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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.  


June 22, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf

On June 22, 2017, the U.S. Food and Drug Administration granted regular approval to the combination of rituximab and hyaluronidase human (RITUXAN HYCELA, Genentech Inc.) for adult patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.

The approval provides patients a subcutaneous route of rituximab administration that shortens the administration time to 5 to 7 minutes as compared to intravenous infusion that can take several hours. This new product also provides for flat dosing.

The approval specifies the combination is indicated for the following previously approved indications for Rituxan:

  • Relapsed or refractory, follicular lymphoma (FL) as a single agent.
  • Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
  • Non-progressing (including stable disease), FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • Previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
  • Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC).

Rituxan Hycela is not indicated for the treatment of non-malignant conditions.

Approval was based on multiple randomized clinical trials demonstrating the following: (a) non-inferior rituximab trough concentrations (Ctrough) levels for Rituxan Hycela 1,400 mg/23,400 Units compared to a intravenous rituximab 375 mg/m2 (b) non-inferior rituximab Ctrough levels for Rituxan Hycela 1,600 mg/26,800 Units compared to intravenous rituximab 500 mg/m2 and (c) comparable efficacy and safety results of the two products. Trial results are provided in the drug prescribing information.

The most common adverse events (≥20%) observed in patients with FL include infections, neutropenia, nausea, constipation, cough, and fatigue. The most common adverse events (≥20%) observed in patients with DLBCL include infections, neutropenia, alopecia, nausea, and anemia. The most common adverse events (≥20%) observed in patients with CLL were infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema.

The recommended doses are 1400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1600 mg rituximab and 26,800 units hyaluronidase human for CLL. Refer to the prescribing information for specific dosing schedules. Rituxan Hycela treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.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

Rituximab/Hyaluronidase Human (Rituxan Hycela) for Adult Patients with Follicular Lymphoma, Diffuse Large B-Cell Lymphoma, and Chronic Lymphocytic Leukemia

Author: Megan Bodge, PharmD BCOP
WVU Medicine Cancer Institute
Morgantown, WV

What is the potential role for rituximab/hyaluronidase human in the treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL)?1,2

  • Rituximab/hyaluronidase human is a new subcutaneous formulation of traditional rituximab that has been approved for use in FL, DLBCL, and CLL.
  • Approval is based on results from three separate trials:
    • Phase 3 SABRINA trial, which included 410 patients with previously untreated FL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or cyclophosphamide, vincristine, and prednisone (CVP)
    • Phase 3b MabEASE trial, which included 576 patients with previously untreated DLBCL in combination with CHOP
    • Phase 1b SAWYER trial, which included 176 patients with previously untreated CLL in combination with the fludarabine and cyclophosphamide (FC) regimen.
  • Data from these clinical trials established pharmacokinetic noninferiority with a fixed dose of rituximab/hyaluronidase human and the same dosing intervals used with rituximab. Dosing for FL and DLBCL is 1,400 mg rituximab and 23,400 units hyaluronidase human delivered as an 11.7 ml single subcutaneous injection, whereas the dosing for CLL has been established at 1,600 mg rituximab and 26,800 units hyaluronidase human delivered as a 13.4 ml single subcutaneous injection.
  • The incidence and safety profile for rituximab/hyaluronidase human is similar to that for rituximab, with the exception of increased local cutaneous reactions (16%). These reactions are commonly grade 1-2 and resolve without any specific treatment. Reactions are expected to decrease over time.
  • In clinical trials, a patient preference analysis indicated that 77% of patients preferred rituximab/hyaluronidase human because the administration required less time in the clinic.

What role can the pharmacist play in the management of patients receiving rituximab/hyaluronidase human?1

  • Pharmacists should ensure that rituximab/hyaluronidase human is used for appropriate patients. Patients will still be required to receive at least one dose of rituximab via the intravenous (IV) route prior to moving to rituximab/hyaluronidase human. Patients who experience an infusion reaction of less than grade 3 with their initial rituximab dose may still move forward to subcutaneous injection for subsequent doses as long as they complete the infusion. For patients who experience a grade 3 reaction but still complete the infusion, clinical judgment must be exercised to assess eligibility for the switch. These patients may repeat a second IV dose and then reassess switching to rituximab/hyaluronidase human if they are able to complete the full dose, they may move straight to the subcutaneous injection with close monitoring, or they may continue receiving IV infusions for the duration of their treatment. If 6 months or more have elapsed since the previous rituximab administration, the IV infusion must be repeated.
  • Dosing for rituximab/hyaluronidase human differs from that for traditional rituximab because it is a fixed dose, irrespective of the patient’s body surface area.
  • Patients receiving rituximab/hyaluronidase human should still receive standard premedications, including acetaminophen and diphenhydramine at a minimum, prior to the injection. Following the injection, patients should be monitored for 15 minutes.
  • Rituximab/hyaluronidase human should not be injected into areas of the skin that are red, bruised, tender, or hard or into areas with moles or scars.
  • Insurance approval of this new formulation may vary, even for patients previously approved to receive IV rituximab. A co-pay card is available for patients with commercial insurance.

Clinical Pearls1

  • Rituximab/hyaluronidase human is prepared in a single 20 ml syringe for subcutaneous injection. No mixing or diluting of the drug is required. The vial contains a label with a peel-off sticker to indicate that administration is via subcutaneous route only. Caution should be taken to ensure that the syringe is not administered via the IV route.
  • The hyaluronidase human component of this agent acts locally to allow for increased permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue, to allow for a large-volume subcutaneous injection. The injection is administered over a period of either 5 minutes (1,400 mg dose) or 7 minutes (1,600 mg dose) into the abdomen only. When the injection is initiated, some resistance may occur, which will gradually reduce as the hyaluronidase agent begins to take effect.
  • Given the length of time required for each subcutaneous injection, it is essential that the patient and nurse administering the agent are comfortable prior to beginning the injection and are equipped with a watch or timer.
  • Although reactions to rituximab are most common with the first administration, patients may still experience local reactions following subcutaneous injection more than 24 hours after injection. This is likely attributable to the difference in time to Cmax with the subcutaneous injection versus the IV infusion.

References

  1. Rituxan Hycela (rituximab/hyaluronidase human) subcutaneous injection [package insert]. South San Francisco, CA: Genentech USA, Inc. and Biogen; June 2017.
  2. U.S. Food and Drug Administration. FDA approves rituximab plus hyaluronidase combination for treatment of FL, DLBCL, and CLL. 22 June 2017. Retrieved from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564235.htm. Accessed August 2, 2017.
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