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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


August 2, 2017–Ibrutinib (Imbruvica®, Pharmacyclics LLC) for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy. This is the first FDA-approved therapy for the treatment of cGVHD (with Pharmacist's Applications to Practice.).

January 29, 2015–Ibrutinib (Imbruvica® Capsules) approved for the treatment of patients with Waldenstrom’s macroglobulinemia.


August 2, 2017 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017lbl.pdf

On August 2, 2017, the U.S. Food and Drug Administration approved ibrutinib (Imbruvica®, Pharmacyclics LLC) for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy. This is the first FDA-approved therapy for the treatment of cGVHD.

Approval was based on Study PCYC-1129-CA (NCT02195869), an open-label, multi-center, single-arm clinical trial enrolling 42 patients with cGVHD after failure of first-line corticosteroid therapy and requiring additional therapy. The majority of patients (88%) had at least two organs involved at baseline. The most common organs involved were mouth (86%), skin (81%), and gastrointestinal tract (33%).

Patients received ibrutinib orally at 420 mg once daily. Investigator-assessed overall response rate was 67%, or 28 patients (95% CI: 51%, 80%). The median time-to-response coinciding with the first scheduled response assessment was 12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen in all organs involved with cGVHD (skin, mouth, gastrointestinal tract, and liver). Responses lasting five months or longer were observed in 48% of the patients (n=20).

The most common adverse reactions (≥20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (Grade 3). Treatment was discontinued due to adverse reactions in 24% of the patients. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.

FDA previously approved ibrutinib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma.

The recommended dose of ibrutinib for cGVHD is 420 mg taken orally once daily (three 140 mg capsules once daily).

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017lbl.pdf.

FDA granted Breakthrough Therapy and Orphan Drug designations to ibrutinib for this indication, as well as priority review. 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

Ibrutinib (Imbruvica) for the Treatment of Adult Patients with Chronic Graft Versus Host Disease After Failure of One or More Lines of Systemic Therapy

Authors: Elisabeth Carroll, PharmD Candidate
University of Colorado
Aurora, CO

Ashley Glode, PharmD BCOP
University of Colorado
Aurora, CO

What is the potential role for ibrutinib in the treatment of chronic graft versus host disease (cGVHD)?1,2

  • cGVHD is predicted to occur in 30%–70% of hematopoietic stem cell transplant patients, although the exact incidence by grade has not been reported. 
  • Systemic corticosteroids are currently the standard of care for cGVHD. In resistant disease, the addition of other systemic immunosuppressant agents, such as calcineurin inhibitors or rituximab, may be considered but are currently not approved by the U.S. Food and Drug Administration (FDA) for this indication.
  • Ibrutinib was approved by the FDA with priority, breakthrough therapy, and orphan drug designations and is the first therapy approved for cGVHD under the caveat that the patient must first fail at least one other systemic therapy, such as corticosteroids.
  • Ibrutinib was studied in a single-arm study of 42 patients with cGVHD whose symptoms persisted despite standard treatment with corticosteroids.
    • Patients included in this study had either >25% body surface area erythematous rash or a National Institutes of Health mouth score greater than 4. The most commonly affected organs were the mouth (86%), skin (81%), and gastrointestinal tract (33%).
    • Sixty-seven percent of patients experienced improvement in their cGVHD symptoms.
    • A major advantage to ibrutinib may be its steroid-sparing effect.
      • In this trial, 62% of patients reduced their steroid doses to less than 0.15 mg/kg/day, and 5 patients (12%) discontinued steroids completely.
  • As this was a single-arm trial, it is currently unknown how ibrutinib compares to other treatment options for this disease.

