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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.


September 26, 2019–Daratumumab (DARZALEX, Janssen) for adult patients with multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant (ASCT).

June 27, 2019–Daratumumab (DARZALEX, Janssen Biotech, Inc.) in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

November 21, 2016–Daratumumab (DARZALEX) approved for treatment of patients with multiple myeloma who have received at least on prior therapy (with Pharmacist's Applications to Practice.)

November 16, 2015–Daratumumab injection (DARZALEX™) granted accelerated approval administered as a single agent for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy.


September 26, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s024lbl.pdf

On September 26, 2019, the Food and Drug Administration approved daratumumab (DARZALEX, Janssen) for adult patients with multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant (ASCT).

Efficacy was investigated in CASSIOPEIA (NCT02541383), an open-label, randomized, active-controlled phase 3 study comparing induction and consolidation treatment with daratumumab 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT.

Approval is based on data from CASSIOPEIA, including progression-free survival (PFS), stringent complete response (sCR) at 100 days post-ASCT, and CR rate at day 100 post-ASCT. The trial demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; with a median follow up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001).The sCR rate at Day 100 post-ASCT was 28.9% in the DVTd arm and 20.3% in the VTd arm.

In patients with newly diagnosed multiple myeloma who received daratumumab in combination with bortezomib, thalidomide and dexamethasone, the most frequent (≥20%) adverse reactions were infusion reactions, peripheral sensory neuropathy, constipation, asthenia, nausea, peripheral edema, neutropenia, thrombocytopenia, pyrexia and paresthesia. Adverse reactions that occurred with at least 5% greater frequency in the DVTd arm were infusion reactions, nausea, neutropenia, thrombocytopenia, lymphopenia and cough. There were no significant differences in the number or type of serious adverse events in the two treatment arms.

The recommended daratumumab dose is 16 mg/kg actual body weight.

View full prescribing information for DARZALEX.

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

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 or by calling 1-800-FDA-1088.


June 27, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s020lbl.pdf.

On June 27, 2019, the Food and Drug Administration approved daratumumab (DARZALEX, Janssen Biotech, Inc.) in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

Approval was based on MAIA (NCT02252172), an open-label, randomized (1:1), active-controlled phase 3 study, comparing dartumumab (16 mg/kg) in combination with lenalidomide and low-dose dexamethasone (DRd) to lenalidomide and low-dose dexamethasone (Rd), in 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant.

The trial demonstrated an improvement in progression-free survival (PFS) in the DRd arm compared with the Rd arm. The median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (HR 0.56; 95% CI: 0.43, 0.73; p<0.0001). The median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median response duration had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.

Daratumumab can cause severe and/or serious infusion reactions, including anaphylactic reactions. Approximately half of all patients in clinical trials experienced an infusion reaction. Patients should be pre‑medicated with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion is recommended.

In newly diagnosed multiple myeloma patients who received daratumumab in combination with lenalidomide and dexamethasone, the most frequent (≥20%) adverse reactions were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea and cough.

The recommended daratumumab dose is 16 mg/kg actual body weight. View full prescribing information for drugs used in combination and schedule.

This application used the Real-Time Oncology Review. FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Project Facilitate: The Oncology Center of Excellence program for Expanded Access—For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

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 or by calling 1-800-FDA-1088.


November 21, 2016 with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf

On November 21, 2016, the U.S. Food and Drug Administration approved daratumumab (DARZALEX, Janssen Biotech, Inc.) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Daratumumab was previously granted accelerated approval in November 2015 as monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.

The current approval was based on two randomized, open-label trials in which daratumumab was added to standard therapies. The POLLUX trial (also known as MMY3003), demonstrated substantial improvement in progression-free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. The estimated median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing a 63% reduction in the risk of disease progression or death in patients treated with daratumumab.

Similar results were observed in the CASTOR trial (also known as MMY3004), which compared the combination of daratumumab, bortezomib, and dexamethasone with bortezomib and dexamethasone. The estimated median PFS was not reached in the daratumumab arm and was 7.2 months in the control arm (HR=0.39; 95% CI: 0.28, 0.53; p<0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with daratumumab.

The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3003 were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasm, cough and dyspnea. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3004 were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. Neutropenia and thrombocytopenia have been added to the Warnings and Precautions of the DARZALEX label.

The recommended dose of daratumumab is 16 mg/kg intravenously (calculated on actual body weight).

