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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.  


November 16, 2017–Obinutuzumab (GAZYVA®, Genentech, Inc.) granted regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL) (With Pharmacist's Applications to Practice.)

February 26, 2016–Obinutuzumab (Gazyva® Injection) approved for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma


November 16, 2017 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125486s017s018lbl.pdf

On November 16, 2017, the Food and Drug Administration granted regular approval to obinutuzumab (GAZYVA®, Genentech, Inc.) in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL).

Approval was based on a multicenter, open-label, randomized phase 3 trial (GALLIUM) for patients with previously untreated non-Hodgkin lymphoma, including 1202 patients with FL. Patients were randomized 1:1 to receive either obinutuzumab + chemotherapy or rituximab + chemotherapy, followed in responding patients by obinutuzumab or rituximab maintenance for up to 2 years. Of the patients with FL, 91% had stage III-IV disease, 44% had bulky disease, and 79% had at least intermediate-risk disease. The chemotherapy backbone was bendamustine in 57%, CHOP in 33% and CVP in 10%. With a median follow-up of 38 months, progression-free survival, as assessed by an independent review committee, was statistically significantly improved in the obinutuzumab arm, with an estimated hazard ratio of 0.72 (95% CI: 0.56, 0.93; p=0.0118) compared to the rituximab arm. Median progression-free survival was not reached in either arm. As assessed by CT, the arms had similar overall response rates (91% with obinutuzumab, 88% with rituximab) and complete remission rates (28% and 27%, respectively).

Among the 1385 patients evaluated for safety, the obinutuzumab arm had higher incidences of serious adverse reactions (ARs; 50% compared to 43% in the rituximab arm), grade ≥ 3 ARs (79% vs. 72%) and fatal infections (2% vs. < 1%). The most common ARs in the obinutuzumab arm (incidence ≥ 20% and ≥ 2% greater than in the rituximab arm) included infusion reactions, neutropenia, upper respiratory tract infection, cough, constipation and diarrhea. The most common grade ≥ 3 ARs (incidence ≥ 5%) observed more frequently with obinutuzumab were neutropenia, febrile neutropenia, thrombocytopenia and infusion reactions. Recipients of bendamustine had higher incidences of serious and fatal infections than recipients of CHOP or CVP.

In patients with previously untreated FL, the recommended dose-schedule of obinutuzumab is 1000 mg intravenously on days 1, 8 and 15 of cycle 1; 1000 mg on day 1 of cycles 2-6 or cycles 2-8; and then 1000 mg every 2 months for up to 2 years.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125486s017s018lbl.pdf

FDA granted priority review to obinutuzumab 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

Obinutuzumab (Gazyva) for Previously Untreated Stage II Bulky, III, or IV Follicular Lymphoma

Author: Patricia Corrigan, PharmD BCOP
Clinical Pharmacy Specialist, Hematology/Oncology
Virginia Commonwealth University Health
Richmond, VA

What is the potential role for obinutuzumab in the treatment of previously untreated follicular lymphoma?1-4

