Overview:
Rituximab is a type of monoclonal antibody that targets the B-cell surface antigen CD20.
Rituximab was the first monoclonal antibody licensed for non-Hodgkin lymphoma treatment. Rituximab was licensed by the FDA (Food and Drug Administration) in 1997 for the treatment of refractory low-grade lymphoma (when treatment is no longer effective for a kind of cancer arising from the cells of the lymphatic system). This drug has since been used to treat a variety of CD20-positive B-cell cancers. The drug's selectivity for B-cells prompted further research into autoimmune B-cell-driven disorders such as rheumatoid arthritis. On February 28, 2006, the FDA authorized Rituximab for the treatment of rheumatoid arthritis.
How Does Rituximab Work?
Rituximab is a chimeric monoclonal immunoglobulin G1 antibody made from human and mouse cells that specifically targets the B-cell differentiation marker CD20. A cell-surface marker called CD20 is only present on pre-B and mature B lymphocytes; it is neither present on other cell types nor in blood circulation. Rituximab's specific binding site is CD20 on B-cells. Rituximab binds to the B lymphocytes' cell surface CD20, which causes the lymphocyte to be destroyed through one of several possible processes, such as complement-dependent cytotoxicity, apoptosis stimulation, or antibody-dependent cytotoxicity. The predominant mechanism in vivo is likely to be complement-mediated cytotoxicity.
Indications:
Rituximab is a CD20-directed cytolytic antibody used to treat non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, microscopic polyangiitis, and pemphigus vulgaris.
Rituximab can be indicated for
1. Non-Hodgkin lymphoma (NHL) in adult patients with:
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Low grade or follicular, relapsed or refractory, CD20-positive B-cell NHL as a single agent.
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Follicular, CD20-positive, B-cell NHL that has not previously received treatment in conjunction with first-line chemotherapy and, in patients who experience a full or partial response to Rituximab in conjunction with chemotherapy, as single-agent maintenance therapy.
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After receiving first-line Cyclophosphamide, Vincristine, and Prednisone (CVP) treatment, Rituximab can be given as a single agent for low-grade, CD20-positive, non-progressing B-cell NHL.
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Combining (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) (CHOP) or other Anthracycline-based chemotherapy regimens with Rituximab can be given for diffuse large B-cell, CD20-positive NHL that has not previously received treatment.
2. Adult individuals with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL) who are taking Fludarabine and Cyclophosphamide (FC) together.
3. Rheumatoid Arthritis (RA) with moderate to highly active, not responding well to one or more TNF antagonist treatments, and Rituximab can be given along with Methotrexate.
4. Adult and pediatric patients aged two years and older with Microscopic polyangiitis (MPA) and Wegener's granulomatosis (GPA) when used along with glucocorticoids.
5. Adult patients with Pemphigus vulgaris (PV).
Contraindications:
The following are some absolute and relative contraindications to the drug:
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Hypersensitivity to any of the formulation's components.
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Severe infection.
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Severe heart failure.
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Cardiovascular illness that is uncontrolled.
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Pregnancy.
Dosage:
Rituximab cannot be administered intravenously as a push or bolus, only as an intravenous (IV) infusion. It can be given by a medical professional with the appropriate assistance to control potentially deadly, severe infusion-related reactions. Rituximab dosing recommendations are generally outlined below:
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375 mg/m2 (milligram per square meter) is the dosage for adult and child B-cell NHL.
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When combined with FC and given every 28 days, the dose for CLL is 375 mg/m2 in the first cycle and 500 mg/m2 in cycles 2 through 6.
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For RA in combination with Methotrexate, the recommended dosage is two 1,000 mg intravenous infusions two weeks apart, given every 24 weeks or as determined by a clinical examination, but no less frequently than every 16 weeks. It is recommended that patients take 100 mg of Methylprednisolone intravenously or an equivalent Glucocorticoid 30 minutes before each infusion.
