1 trial and 29 from the phase 2 trial) were resistant or intolerant to previous treatment with imatinib. The majority of patients were treated with dasatinib tablets 60 mg/m2 once daily. Patients were treated until disease progression or unacceptable toxicity.

After 24 months of treatment, 96.1% of newly diagnosed patients (95% CI: 86.5, 99.5) and 82.6% of patients resistant or intolerant to imatinib (95% CI: 68.6, 92.2) had complete cytogenic response (CCyR). With a median follow-up of 4.5 years in newly diagnosed patients and 5.2 years in imatinib-resistant or -intolerant patients, the median durations of CCyR, major cytogenic response (MCyR), and major molecular response (MMR) could not be estimated as more than half of the responding patients had not progressed at the time of data cut-off.

Adverse reactions reported in ³10% of dasatinib-treated pediatric patients (n=97) were headache, nausea, diarrhea, skin rash, vomiting, pain in extremity, abdominal pain, fatigue, and arthralgia.

The recommended dose of dasatinib in pediatric patients is based on body weight. Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf

FDA granted priority review and orphan product designation to dasatinib for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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 http://www.fda.gov/medwatch/report.htm, 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

Dasatinib for Pediatric Patients with Chronic-Phase Chronic Myelogenous Leukemia

Author: Mary K Walters, PharmD
PGY-2 Pharmacy Resident in Oncology
Aurora Health Care Metro, Inc.
Milwaukee, WI

What is the potential role for dasatinib in the treatment of pediatric chronic-phase chronic myelogenous leukemia (CP-CML)?

  • For more than a decade, the only BCR-ABL–targeted tyrosine kinase inhibitor (TKI) approved by the U.S. Food and Drug Administration (FDA) for pediatric patients with CML was imatinib (Gleevec). Utilization of targeted therapies in this patient population have thus been limited, particularly for the 25%–30% of patients who do not respond to, or are intolerant of, imatinib therapy.1
  • The approval of dasatinib as first-line therapy for children at least 1 year old and adolescents with Philadelphia chromosome–positive (Ph+) CP-CML provides an alternative to imatinib for patients.
  • Approval was based on two trials (a phase 1 open-label nonrandomized dose-ranging trial and a phase 2 open-label nonrandomized trial) in pediatric patients with newly diagnosed and relapsed or refractory CP-CML.2-5
    • After 24 months of treatment, complete cytogenetic response occurred in 96.1% of newly diagnosed patients and in 82.6% of patients with resistance or intolerance to imatinib.
    • Duration of response, cytogenic response, and major molecular response could not be estimated by the data cut-off because the disease had progressed in less than half of the patients.
    • Compared to studies of imatinib, dasatinib in this study appeared to produce a more robust and durable cytogenic response; however, the two drugs have not been compared head-to-head at this time.
  • CML is a rare pediatric leukemia (<3%); therefore, it is poorly studied in this patient population. As such, the National Comprehensive Cancer Network guidelines offer few evidence-based recommendations regarding dasatinib’s place in therapy versus imatinib or other TKIs.1
  • The role of other TKIs (nilotinib, bosutinib, and ponatinib) in children with CML is still investigational.1

What role can the pharmacist play in the management of patients on dasatinib?
Dosing information2

  • Unlike dosing for adults, dasatinib dosing recommendations for pediatric patients is stratified into weight categories:
    • 10 to <20 kg: 40 mg daily; dose may be escalated to 50 mg daily if hematologic or cytogenetic response is not achieved.
    • 20 to <30 kg: 60 mg daily; dose may be escalated to 70 mg daily if hematologic or cytogenetic response is not achieved.
    • 30 to <45 kg: 70 mg daily; dose may be escalated to 90 mg daily if hematologic or cytogenetic response is not achieved.
    • 45 kg or more: 100 mg daily; dose may be escalated to 120 mg daily if hematologic or cytogenetic response is not achieved.
  • There are no dosing recommendations for patients weighing less than 10 kg.
  • Dasatinib should be continued until the disease progresses or an unacceptable level of toxicity is reached.
  • Because children may grow during therapy, it is recommended that the dose be recalculated every 3 months or as clinically necessary based on changes in body weight.

Drug interactions2

  • Dasatinib is a major CYP3A4 substrate. Dosage adjustment recommendations based on drug interactions in pediatric patients are the same as those listed for adult patients.
    • Dosage adjustment for concomitant strong CYP3A4 inhibitors: Avoid concomitant administration of dasatinib with strong CYP3A4 inhibitors. If concomitant administration cannot be avoided, consider reducing dasatinib dose as follows:
      • Original dose: 100 mg once daily → 20 mg once daily
      • Original dose: 70 mg once daily → 20 mg once daily, with close monitoring
      • Original dose: 60 mg or 40 mg once daily → Withhold dasatinib until the strong CYP3A4 inhibitor is discontinued; allow a washout period (about 1 week) prior to reinitiating dasatinib.
    • Dosage adjustment for concomitant strong CYP3A4 inducers: Avoid concomitant administration with a strong CYP3A4 inducer. If concomitant administration with a strong CYP3A4 inducer cannot be avoided, consider increasing the dasatinib dose with careful monitoring.