  • Obinutuzumab, in combination with chemotherapy, received regular approval by the U.S. Food and Drug Administration (FDA) for previously untreated advanced follicular lymphoma (FL). Patients achieving at least a partial response can then receive obinutuzumab monotherapy as maintenance for up to 2 years.
    • Approval was based on data from the GALLIUM trial, a randomized phase 3 study in patients with untreated CD20-positive grades 1–3a FL. Patients had bulky stage II or stage III or stage IV disease and met Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria for initiation of treatment. Patients were randomly assigned to obinutuzumab (n = 601) or rituximab (n = 601) plus induction chemotherapy (cyclophosphamide, vincristine, and prednisone [CVP, n = 118]; cyclophosphamide, vincristine, doxorubicin, and prednisone [CHOP, n = 398]; or bendamustine [n = 686]). Patients with a partial or complete response after induction received maintenance with the same antibody administered during induction.
    • During a planned interim analysis after a median follow-up of 34.5 months, the 3-year progression-free survival was longer in the obinutuzumab group than in the rituximab group (80% vs 73.3%; hazard ratio [HR] 0.66; p = .001).
    • There was no difference in overall response rate among the treatment groups (88.5% obinutuzumab vs. 86.9% rituximab; p = .33).
    • The overall survival rate was similar, with 94% of the obinutuzumab patients and 92.1% of the rituximab patients alive at 3 years (HR 0.75; 95% confidence interval [CI] .49–1.17; p = .21).
  • Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity, phagocytosis, and B-cell killing than rituximab and lower complement-dependent cytotoxicity.
  • Obinutuzumab is currently recommended by the National Comprehensive Cancer Network (NCCN) as a first-line treatment option for grades 1–2 advanced (stage II bulky, stage III, or stage IV) FL in combination with bendamustine, CVP, or CHOP chemotherapy (category 2A for all chemotherapy combinations). Rituximab plus bendamustine, CVP, or CHOP remains a category-1 recommendation in this population. Grade 3a FL is not included in these recommendations because of the controversy of managing it in the same way that diffuse large B-cell lymphoma is managed.
  • Maintenance obinutuzumab was added by the NCCN as optional consolidation treatment for FL after induction therapy with obinutuzumab plus chemotherapy (category 2A). Rituximab maintenance remains a category-1 recommendation in this setting.
  • On the basis of the interim results of the GALLIUM trial, obinutuzumab plus chemotherapy can be considered a first-line option for treating advanced FL, particularly in women, who appeared to have greater benefit from obinutuzumab plus chemotherapy in subgroup analyses. However, patients with comorbidities that may place them at higher risk of infusion reactions or infections should be treated with rituximab plus chemotherapy because of the higher rates of adverse reactions with obinutuzumab.

What role can the pharmacist play in the management of patients on obinutuzumab?2,3,5

  • The dosing of obinutuzumab in FL differs from the dose used in chronic lymphocytic leukemia. All doses of obinutuzumab in FL are 1,000 mg. In combination with chemotherapy, obinutuzumab is administered on days 1, 8, and 15 for cycle 1, then on day 1 for cycles 2–8, followed by obinutuzumab monotherapy every 2 months for up to 2 years.
  • Approximately 65% of patients treated with obinutuzumab for untreated FL experience an infusion reaction with the first dose. Some common symptoms include nausea, vomiting, fatigue, dyspnea, dizziness, chest discomfort, hypotension, hypertension, dyspnea, pyrexia, and chills.
    • Premedication with the following is required 60 minutes before the first infusion:
      • Dexamethasone 20 mg or methylprednisolone 80 mg intravenously
      • Acetaminophen 650–1,000 mg
      • Diphenhydramine 50 mg or an equivalent antihistamine
    • Premedication for subsequent infusions should include acetaminophen and, depending on the grade of the reaction with the previous infusion, an antihistamine or an intravenous glucocorticoid.
    • Because of the risk of hypotension, consider withholding antihypertensives for at least 12 hours before and 1 hour after each obinutuzumab infusion.
  • Tumor lysis prophylaxis was not required when obinutuzumab was given in first-line FL, but it should be considered in patients at risk for tumor lysis syndrome.
  • Because of the risk of hepatitis B virus (HBV) reactivation, all patients should be screened for HBV infection prior to initiation of obinutuzumab therapy. HBV antiviral therapy should be considered for patients showing evidence of HBV infection.
  • Except for the inactivated influenza vaccine, inactivated and live vaccines should be withheld during obinutuzumab treatment and for at least 6 months after completion of therapy.