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The induction dose of Rituximab plus Glucocorticoids for adult patients with active GPA and MPA is 375 mg/m2 once per week for four weeks. Adult patients with GPA and MPA who have completed induction therapy with Glucocorticoids and established disease control should get two 500 mg intravenous infusions two weeks apart, followed by a 500 mg intravenous infusion every six months after that, according to clinical examination.
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For pediatric patients with GPA and MPA taking Rituximab with Glucocorticoids, the induction dose will be 375 mg/m2 once a week for a period of four weeks. Following two 250 mg/m2 intravenous infusions two weeks apart, followed by a 250 mg/m2 intravenous infusion every six months afterward based on the clinical assessment. This is the maintenance dose for pediatric patients with GPA and MPA who have established disease control with induction therapy and Glucocorticoids.
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The recommended dosage for PV is two intravenous infusions of 1,000 mg, spaced over two weeks, along with a tapering course of Glucocorticoids, followed by an intravenous infusion of 500 mg at Month 12 and then every six months after that, or as determined by a clinical examination. Upon relapse, a 1,000 mg intravenous (IV) infusion is indicated, with consideration given to continuing or increasing the Glucocorticoid dose based on clinical evaluation. The time between subsequent infusions and the prior infusion must be less than 16 weeks. It is advised to take Methylprednisolone 100 mg intravenously or a similar Glucocorticoid 30 minutes before each infusion.
Dosage Forms and Strengths:
Rituximab is available as an injectable in single-dose vials of 100 mg/10 milliliters (mL) (10 mg/mL) and 500 mg/50 mL (10 mg/mL) solutions.
Warnings and Precautions:
The warnings and precautions are as follows:
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Tumor Lysis Syndrome: Administer vigorous intravenous hydration and anti-hyperuricemic medications and keep an eye on renal function if the patient has tumor lysis syndrome.
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Infections: Withhold Rituximab and start the proper anti-infective therapy if the patient has an infection.
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Cardiac Adverse Reactions: Infusions should be stopped in the event of serious or life-threatening cardiac side effects.
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Renal Toxicity: Stop treatment in patients who have oliguria (low urine output) or an increase in serum creatinine.
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Bowel Obstruction and Perforation: Take into account and assess for nausea or other similar symptoms, as well as abdominal pain.
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Immunizations: It is not advised to receive a live virus immunization before or while receiving Rituximab treatment.
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Embryo-Fetal Toxicity: This may be harmful to the fetus. Inform women who are capable of becoming pregnant about the risks to an unborn child and the importance of using efficient contraception.
Adverse Reactions:
The following were the most common adverse reactions seen in clinical trials:
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NHL (More Than or Equal to 25 Percent): Infusion-related events, fever, lymphopenia (a condition in which the blood has few white blood cells called lymphocytes), chills, infection, and asthenia (abnormal physical weakness).
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Pediatric B-Nhl/B-Al With Chemotherapy (Grade 3 or Greater Than 15 Percent): Febrile neutropenia (fever with signs of infection and the patient's blood has an abnormally low neutrophil granulocyte (a type of white blood cell)), enteritis (inflammation of the small intestine), stomatitis(inflammation of the oral mucosa), sepsis(a life-threatening condition that occurs when the body's immune system reacts strongly to an infection), increased alanine aminotransferase(a sign of liver damage), and hypokalemia (low potassium levels).
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Cll (More Than or Equal to 25 Percent): Infusion-related events and neutropenia.
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Ra (More Than or Equal to 10 Percent): Upper respiratory tract infection, nasopharyngitis (common cold that is the infection of the nose and throat), urinary tract infection, and bronchitis (additional significant side reactions include infusion-related events, severe infections, and cardiovascular events).
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GPA and MPA (More Than or Equal to 15 Percent): Infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related manifestations.
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PV (More Than or Equal to 15 percent): Infusion-related events, depression, upper respiratory tract infection/nasopharyngitis, headache (infections are also major side effects).
For Patients
Why Is Rituximab Prescribed?
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Rituximab injections are used for the management of various non-Hodgkin's lymphoma (a type of cancer that starts in white blood cells that normally fight infection) in humans, either alone or in combination with other medications.
