Overview
On June 22, 2017, the U.S. Food and Drug Administration (FDA) approved Rituximab and Hyaluronidase human as a new subcutaneous formulation of Rituximab for the treatment of adult patients with follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia. This innovative medication provides a more efficient and convenient subcutaneous route of administration, significantly shortening the administration time to five to seven minutes compared to intravenous infusion, which can take several hours. It also offers the convenience of flat dosing for healthcare providers and patients.
How Do Rituximab and Hyaluronidase Human Work?
Rituximab and Hyaluronidase work through a combination of mechanisms to target and combat cancer cells and B cells within the immune system. Rituximab, a synthetic antibody, is designed to specifically bind to CD20, a protein present in both normal and cancerous B-cells. Once attached to B cells expressing CD20, this medication triggers the death of these cells. This process effectively eliminates cancer cells but can also temporarily impair the immune system's ability to defend against infections due to the concurrent destruction of functional B cells.
Hyaluronidase, an enzyme, is included in this medication to enhance the absorption of Rituximab when administered subcutaneously. This enzyme assists in breaking down hyaluronic acid, allowing improved drug dispersion and absorption in the skin.
Clinical Efficacy and Safety of Rituximab and Hyaluronidase Human:
The SABRINA trial demonstrated that subcutaneous Rituximab and Hyaluronidase human combined with chemotherapy had comparable clinical efficacy and safety profiles to intravenous Rituximab. The subcutaneous formulation offers the advantage of shorter administration times and may reduce the treatment burden for patients while maintaining the anti-lymphoma activity of Rituximab.
For Patients:
What Is Follicular Lymphoma?
Follicular lymphoma (a type of cancer) is characterized by its slow growth and is the prevalent subtype of non-Hodgkin's lymphoma (NHL), representing roughly 20 % of all NHL cases. Regrettably, it is regarded as incurable, with a high likelihood of recurrence.
What Is Rituximab and Hyaluronidase Human?
Rituximab and Hyaluronidase human injection is a man-made synthetic antibody designed to target CD20, a protein present on the surface of normal and cancerous B-cells, a crucial immune system component. Upon binding to B cells expressing CD20, this medication initiates a process that leads to the demise of these cells. This mechanism effectively eliminates cancerous cells but may also impact functional B cells temporarily, potentially compromising the immune system's ability to combat infections. To enhance the absorption of Rituximab when administered subcutaneously (under the skin), Hyaluronidase, an enzyme, is incorporated into this medication.
How Should the Patient Take Rituximab and Hyaluronidase Human?
A nurse or trained healthcare professional will administer Rituximab and Hyaluronidase human subcutaneous injection in the abdominal area. Before each dose, patients will receive Acetaminophen, antihistamines, and possibly a corticosteroid to prevent adverse reactions. Before this, patients must have received at least one full dose of Rituximab via intravenous (IV) infusion.
What Are the Things to Inform the Doctor Before Taking Rituximab and Hyaluronidase Human?
Before taking Rituximab and Hyaluronidase human, inform the healthcare provider of the following:
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Any history of severe reactions to Rituximab products or Rituximab and Hyaluronidase human.
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The presence of heart issues, irregular heartbeats, or chest pain in the medical history.
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Pre-existing lung or kidney problems.
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Current infections or a weakened immune system.
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A history of severe infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), Herpes Simplex Virus (HSV), parvovirus B19, varicella zoster virus (chickenpox or shingles), or West Nile virus.
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Recent vaccinations or scheduled vaccinations, as some vaccines, should not be administered before or during Rituximab and Hyaluronidase human treatment.
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Pregnancy or plans to become pregnant. If pregnancy is possible, birth control should be used during treatment and 12 months after the last dose. Notify the healthcare provider if pregnancy occurs during treatment.
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Breastfeeding or plans to breastfeed. It is not advisable to breastfeed during treatment and six months after the final dose due to the potential passage of Rituximab and Hyaluronidase human into breast milk.
Additionally, disclose all medications, both prescription and over-the-counter, vitamins, and herbal supplements being taken or planned for use. This information will help ensure safe and effective treatment.