Clinical Pearls2,3,6,7

  • Obinutuzumab is administered as a titrated infusion, with the rate of infusion based on cycle number and history of infusion reactions with prior dose.
  • In the planned interim analysis of the GALLIUM trial, a significant 3-year progression-free survival benefit was seen; however, no difference was seen in response rates or overall survival rates for obinutuzumab compared to rituximab. Longer follow-up is needed to fully assess outcomes.
  • In subgroup analyses in the GALLIUM trial, there appeared to be a stronger treatment benefit for obinutuzumab in women (HR for progression, relapse, or death, 0.49; 95% CI, 0.33–0.74) than in men (HR 0.82; 95% CI, 0.59–1.15). However, this interaction of gender and treatment did not reach significance (p = .06).
  • Grade 3 or higher adverse reactions were higher with obinutuzumab (74.6%) than with rituximab (67.8%). These included more infection, neutropenia, and infusion reactions.
  • Consistent with other trials comparing obinutuzumab and rituximab, the rate of all grades of infusion reactions in the GALLIUM trial was greater with obinutuzumab (59.3%) than with rituximab (48.9%).
  • Patients receiving obinutuzumab should be monitored for the following:
    • Second neoplasms, which occurred more frequently in the obinutuzumab patients than in rituximab patients
    • Progressive multifocal leukoencephalopathy (PML), which can present as new onset or worsened neurological symptoms.
  • Financial support, including patient assistance, benefits investigation, and copay assistance is available from the obinutuzumab manufacturer. Applications can be found at https://www.genentech-access.com/hcp/brands/gazyva/find-patient-assistance.html or by calling 888.249.4918.

References

  1. U.S. Food and Drug Administration. FDA approves obinutuzumab for previously untreated follicular lymphoma. November 16, 2017 https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm585660.htm
  2. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017:377:1331-1344.
  3. Gazyva (obinutuzumab) injection [package insert]. South San Francisco, CA: Genentech, Inc.; 2017.
  4. National Comprehensive Cancer Network. B-cell Lymphomas. Version 7.2017. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed December 23, 2017.
  5. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices. General Best Guidance for Immunization—Altered Immunocompetence. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html. Accessed December 27, 2017.
  6. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110.
  7. Sehn L, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015;33:3467-3474.

February 26, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125486s013lbl.pdf

On February 26, 2016, the U. S. Food and Drug Administration approved obinutuzumab (Gazyva® Injection, Genentech, Inc.) for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen. Obinutuzumab was previously approved for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia.

This new approval was based on demonstration of an improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial in patients with FL who had no response to or have progressed during or within 6 months of a rituximab-containing regimen. This trial compared 6 cycles of obinutuzumab plus bendamustine combination therapy followed by continued obinutuzumab monotherapy for up to 2 years with 6 cycles of bendamustine therapy.

Efficacy was assessed in 321 patients with follicular lymphoma randomized to either obinutuzumab plus bendamustine (n=155) or bendamustine (n=166). The median age was 63 years (range 34-87). Patients had received a median of 2 prior therapies (range 1-10). The independent review assessed median PFS was 13.8 months in the bendamustine arm while the median PFS was not reached in the obinutuzumab plus bendamustine arm [HR 0.48 (95% CI: 0.34-0.68), log-rank test p-value < 0.0001).

This trial also enrolled 46 patients with marginal zone lymphoma and 28 with small lymphocytic lymphoma who were also included in the safety analysis. The most common adverse reactions (greater than or equal to 10%) in the safety population treated with obinutuzumab plus bendamustine followed by obinutuzumab monotherapy were infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia and urinary tract infection. Serious adverse reactions were reported in 38% of patients treated with obinutuzumab plus bendamustine followed by obinutuzumab monotherapy. The most common serious adverse reactions (greater than 2%) were febrile neutropenia, neutropenia, infusion related reactions, sepsis, pneumonia and pyrexia.

The recommended dose and schedule for the regimen follows:

  • Obinutuzumab: 1000 mg by intravenous infusion on days 1, 8 and 15 of cycle 1; on day 1 of cycles 2-6 (28-day cycles); and then every 2 months for 2 years.

  • Bendamustine: 90 mg/m2 by intravenous infusion on days 1 and 2 of cycles 1-6.

This application was granted Priority Review. 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/2016/125486s013lbl.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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