What role can the pharmacist play in the management of patients on ibrutinib?2,3

  • Because ibrutinib is administered orally, pharmacists may help their patients gain access to medication and counseling and also help with monitoring and adherence.
  • Ibrutinib is metabolized via cytochrome P450 3A4 (CYP3A4); pharmacists need to evaluate the risk of drug-drug interactions because concurrent use with strong 3A4 inducers or inhibitors (including grapefruit juice) should be avoided.
    • Specific dosing recommendations regarding concomitant administration with posaconazole and voriconazole can be found in the package insert.
  • Caution should also be exercised in patients on concomitant anticoagulant and antiplatelet agents because ibrutinib may increase the risk of bleeding.
  • Serious adverse events (grade 3 or 4) have occurred, including bleeding events (6%), infections (14%–29%), cytopenias (0%–29%), atrial fibrillation (6%–9%), and tumor lysis syndrome (rare).
  • In this study, the most common adverse events were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Adverse events of grade 3 or higher included pneumonia (n = 6), fatigue (n = 5), diarrhea (n = 4), and atrial fibrillation (n = 1). Other serious adverse events included septic shock (n = 2) and pyrexia (n = 2).

Clinical Pearls2-4

  • Patients in this study were treated with ibrutinib 420 mg daily until cGVHD progressed or an unacceptable level toxicity was reached. Dose modifications are recommended for hepatic impairment and grade 3 or higher adverse reactions. 
    • Chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenström macroglobulinemia are also treated with 420 mg once daily; mantle cell lymphoma and marginal zone lymphoma are treated with 560 mg once daily.
    • In mild hepatic impairment (Child-Pugh class A), decrease dose to 140 mg daily. Avoid use in moderate to severe hepatic impairment (Child-Pugh classes B and C).
    • Although ibrutinib is not renally cleared, its use has not been studied in patients with CrCl less than 25 ml/minute. No dose modifications are needed in patients with CrCl greater than 25 ml/minute.
  • Consider withholding ibrutinib for at least 3–7 days before and after surgery, depending on the type of surgery and the patient’s risk of bleeding.
  • Ibrutinib, manufactured only as 140-mg capsules, should not be crushed, altered, or chewed. Appropriate precautions for handling hazardous drugs should be taken.
  • For patients with commercial health insurance, financial assistance is available through the manufacturer (https://www.imbruvica.com/patient-support/cost-support). The estimated wholesale acquisition price for 1 month of therapy is $11,100.

References

  • Chao NJ. Treatment of chronic graft-versus-host disease. UpToDate. Waltham, MA: UpToDate; 2017. Accessed September 5, 2017.
  • Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. 2016 American Society of Hematology Annual Meeting. Abstract LBA3. December 2016.
  • Imbruvica [package insert]. Pharmacyclics LLC, Sunnyvale, CA; August 2017. www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017lbl.pdf. Accessed September 5, 2017.
  • Active Ingredient: Ibrutinib. RED BOOK Online. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics; 2017. Accessed September 5, 2017.

January 29, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf

On January 29, 2015 the U. S. Food and Drug Administration approved ibrutinib (Imbruvica® Capsules, Pharmacyclics, Inc.) for the treatment of patients with Waldenstrom’s macroglobulinemia (WM). Ibrutinib was initially approved in November 2013 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Ibrutinib also received approval in February 2014 for the treatment of chronic lymphocytic leukemia (CLL) in patients who received at least one prior therapy and in July 2014 for the treatment of CLL with 17p deletion.

The approval was based on demonstration of durable responses in a single arm, multi-center clinical trial enrolling 63 patients with previously treated WM. Patients received ibrutinib 420 mg orally once daily.

The response rate included complete response (CR), very good partial response (VGPR), and partial response (PR). The response rate was 61.9% (95%CI 48.8, 73.9). The responses consisted of VGPR (11.1%) and PR (50.8%). No patient achieved a complete response. The median response duration was not reached (range of 2.8+ to 18.8+ months). The median time to response was 1.2 months.

The most common adverse reactions (greater than or equal to 25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash.

The recommended dose and schedule for ibrutinib for the treatment of patients with WM is 420 mg orally once daily.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.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).

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