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Rituximab


Rituximab

Article Author:
Nazma Hanif
Article Editor:
Faiz Anwer
Updated:
11/3/2020 4:59:43 AM
For CME on this topic:
Rituximab CME
PubMed Link:
Rituximab

Indications

Rituximab is an anti-CD20 monoclonal antibody that was first approved by the FDA in 1997. Currently, it is approved for use by the FDA in the following conditions.

CD20 positive B-cell Non-Hodgkin’s Lymphoma (NHL)

  • Approved for use as a single agent in relapsed/refractory, low-grade, or follicular B cell NHL.
  • Single-agent maintenance therapy for patients with previously untreated follicular B cell NHL who are achieving a complete or some degree of response to combination chemotherapy with rituximab.
  • As a single agent in low grade non-progressive/stable B cell NHL after CVP chemotherapy.
  • In combination with anthracycline-based chemotherapy in previously untreated diffuse large B cell NHL.

Chronic Lymphocytic Leukemia (CLL)

  • Approved for use in combination with fludarabine and cyclophosphamide for the treatment of newly diagnosed or previously treated CLL.

Rheumatoid Arthritis

  • It is considered a biologic DMARD for the treatment of RA. It is approved for use with methotrexate in adult patients who have an inadequate response to one or more anti-TNF therapies.

Microscopic Polyangiitis (MP) and Granulomatosis with Polyangiitis (GPA)

  • Approved for use in combination with glucocorticoids.

Pemphigus Vulgaris (PV)

  • Approved in 2018 for use in combination with glucocorticoids for adult patients with moderate to severe disease.[1]

In addition to these, rituximab has orphan designations for immune thrombocytopenic purpura (ITP) and Rasmussen encephalitis.

The FDA has recently approved two biosimilars of rituximab for use in adult patients. Biosimilars are drugs which have no clinically significant difference from the reference drug. These have a similar structure, safety profile, and function. The aim of developing biosimilars is to make drugs more accessible by lowering the cost of the drug.[2] Rituximab-abbs is approved for use in NHL alone or in combination chemotherapy, and CLL in combination with fludarabine and cyclophosphamide. Rituximab-pvvr is approved for use in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

There are numerous off label uses of rituximab. According to a retrospective cross-sectional study done in the US, the use of rituximab for off-label indications increased from 1.2% in 2009 to 55.6% in 2017.[1] Off-label uses include refractory autoimmune hemolytic anemia, refractory myasthenia gravis, multiple sclerosis, chronic steroid-refractory GVHD, Hodgkin lymphoma, systemic lupus erythematosus, thrombotic thrombocytopenia purpura, Waldenstrom macroglobulinemia, membranous nephropathy, etc.

Rituximab, in combination with hyaluronidase (rituximab-hyaluronidase human), was approved by FDA in 2017. This formulation is available for use in the subcutaneous form, giving the advantage of a faster administration over five to seven minutes as opposed to the prolonged infusion times with IV formulations. It is approved for use in chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma. One limitation of use is that it can only be given after receiving at least one full dose of a rituximab product by IV infusion.[3]

Mechanism of Action

Rituximab is an anti CD20 chimeric antibody with human IgG1 immunoglobulin constant regions and variable regions from an anti CD20 murine antibody. CD20 is a surface transmembrane protein marker expressed on B cells during differentiation from pre B cell until the plasma cell stage. CD20 is believed to function as a calcium channel and play a role in the maturation and activation of B cells.[4][5]

Once rituximab is bound to CD20 positive cells, cell death is induced by various mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated-cytotoxicity(CDC) antibody-dependent phagocytosis (ADP), and direct effects of binding of rituximab to CD20.[4] The mechanism of action of rituximab in autoimmune disease is thought to be due to disruption in B cells function in the immune system or due to a decrease in plasma cell production as CD20+ B cells are intermediates in the process of maturation.[6]

The combination of rituximab and hyaluronidase (rituximab-hyaluronidase human) is used in the subcutaneous form. Hyaluronidase causes a reversible increase in permeability of subcutaneous tissue by causing depolymerization of hyaluronan, which leads to an increase in the absorption rate of rituximab.

Administration

Rituximab and its biosimilars are approved for use by intravenous infusion. They should not be administered as IV bolus or push. Patients should be given acetaminophen and antihistamine before each infusion. Rituximab should be diluted in an infusion bag of either 0.9% sodium chloride, 5% dextrose in water, or USP. No other drugs should be mixed with it, and patients should be closely monitored for infusion reactions.[7]

Rituximab-hyaluronidase human is approved for subcutaneous use. It should be administered in the subcutaneous abdominal tissue over five to seven minutes. Patients should be observed for 15 minutes after administration.[3]

Adverse Effects

Infusion reactions These are the most common and most serious adverse effects of the drug. Allergic or anaphylactic reactions were seen in 80 to 90% of patients receiving rituximab in randomized controlled trials[8]. These are usually seen within 30 to 120 minutes after the first infusion and range from mild to life-threatening. Infusion reactions can include fever, chills, skin rash, urticaria, angioedema, hypotension, ARDS, ventricular fibrillation, shock, anaphylaxis, and death.