What Are the Side Effects of Rituximab and Hyaluronidase Human?
Rituximab and Hyaluronidase human can lead to severe side effects, some of which may be life-threatening. These side effects include:
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Tumor Lysis Syndrome (TLS): TLS is caused by rapid cancer cell breakdown and can result in kidney failure and abnormal heart rhythm, and requires dialysis treatment. It can occur within 12 to 24 hours after Rituximab and Hyaluronidase human injection. Blood tests may be performed to detect TLS, and medication might be given to prevent it.
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Serious Infections: Treatment with Rituximab and Hyaluronidase human can increase the risk of serious infections, potentially leading to death. This medication can lower the immune system's ability to fight infections, making the patient susceptible to bacterial, fungal, and viral infections. Some individuals may have reduced antibody levels, leading to infections. Symptoms of infection include fever, persistent cold symptoms, flu-like symptoms, earache, headache, painful urination, mouth or throat white patches, and red, swollen, or painful cuts, scrapes, or incisions.
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Heart Problems: Rituximab and Hyaluronidase human may cause chest pain, irregular heartbeats, and heart attacks. The healthcare provider may monitor the patient's heart if there are symptoms of heart problems or a history of heart issues. Chest pain or irregular heartbeats during treatment should be reported immediately.
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Kidney Problems: Severe kidney problems, potentially fatal, can occur as a side effect. Kidney function should be monitored through blood tests.
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Stomach and Serious Bowel Problems: These issues, including bowel blockages or tears, may occur when Rituximab and Hyaluronidase human are combined with chemotherapy medications. Severe abdominal pain or repeated vomiting should be reported promptly.
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Severe Skin and Mouth Reactions: These reactions may include painful sores or ulcers on the skin, lips, or inside the mouth, blisters, peeling skin, rash, and pustules. Seek immediate medical attention if these symptoms arise during treatment.
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Hepatitis B Virus (HBV) Reactivation: If the patient has a history of hepatitis B or is a carrier, Rituximab and Hyaluronidase human can reactivate the virus, potentially causing serious liver problems, including failure and death. Monitoring for hepatitis B infection is essential during and after treatment.
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Progressive Multifocal Leukoencephalopathy (PML): A rare and severe brain infection can occur, especially in individuals with weakened immune systems. PML can lead to death or severe disability. Symptoms include confusion, dizziness, difficulty walking or talking, muscle weakness on one side of the body, and vision problems.
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Serious Allergic Reactions: These can be life-threatening, including skin reactions at or near the injection site. Symptoms of allergic reactions include hives, itching, swelling of the lips, tongue, throat, or face, sudden cough, shortness of breath, weakness, dizziness, palpitations, chest pain, fever, chills, or shaking chills.
Patients should promptly report any of these side effects to their healthcare provider during or after treatment with Rituximab and Hyaluronidase human.
How Should the Rituximab and Hyaluronidase Human Stored?
Rituximab and Hyaluronidase human should be stored as follows:
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Keep the vials in the refrigerator at a temperature between 2 degrees Celsius and 8 degrees Celsius (36 degrees Fahrenheit to 46 degrees Fahrenheit).
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Ensure they are stored in the original carton to protect them from light.
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Do not freeze the medication.
Proper storage is essential to maintain the effectiveness and stability of Rituximab and Hyaluronidase human.
For Doctors:
Indication and Usage: Rituximab and Hyaluronidase human is a medication indicated for various conditions in adults. Its approved indications and usage include:
1. Chronic Lymphocytic Leukemia (CLL): Rituximab and Hyaluronidase human is used in combination with Fludarabine Phosphate and Cyclophosphamide to treat CLL in adults. This combination therapy is intended for both previously untreated and previously treated CLL patients.
2. Diffuse Large B-cell Lymphoma (DLBCL): Rituximab and Hyaluronidase human are combined with Anthracycline chemotherapy in adults with diffuse large B-cell lymphoma. This application is specifically for patients whose disease has not been treated previously.
3. Follicular Lymphoma: Rituximab and Hyaluronidase human is employed in the treatment of follicular lymphoma in adults under several circumstances, including:
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Relapsed or refractory follicular lymphoma when used as a single agent.