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Adults are also treated with Rituximab injections in conjunction with other drugs for chronic lymphocytic leukemia (a kind of white blood cell malignancy).
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Adults who have previously been treated with a tumor necrosis factor (TNF) inhibitor are given Rituximab injections along with Methotrexate to manage the symptoms of rheumatoid arthritis (a condition in which the body attacks its own bone joints, causing pain, swelling, and loss of function).
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Rituximab injections are also used to treat granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis (conditions in which the body's immune system attacks its own veins and other blood vessels, thereby causing damage to organs such as the heart and lungs) in adults and children aged two years of age and older.
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Rituximab injection is used to treat pemphigus vulgaris (a skin condition that causes painful blisters on the skin as well as the lining of the mouth, nose, throat, and genitals).
Rituximab injections are a type of drug known as a monoclonal antibody. To treat various types of NHL and CLL, these medications may target cancer cells. Certain Rituximab injections are also used to treat rheumatoid arthritis (a chronic autoimmune inflammatory disease of joints especially hands and feet), granulomatosis with polyangiitis (a condition that causes inflammation of the blood vessels in the nose, ears, throat, lungs, and kidneys), microscopic polyangiitis (inflammation of small blood vessels), and pemphigus vulgaris (a rare autoimmune skin disorder causing blisters on the skin and mucous membrane) by restricting an immune system's function that can cause joint, vein, and blood vessel damage.
How Should Rituximab Be Used?
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Rituximab injections are given as a solution (liquid) to be administered into a vein.
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A healthcare professional will administer Rituximab injections in a medical office, and dosage will be determined by the patient's condition, any additional medications the patient is taking, and how well the body responds to treatment.
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Rituximab injections must be administered slowly into a vein because the initial dosage of Rituximab injection may take several hours or longer.
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Based on how effectively the patient reacts to treatment, a Rituximab injection may be administered sooner than the initial dose.
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During the first dose of a Rituximab medication, patients may have symptoms like fever, chills, joint discomfort, fatigue, headache, or nausea.
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Inform a healthcare professional if patients develop any of these symptoms while taking this medicine.
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Other medications may be prescribed by a doctor in order to avoid or relieve these symptoms. The healthcare professional will instruct patients to take the medications before receiving each dose of Rituximab.
What Special Precautions Should Be Taken?
It is critical to take measures before and during the use of Rituximab. It is necessary to inform the doctor if the patient has a history of allergies, is taking prescribed and nonprescribed drugs, vitamins, nutritional supplements, and herbal products, has ever suffered from an infection that did not go away or an infection that changes periodically, is pregnant or on birth control during treatment, is breastfeeding, and is getting vaccinations. Because the doctor may adjust the dose or closely monitor for adverse effects, Rituximab treatment during pregnancy may harm the fetus; in the case of nursing, it is advised not to breastfeed throughout the treatment with a Rituximab injection and for six months after the final dose.
Side Effects of Rituximab:
Rituximab, like many drugs, can produce adverse reactions. In the case of any of the following symptoms, the patient must notify the doctor:
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Diarrhea.
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Back or joint pain.
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Flushing.
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Night sweats.
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Mouth sores (painful lesions in the mouth).
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Unusual anxiety or worry.
The adverse effects can be severe at times. The following side effects are infrequent; however, patients must be reported to the doctor immediately if these effects occur:
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Bruising or bleeding is uncommon.
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Sore throat, runny nose, cough, fever, chills, or other infection symptoms.
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Earache.
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Redness, tenderness, edema (abnormal fluid accumulation in the body tissues or cavities), or warmth of the skin area.
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Chest tightness.
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Severe abdominal pain or vomiting.
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Nausea, vomiting, diarrhea, and fatigue.
Before beginning treatment, the patient should consult with a doctor about any potential adverse effects.
Storage of Rituximab:
Rituximab infusion solutions can be kept at two degree Celsius to eight degree Celsius (36°F to 46°F) for 24 hours. Rituximab infusion solutions have been demonstrated to be stable at ambient temperature for an extra 24 hours; however, because Rituximab solutions do not contain preservatives, diluted solutions should be refrigerated at degree Celsius to eight degree Celsius.