FDA granted daratumumab breakthrough therapy and orphan drug designation, as well as priority review. The current approval was granted three months prior to the PDUFA date of February 17, 2017. A description of these 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.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.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 Application to Practice

Daratumumab for Multiple Myeloma

Author: Sarah Ussery, PharmD BCOP
Senior Medical Science Liaison—Hematology
Celgene Corporation
Midlothian, TX

What is the potential role for daratumumab in the treatment of multiple myeloma (MM)?

  • Daratumumab indication was expanded to include its use, in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received one prior therapy.1
    • The current new indication approval was based on two randomized, open-label trials (the POLLUX trial2 and the CASTOR trial3), in which daratumumab was added to standard therapies. Estimated median progression-free survival end points were not reached in either trial; however, both studies showed a statistically significant reduction in the risk of disease progression or death (63%2 and 61%3) in patients treated with daratumumab.
  • Daratumumab is approved in combination for second-or-greater-line treatment of MM and as monotherapy for patients with MM who have received at least three prior lines of therapy that includes a proteasome inhibitor and an immunomodulatory agent.1

What role can the pharmacist play in the management of patients on daratumumab?4

    • Patients receiving this combination should have received one prior line of therapy, which could have included a prior autologous stem cell transplant.
    • Patients should be appropriately premedicated for prevention of infusion reactions with daratumumab, most frequently occurring with the first infusion.
    • Herpes zoster prophylaxis should be initiated within the first week of treatment and continued until 3 months past completion of treatment.
    • Patients may be at a slightly higher risk for cytopenias when daratumumab is given in combination versus as monotherapy; patients should have close monitoring of blood counts and be monitored for signs and symptoms of infection.

Clinical Pearls

    • The dose of daratumumab is the same for monotherapy administration and combination administration at 16 mg/kg based on actual body weight.1,4
    • The dosing cycle differs between the two combination regimens:1,4
      • When given in combination with lenalidomide/dexamethasone, the cycle is based on a 4-week schedule, so weekly dosing is given for weeks 1–8, then every 2 weeks for weeks 9–24, and then every 4 weeks thereafter until disease progression.
      • When given in combination with bortezomib/dexamethasone, the cycle is based on a 3-week schedule, so weekly dosing is given for weeks 1–9, then every 3 weeks for weeks 10–24, and then every 4 weeks thereafter until disease progression.

References

  1. U.S. Food and Drug Administration. Daratumumab (Darzalex). www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm530249.htm. Updated November 22, 2016. Accessed February 1, 2017.
  2. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma (POLLUX trial). N Engl J Med. 2016 October 6;375(14):1319-31.
  3. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma (CASTOR trial). N Engl J Med. 2016 August 25;375(8):754-66.
  4. Darzalex® [prescribing information]: Janssen Biotech, Inc., Horsham, PA; November 2016. https://www.janssenmd.com/pdf/darzalex/DARZALEX_PI.pdf. Accessed February 1, 2017.

November 16, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761036s000lbl.pdf

On November 16, 2015, the U.S. Food and Drug Administration granted accelerated approval to daratumumab injection (DARZALEX™, Janssen Biotech, Inc.), administered as a single agent for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.    

Daratumumab is the first monoclonal antibody approved for the treatment of multiple myeloma. The approval was based on a multi-center, open-label study evaluating response rates in 106 patients with relapsed or refractory multiple myeloma treated with daratumumab monotherapy. The objective response rate was 29% (95% CI: 21-39%) with a median response duration of 7.4 months (range: 1.2 to 13.1+ months).

Safety data was evaluated in 156 patients who received the proposed dose and schedule of daratumumab. The most frequently reported adverse reactions (incidence greater than or equal to 20%) were infusion reactions, fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection. Pre-medication and post-infusion medications are recommended to prevent infusion reactions. The most common laboratory abnormalities were lymphopenia, neutropenia, anemia, and thrombocytopenia.

Daratumumab interferes with blood bank crossmatching, specifically with Indirect Antiglobulin Tests. If blood transfusion is necessary, inform the blood bank that a patient has received daratumumab.

As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing multicenter, randomized trials in patients with multiple myeloma with a primary endpoint of progression-free survival.

The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.

Daratumumab is being approved prior to the Prescription Drug User Fee Act (PDUFA) goal date of March 9, 2016. This application was granted Priority Review, Breakthrough Therapy Designation and Accelerated Approval. A description of these 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

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761036s000lbl.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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