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As part of the first-line chemotherapy regimen in combination with Rituximab, followed by single-agent maintenance therapy for patients achieving a complete or partial response.
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Treatment of non-progressing (including stable disease) follicular lymphoma as a single agent after initial Cyclophosphamide, Vincristine, and Prednisone (CVP) chemotherapy
Additionally, this medication is administered as a subcutaneous injection, providing a more time-efficient alternative to Rituximab infusion. However, it should only be used after patients have received one full dose of Rituximab by infusion.
Rituximab and Hyaluronidase human is not indicated for the treatment of non-malignant conditions. The specific treatment plan should be determined by healthcare professionals based on the patient's diagnosis and individual medical history.
Dosage and Administration: The recommended dosage and administration of Rituximab and Hyaluronidase human are as follows:
Recommended Dosage for Follicular Lymphoma (FL): All patients must receive at least one full dose of a Rituximab product by intravenous infusion before starting treatment with Rituximab and Hyaluronidase human.
Premedicate before each dose.
The recommended dose is Rituximab and Hyaluronidase human 1,400 mg/23,400 Units (1,400 mg Rituximab and 23,400 Units Hyaluronidase human) subcutaneously at a fixed dose irrespective of the patient's body surface area according to the following schedules:
Relapsed or Refractory, Follicular Lymphoma: Administer once weekly for three or seven weeks following a full dose of a Rituximab product by intravenous infusion at week 1 (i.e., 4 or 8 weeks in total).
Retreatment for Relapsed or Refractory Follicular Lymphoma: Administer once weekly for three weeks following a full dose of a Rituximab product by intravenous infusion at week 1 (i.e., four weeks in total).
Previously Untreated, Follicular Lymphoma: Administer on Day 1 of Cycles 2 to8 of chemotherapy (every 21 days), for up to 7 cycles following a full dose of a Rituximab product by intravenous infusion on Day 1 of Cycle 1 of chemotherapy (i.e., up to 8 cycles in total).
In patients with complete or partial response, initiate Rituximab and Hyaluronidase human maintenance treatment eight weeks after completing Rituximab and Hyaluronidase human combined with chemotherapy.
Administer Rituximab and Hyaluronidase human as a single-agent every eight weeks for 12 doses.
Non-progressing Follicular Lymphoma After First Line CVP Chemotherapy: Following completion of 6–8 cycles of CVP chemotherapy and a full dose of a rituximab product by intravenous infusion at week 1, administered once weekly for three weeks (i.e., four weeks in total) at 6-month intervals to a maximum of 16 doses.
Clinical Pharmacology
1. Mechanism of Action: Rituximab is a monoclonal antibody that targets the CD20 antigen on pre-B and mature B-lymphocytes. Once it binds to CD20, Rituximab initiates a process leading to the lysis (destruction) of B-cells. This cell lysis's mechanisms include Complement-Dependent Cytotoxicity (CDC) and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC).
In parallel, hyaluronan, a polysaccharide present within the extracellular matrix of subcutaneous tissue, undergoes depolymerization through the action of the naturally occurring enzyme hyaluronidase. Unlike other stable structural components within the interstitial matrix, hyaluronan has a short half-life of around 0.5 days.
The inclusion of hyaluronidase human in Rituximab and Hyaluronidase human increases the subcutaneous tissue's permeability by temporarily depolymerizing hyaluronan. Importantly, the effects of hyaluronidase human are reversible, and normal permeability of the subcutaneous tissue is typically restored within 24 to 48 hours.
Notably, research has demonstrated that hyaluronidase human enhances the absorption rate of Rituximab into the systemic circulation when administered in the subcutaneous tissue of Göttingen Minipigs. This mechanism enables more efficient and localized drug delivery.
2. Pharmacodynamics: For individuals with Follicular Lymphoma (FL), the decrease in peripheral B-cell counts below normal occurs after the initial cycle of Rituximab and is consistently maintained during treatment with Rituximab and Hyaluronidase human. Following the discontinuation of Rituximab and Hyaluronidase human treatment, the repletion of B cells follows a pattern similar to that observed with Rituximab, with B-cell recovery starting approximately six months after stopping the treatment, although in some patients, this process may take longer.