What Should Be Done in the Event of an Overdose?
In the case of an overdose, call emergency services or poison control center immediately if the patient has collapsed, had a seizure, is having difficulty breathing, or cannot be awakened.
For Doctors:
Clinical Trials
As clinical trials are conducted under significantly different settings, adverse reaction rates reported in clinical trials for a particular drug cannot be directly compared to rates observed in clinical trials for a different drug and may differ from rates experienced in practice. A placebo-controlled, double-blind, randomized study was done to assess the efficacy and safety of Rituximab for patients with rheumatoid arthritis. Over 10 percent of all exposed patients experienced infusion-related reactions, upper respiratory tract infection, nasopharyngitis (viral infection that affects the nose and throat), urinary tract infection, and bronchitis (large and medium-sized bronchial tube inflammation). During a 24-week period, participants received two 500 milligrams (mg) or two 1000 milligrams (mg) intravenous infusions of Rituximab or placebo along with Methotrexate. hypertension (consistently high blood pressure), nausea, upper respiratory tract infection, arthralgia (joint pain), pyrexia (fever), and pruritus (severe skin itching) were noted in five percent of participants. The rates and types of adverse reactions seen in patients given Rituximab 2 x 500 mg were comparable to those seen in patients given Rituximab 2 x 1000 mg.
What Are the Pharmacological Aspects of Rituximab?
Pharmacodynamics:
Rituximab treatment resulted in peripheral B cell depletion in RA patients, with the majority displaying near-complete depletion within two weeks. This depletion persisted for at least six months, with only a minority reporting chronic depletion lasting more than three years. At six months, total serum immunoglobulin levels dropped, with IgM being the most affected. Repeated therapy resulted in IgM, IgG, and IgA concentrations falling below the lower range of normal. Inflammation indicators such as IL-6, CRP, SAA, anti-CCP, and RF were lowered by treatment.
Mechanism of Action:
Rituximab binds to the CD20 antigen, triggering B-cell lysis via complement-dependent and antibody-dependent cell-mediated cytotoxicity. B cells contribute to rheumatoid arthritis and chronic synovitis by producing autoantibodies and rheumatoid factor, as well as antigen presentation, T-cell activation, and proinflammatory cytokine production.
Half-Life in Adults:
The average half-life of Rituximab in adults is three weeks.
Pharmacokinetics:
The pharmacokinetics are as follows:
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Absorption and Distribution: When administered in single doses or weekly for four weeks, serum Rituximab is dosage proportionate. Peak serum concentrations increased from the first to the fourth infusion when delivered at 375 mg/m2 once weekly, increasing the half-life time. Even three months following treatment, Rituximab is still detectable in patients' serum. Cerebrospinal fluid and endothelial cells that express CD20 are among the locations of distribution.
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Metabolism and Excretion: Rituximab reduces clearance by fourfold, from 0.038 L/h to 0.009 L/h, suggesting alterations in CD20-positive B-cell populations. This is related to the reduction of a B-cell subset that is replaced by stem cells, the accumulation of Rituximab, and the increasing half-life of the drug.
Drug Interactions:
Drug interaction occurs when used with Cisplatin; there is a risk of renal toxicity.
Specific Considerations:
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Geriatric Use: Exploratory studies in CLL patients over the age of 70 show no benefit in adding Rituximab to Fludarabine and Cyclophosphamide.
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Lactation: Not recommended for breastfeeding.
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Pregnancy: Minimal human data; infants treated in utero developed B-cell lymphocytopenia.
Conclusion:
Rituximab is a monoclonal antibody that has been clinically shown to be both effective and safe for the management of RA. It is a choice to consider for patients who have become resistant or intolerant to anti-TNF biologic drugs. Rituximab works by decreasing the number of B-cells in the body, which causes swelling and joint damage in patients with rheumatoid arthritis. When compared to other existing biological treatments, infusion reactions appear to be the drawback of this drug. However, their occurrence is reduced by glucocorticoid premedication and subsequent infusions.
