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U.S. Department of Health and Human Services

Drugs

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Gazyva (obinutuzumab)

On November 1, 2013, the U.S. Food and Drug Administration approved obinutuzumab (GAZYVA™ injection, for intravenous use, Genentech, Inc.; previously known as GA101) for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval was based on demonstration of an improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial comparing obinutuzumab in combination with chlorambucil (GClb) to chlorambucil (Clb) alone in patients with previously untreated  CD20-positive CLL.  The study also included a rituximab in combination with chlorambucil (RClb) arm. The results of RClb compared to GClb will be available at a later stage.

Patients randomized to the combination arm received 1000 mg doses of obinutuzumab intravenously on day 1 (later divided into 100 mg on day 1, followed by 900 mg on day 2), day 8 and day 15 of the first cycle.  Chlorambucil, 0.5 mg/kg, was administered on days 1 and 15.   During treatment cycles 2-6, patients received obinutuzumab, 1000 mg intravenously only on day 1 in combination with chlorambucil, 0.5 mg/kg, on days 1 and 15.  Patients received pre-medication with a glucocorticoid, acetaminophen and anti-histamine prior to initial obinutuzumab infusions, and subsequently as needed. Patients assigned to single-agent chlorambucil received 0.5 mg/kg on days 1 and 15 of all treatment cycles (cycles 1 to 6).  Cycles were repeated every 28 days.

A total of 356 patients were randomized (2:1) to GClb (n=238) and Clb (n=118).  The median age was 73 years (range 39 -88).  The independent review committee assessed median PFS was 23.0 and 11.1 months in the  GClb and Clb arms, respectively [HR 0.16 (95% CI: 0.11, 0.24), log-rank p-value <0.0001]. 

The most common adverse reactions (greater than or equal to 10%) with obinutuzumab in combination with chlorambucil (with a higher frequency than in the control arm) were infusion-related reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder.  The most common grade 3-4 adverse reactions (greater than or equal to 10%) were infusion-related reactions, neutropenia, and thrombocytopenia.
Infusion reactions occurred in 69% of patients receiving obinutuzumab; 21% experienced Grade 3 or 4 reactions.  Symptoms (greater than 10%) included dyspnea, hypotension, nausea, vomiting, chills, flushing, and pyrexia. 

Obinutuzumab is approved with a BOXED WARNING regarding Hepatitis B virus reactivation and Progressive Multifocal Leukoencephalopathy.  Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk.  Infusion reactions are included in the WARNING and PRECAUTIONS section of the label.

The recommended dose and schedule for the approved regimen is:

Obinutuzumab:
Cycle 1: 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15. 
Cycles 2-6: 1000 mg administered intravenously every 28 days

Chlorambucil:
0.5 mg/kg orally on days 1 and 15 of each cycle

Full prescribing information is available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s000lbl.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).