Dose adjustments2

  • There are no dosage adjustments provided in the manufacturer’s labeling for hepatic or renal dysfunction. However, less than 4% of dasatinib and metabolites are renally excreted. Use with caution in patients with elevated transaminase or bilirubin.
  • Specific dose modifications for drug toxicity in pediatric patients are listed in the package insert.

Adverse events2-5

  • Frequency of adverse events experienced by participants in the trials:
    • Most common
      • Headache (28%)
      • Diarrhea (21%)
      • Nausea (20%)
      • Rash (19%)
      • Myalgia/Arthralgia (19%)
    • Severe (Grade 3/4)
      • Headache (3%)
      • Extremity Pain (1%)
      • Arthralgia (1%)
  • Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (~1%).2,3
  • In children with CML, TKI use for at least 2 years, especially in prepubertal children, has led to substantial growth abnormalities (e.g., epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia), possibly through disruption of the growth hormone/IGF-1 axis.2,4,5
    • Adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients in the dasatinib trials.4,5
    • Cotreatment with growth hormone or recombinant IGF-1 may improve the final adult height in children receiving TKIs; however, no study has demonstrated the safety or efficacy of this strategy. Bone growth and development in pediatric patients should be monitored.6,7
  • Patient assistance programs are available for the uninsured through the manufacturer, Bristol-Myers Squibb, according to an undisclosed income guideline.8 Assistance program details can be found at https://www.sprycel.com/sprycel-assist.

Clinical Pearls

  • Dasatinib is available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, and 140-mg tablets.2 The tablets may be taken with or without food.
  • Do not crush or cut the tablets (use protective chemotherapy gloves if the tablets need to be crushed).
    • It is recommended that patients take the tablet whole if possible. Drug exposure in patients receiving a crushed tablet is lower than in those swallowing an intact tablet.9
    • In the phase 1 and 2 trials, if patients were unable to swallow whole tablets, it was allowed that the tablets be dissolved and administered in 100% fruit juice with no preservatives by the following process:4,5
      • Place total dose in 30 ml of juice and let it stand.
      • Swirl the contents for 3 seconds after 5 minutes, 15 minutes, and 20 minutes. Then have the patient drink the mixture immediately or administer it through a nasogastric tube.
      • Rinse the container with an additional 15 ml of juice and administer to the patient to ensure that the entire dose is delivered.
    • Note: The compounded product is known to have a bitter taste, and juice best masks the flavor.
  • No data are available reporting long-term outcomes regarding the cessation of TKI therapy in children after achievement of cytogenetic response.3
  • Dasatinib has a minimal emetogenic risk.10
  • This agent may prolong the QT interval and may lead to torsade de pointes. Review the patient medication profile for concomitant administration of QT-prolonging drugs. EKG monitoring should be completed as clinically indicated.2
  • Dasatinib may cause severe diarrhea. Consider management with antidiarrheals (e.g., loperamide) as needed.1 Because of the paucity of literature on the use of dasatinib in pediatric patients, there is little reported information on the onset of diarrhea and development of tolerance to this side effect. Onset in adult trials appears to occur 2–3 days after initiation of therapy.2

References

  1. National Comprehensive Cancer Network. Chronic Myeloid Leukemia. Version 4.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed January 25, 2018.
  2. Sprycel (dasatinib) tablets [package insert]. Princeton, NJ. Bristol-Myers Squibb. November 9, 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf. Accessed December 11, 2017.
  3. U.S. Food and Drug Administration. FDA approves dasatinib for pediatric patients with CML. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm584725.htm. Accessed December 17, 2017.
  4. Zwaan CM, Rizzari C, Mechinaud F, Lancaster DL, Lehrnbecher T, Van der Velden VHJ. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 Phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol. 2013 Jul 1;31(19):2460-2468.
  5. U.S. National Library of Medicine. Clinical Trials.gov. A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib. Available at https://clinicaltrials.gov/ct2/show/NCT00777036. Accessed January 7, 2018.
  6. Rastogi MV, Stork L, Druker B, Blasdel C, Nguyen T, Boston BA. Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia. Pediatr Blood Cancer 2012;59(5):840-845.
  7. Hobernicht SL, Schweiger B, Zeitler P, Wang M, Hunger SP. Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy. Pediatr Blood Cancer. 2011;56(4):671-673.
  8. Bristol-Myers Squibb. Bristol-Myers Squibb Patient Assistance Program for Sprycel. Available at https://www.patientassistance.com/profile/bristolmyerssquibbcompany-93/ Accessed December 22, 2017.
  9. U.S. National Library of Medicine. Clinical Trials.gov. Pharmacokinetic Study Comparing Blood Levels of Dasatinib in Healthy Participants Who Received the Tablet Formulation With Those Who Received Liquid and Tablet-dispersed Formulations. Available at https://clinicaltrials.gov/ct2/show/NCT01392703. Accessed December 22, 2017.
  10. National Comprehensive Cancer Network. Antiemesis. Version 2.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed January 15, 2018.
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