What is rituximab/hyaluronidase?
A new subcutaneous formulation of rituximab, combined with human hyaluronidase to help increase dispersion and absorption of rituximab after subcutaneous administration.
How does rituximab/hyaluronidase work?
Rituximab is a monoclonal antibody targeting CD20. Upon binding to the receptor, cell lysis occurs through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Hyaluronidase is included to increase the permeability of the subcutaneous tissue by depolymerizing hyaluronan at the site of injection.
What is this approved for?
This formulation is only approved for the treatment of adult patients with chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). It is not approved for pediatric use or non-malignant conditions.
What is the basis for this approval?
Rituximab/hyaluronidase was approved based on three clinical studies, one in each malignancy for which it received indication. The SAWYER study included 176 CLL patients randomized 1:1 to each product, in combination with fludarabine and cyclophosphamide. The mean trough concentration was higher in the rituximab/hyaluronidase arm (ratio 1.53) prior to cycle 5. Response rates were similar between subcutaneous and IV routes, with overall response rate of 85 percent and 81 percent, and complete response rate (CRR) of 26 percent and 33 percent, respectively (Lancet Haematol 2016;3:e128-e138).
The MabEase study included 576 DLBCL patients and randomized patients to receive either formulation in combination with CHOP. CRR was 47 percent and 42 percent for subcutaneous and IV patients. Progression-free survival was similar (HR 1.22, CI 0.85-1.73), as was overall survival (HR 1.08, CI 0.70-1.68).
The SABRINA study included 410 untreated FL patients. Patients were randomized to receive either product in combination with CHOP or CVP, followed by maintenance therapy, if indicated. Mean trough concentration was higher in the rituximab/hyaluronidase arm (ratio 1.52) prior to cycle 7. Response rates were similar in each group at the end of combination therapy as well as at the completion of maintenance. No difference in progression-free survival or overall survival was detected (Lancet Haematol 2017;4:e272-e282).
How do you administer this drug?
Rituximab/hyaluronidase should only be administered after a patient has received and tolerated at least one full dose of IV rituximab. Each 1,400 mg fixed dose replaces one dose of IV rituximab 375 mg/m2. Each 1,600 mg fixed dose replaces one dose of IV rituximab 500 mg/m2. Frequency of administration follows the IV rituximab schedule (i.e., 1 dose of subcutaneous rituximab = 1 dose of IV rituximab).
Each 1,400 mg dose should be administered over 5 minutes, and the 1,600 mg dose should be administered over 7 minutes. Doses should be given in the abdomen.
Are there any premedications needed?
Acetaminophen and an antihistamine are recommended prior to each dose. A glucocorticoid may also be considered. Tumor lysis prophylaxis and monitoring should be considered in patients at risk.
What are the common side effects (> or =10%)?
The side effects of rituximab/hyaluronidase are similar to IV rituximab, with the exception of local injection site reactions, which occurred in 20-40 percent in clinical trial participants. Erythema, pain, and pruritis were the most common, but were mostly grade 1-2.
What are the uncommon side effects (less than 10%)?
Less frequent toxicities are similar to IV rituximab and include infection, hepatitis B reactivation, progressive multifocal leukoencephalopathy, mucocutaneous reactions, bowel obstruction and perforation, and cardiac events.
Are there any important drug interactions I should be aware of?
No drug interactions have been identified due to metabolism or transport effects.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Dose reductions are not necessary for renal or hepatic dysfunction.
Practical tips
All patients must first receive and tolerate an IV rituximab dose. The subcutaneous formulation is not approved for pediatric use, nor for non-malignant conditions.
Overall cost of therapy should be included in decision-making, including drug cost, infusion chair time, reimbursement, and patient cost.
What should my patients know about rituximab/hyaluronidase?
Patients should be instructed to report any local or systemic reactions and should be observed for 15 minutes after administration.
What else should I know about rituximab/hyaluronidase?
In a crossover study, patients were administered four doses of rituximab via each route. After eight cycles, 81 percent of patients preferred the subcutaneous injection over IV infusion (Ann Oncol 2017;28:836-842).
What useful links are available?
* https://www.gene.com/medical-professionals/medicines/rituxan-hycela
* https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf
* http://www.clinicaltrials.gov for updated information on current clinical trials involving rituximab/hyaluronidase
ADAM MELARAGNO, PHARMD, BCOP, is Clinical Pharmacy Specialist, Blood and Marrow Transplant, University of Rochester Medical Center, Rochester, N.Y. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.