Infections - Serious bacterial, viral, and fungal infections can occur. New or reactivated viral infections can include JC virus infection, herpes simplex, CMV, varicella-zoster, West Nile Virus, and hepatitis B and C. Due to the risk of reactivation, live vaccines are contraindicated during treatment with rituximab. They should be given at least four weeks before starting rituximab.

Reactivation of hepatitis B with fulminant hepatitis, hepatic failure, and death can occur. All patients should be screened with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before starting rituximab. Patients should also be monitored for hepatitis B reactivation during and after treatment.[9][10]

Reactivation of Hepatitis B and the development of PML (progressive multifocal leukoencephalopathy) due to the JC virus are indications to discontinue rituximab.

PCP is an opportunistic fungal infection whose prophylaxis is recommended in patients receiving fludarabine/cyclophosphamide/rituximab combination in CLL. It should be started during treatment and continued for a year following completion. It is also recommended in patients with GPA and MPA during treatment and for at least six months after stopping rituximab.[11]

Hematologic - Lymphopenia is the most commonly seen hematologic adverse effect. Others include leukopenia, neutropenia, thrombocytopenia, and anemia.

Dermatologic/mucocutaneous reactions - Include pruritis, alopecia, skin rash, and life-threatening reactions like toxic epidermal necrolysis, paraneoplastic pemphigus, and Stevens-Johnson syndrome.

Renal - Tumor lysis syndrome can present with hypocalcemia, hyperphosphatemia, hyperkalemia, hyperuricemia, and acute renal failure within 24 hours of the first infusion. Aggressive hydration and uric acid lowering therapy should be given to high-risk patients. Renal toxicity has been seen in trials where rituximab was administered with cisplatin.

Respiratory - These include cough, upper respiratory tract infections, rhinitis, epistaxis, bronchospasm, dyspnea, pulmonary toxicity, ILD. There have been reports of rare cases of hypersensitivity pneumonitis, status asthmaticus, diffuse alveolar hemorrhage, and bronchiolitis obliterans.[8]

Cardiovascular - Tachycardia, supraventricular arrhythmias, non-ischemic cardiomyopathy, peripheral edema, chest pain, hypertension.[12]

GI - Diarrhea, nausea, and vomiting can be seen. Symptoms of abdominal pain should be thoroughly investigated as there have been reports of bowel obstruction and perforation.

Neuropsychiatric - Dizziness, headache, anxiety, depression, and insomnia can occur.

Pregnancy - A limited amount crosses the placental barrier during the first trimester but crossing increases in the second and third trimester. Administration of rituximab during the third trimester can lead to immunosuppression in the neonate. Levels of rituximab in fetal circulation are similar to maternal levels near term, and live vaccines are contraindicated in the neonate during the first six months of birth.[13]

Due to poor understanding of long term effects, it is recommended to use effective contraception during treatment with rituximab and for a year after the last dose.[14][15]

Constitutional adverse effects - These include asthenia, fever, chills, myalgia, arthralgia, muscle spasms, back pain, night sweats, and fatigue.

Contraindications

Some absolute and relative contraindications of the drug include[6][10]:

  • Severe, active infection
  • Hypersensitivity to any of the components of the formulation
  • Severe heart failure
  • Uncontrolled cardiac disease
  • Pregnancy

Monitoring

Rituximab has an excellent safety profile, and overdosage has not been experienced in clinical trials. Patients should be regularly monitored for the development of adverse effects.

Before initiating treatment with rituximab, CBC, routine chemistries, serum immunoglobulin levels, chest X-ray, and serologic testing for hepatitis B, C, and HIV should be obtained. If HBsAg or anti-HBc is positive, HBV DNA PCR should be obtained. If HBV DNA is positive, entecavir should be given for prophylaxis. Lamivudine prophylaxis is indicated if HBV DNA is negative.[9]

The following should be regularly monitored during the course of treatment:

  • Development of infusion reactions. Acetaminophen and an antihistamine should be administered before starting the infusion to reduce the incidence of infusion reactions.
  • CBC to look for the development of any cytopenias.
  • Electrolytes and renal function in patients at high risk of tumor lysis syndrome.
  • Cardiac monitoring for patients with a history of cardiac disease.
  • Serum immunoglobulin levels.
  • Liver function tests and HBV DNA in patients with risk of reactivation of Hep B.
  • Patients should be monitored for signs and symptoms of opportunistic infections. The neurological function should be assessed to look for the onset of any new deficits.

Enhancing Healthcare Team Outcomes

Rituximab is a relatively safe and well-tolerated drug, and its off label use has increased dramatically over the years. Patients should be well educated about the benefits and risks of rituximab therapy.

Hypersensitivity reactions (HSR) are commonly seen with rituximab infusions. These can be reduced through premedication and titrated infusions. Priming the IV line with rituximab can have a positive impact. Reducing the HSR rate can reduce the cost for cancer centers, improve patient safety and satisfaction, and prevent delays in treatment. Nurses have a key role to play as members of the multidisciplinary team involved in the care of these patients. Care should be coordinated between the oncologist, nurses, and pharmacists.[16]

Recent evidence has shown a comparable clinical efficacy of subcutaneous and IV rituximab. SC rituximab allows faster delivery of the drug, reduced dosage errors, and drug wastage. Faster delivery time allows more patients to be scheduled. Cancer centers should consider the subcutaneous route for most patients with chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B cell lymphoma. The subcutaneous route could also be an alternative for patients with poor IV access.[17][18]


References

[1] Delate T,Hansen ML,Gutierrez AC,Le KN, Indications for Rituximab Use in an Integrated Health Care Delivery System. Journal of managed care     [PubMed PMID: 32584674]
[2] Greenwald M,Tesser J,Sewell KL, Biosimilars Have Arrived: Rituximab. Arthritis. 2018;     [PubMed PMID: 29765782]
[3] Yelvington BJ, Subcutaneous Rituximab in Follicular Lymphoma, Chronic Lymphocytic Leukemia, and Diffuse Large B-Cell Lymphoma. Journal of the advanced practitioner in oncology. 2018 Jul-Aug;     [PubMed PMID: 31086689]
[4] Maloney DG,Smith B,Rose A, Rituximab: mechanism of action and resistance. Seminars in oncology. 2002 Feb;     [PubMed PMID: 11842383]
[5] Pierpont TM,Limper CB,Richards KL, Past, Present, and Future of Rituximab-The World's First Oncology Monoclonal Antibody Therapy. Frontiers in oncology. 2018;     [PubMed PMID: 29915719]
[6] Randall KL, Rituximab in autoimmune diseases. Australian prescriber. 2016 Aug;     [PubMed PMID: 27756976]
[7] Kosmidis ML,Dalakas MC, Practical considerations on the use of rituximab in autoimmune neurological disorders. Therapeutic advances in neurological disorders. 2010 Mar;     [PubMed PMID: 21179602]
[8] Kasi PM,Tawbi HA,Oddis CV,Kulkarni HS, Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective. Critical care (London, England). 2012 Aug 31;     [PubMed PMID: 22967460]
[9] Nixon A,Ogden L,Woywodt A,Dhaygude A, Infectious complications of rituximab therapy in renal disease. Clinical kidney journal. 2017 Aug;     [PubMed PMID: 28852481]
[10] Buch MH,Smolen JS,Betteridge N,Breedveld FC,Burmester G,Dörner T,Ferraccioli G,Gottenberg JE,Isaacs J,Kvien TK,Mariette X,Martin-Mola E,Pavelka K,Tak PP,van der Heijde D,van Vollenhoven RF,Emery P, Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2011 Jun;     [PubMed PMID: 21378402]
[11] Maertens J,Cesaro S,Maschmeyer G,Einsele H,Donnelly JP,Alanio A,Hauser PM,Lagrou K,Melchers WJ,Helweg-Larsen J,Matos O,Bretagne S,Cordonnier C, ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. The Journal of antimicrobial chemotherapy. 2016 Sep;     [PubMed PMID: 27550992]
[12] Cheungpasitporn W,Kopecky SL,Specks U,Bharucha K,Fervenza FC, Non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy. Journal of renal injury prevention. 2017;     [PubMed PMID: 28487867]
[13] Chakravarty EF,Murray ER,Kelman A,Farmer P, Pregnancy outcomes after maternal exposure to rituximab. Blood. 2011 Feb 3;     [PubMed PMID: 21098742]
[14] Traila A,Dima D,Achimas-Cadariu P,Micu R, Fertility preservation in Hodgkin's lymphoma patients that undergo targeted molecular therapies: an important step forward from the chemotherapy era. Cancer management and research. 2018;     [PubMed PMID: 29942153]
[15] Leroy C,Rigot JM,Leroy M,Decanter C,Le Mapihan K,Parent AS,Le Guillou AC,Yakoub-Agha I,Dharancy S,Noel C,Vantyghem MC, Immunosuppressive drugs and fertility. Orphanet journal of rare diseases. 2015 Oct 21;     [PubMed PMID: 26490561]
[16] Laudati C,Clark C,Knezevic A,Zhang Z,Barton-Burke M, Hypersensitivity Reactions: Priming Practice Change to Reduce Incidence in First-Dose Rituximab Treatment. Clinical journal of oncology nursing. 2018 Aug 1;     [PubMed PMID: 30035788]
[17] Stewart D,Aucoin JS,Crosbie T,Forman M,Lye E,Christofides A,Mitha A, Update on the subcutaneous administration of rituximab in Canadian cancer centres. Current oncology (Toronto, Ont.). 2020 Apr;     [PubMed PMID: 32489254]
[18] Davies A,Berge C,Boehnke A,Dadabhoy A,Lugtenburg P,Rule S,Rummel M,McIntyre C,Smith R,Badoux X, Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development. Advances in therapy. 2017 Oct;     [PubMed PMID: 28983819]