3. Pharmacokinetics: The terminal elimination half-life of Rituximab and Hyaluronidase human is around 32 to 34.1 days, and it exhibits a clearance rate of 0.18 to 0.204 liters per day.
What Are the Contraindications of Rituximab and Hyaluronidase Human?
No contraindications are known.
What Are the Adverse Effects of Rituximab and Hyaluronidase Human?
The subsequent clinically significant adverse effects are listed below.
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Mucocutaneous reactions.
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Reactivation of hepatitis B, including fulminant hepatitis.
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Progressive multifocal leukoencephalopathy.
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Hypersensitivity and other adverse reactions related to administration.
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Tumor lysis syndrome.
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Infections.
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Cardiac arrhythmias.
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Renal toxicity.
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Bowel obstruction and perforation.
Warnings and Precautions: The warning and precautions are listed below.
1. Severe Mucocutaneous Reactions: Patients may experience severe mucocutaneous reactions, including life-threatening conditions. Discontinue treatment in such cases.
2. Hepatitis B Virus Reactivation: Screen all patients for hepatitis B virus (HBV) infection before treatment. Monitor for HBV reactivation, which can be fatal, during and after treatment.
3. Progressive Multifocal Leukoencephalopathy (PML): PML, a potentially fatal brain infection, has been observed. Discontinue treatment if suspected.
4. Hypersensitivity and Administration Reactions: Be cautious with the first infusion due to a higher risk of hypersensitivity reactions. Monitor for systemic reactions and provide premedication.
5. Local Cutaneous Reactions: Injection site reactions may occur but are typically mild to moderate.
6. Tumor Lysis Syndrome (TLS): TLS can occur within 12-24 hours after treatment. Manage high-risk patients with hydration and anti-hyperuricemic therapy.
7. Infections: Serious infections, including reactivated viral infections, can happen. Discontinue treatment for severe infections.
8. Cardiovascular Adverse Reactions: Cardiac events, including arrhythmias, may occur. Monitor patients with cardiac history closely.
9. Renal Toxicity: Severe renal toxicity has been reported, especially in those with tumor lysis syndrome. Monitor renal function and discontinue if necessary.
10. Bowel Obstruction and Perforation: Abdominal issues have occurred, including obstruction and perforation.
11. Immunization: Avoid live viral vaccines during treatment.
12. Embryo-Fetal Toxicity: Rituximab-containing products can harm a fetus. Advise pregnant women and females of childbearing potential to use contraception during and after treatment.
Drug Interactions of Rituximab and Hyaluronidase Human
Rituximab and Hyaluronidase human may have interactions with certain medications and vaccines:
Cisplatin Interaction: Rituximab and Hyaluronidase human can interact with cisplatin, a chemotherapy drug. This combination can lead to dangerous levels of these drugs in the kidneys, potentially causing kidney failure. Therefore, taking these drugs together is not recommended. If taking cisplatin, inform the healthcare provider before starting Rituximab and Hyaluronidase human. They may suggest an alternative medication.
Live Vaccines: While using Rituximab and Hyaluronidase human, it is advisable to avoid receiving live vaccines. Live vaccines contain weakened forms of bacteria or viruses meant to prevent diseases. However, live vaccines can lead to infections when the immune system is compromised, such as during Rituximab and Hyaluronidase human treatment. It is unknown whether receiving any live vaccines while using this medication is safe. Ensure vaccinations are current before starting treatment, and consult the healthcare provider for guidance.
Herbs and Supplements: No specific herbs or supplements have been reported to interact with Rituximab and Hyaluronidase human. Nonetheless, it is prudent to consult the doctor or pharmacist before using any herbal products or supplements while taking this medication.
Foods: There are no known food interactions with Rituximab and Hyaluronidase human. If there are any concerns or questions about specific dietary choices while using this medication, discuss them with the doctor.
Clinical Studies: Rituximab and Hyaluronidase human clinical efficacy and safety were evaluated in the SABRINA trial, a randomized phase III study conducted in 410 patients with previously untreated follicular lymphoma. In this trial, patients were randomized to receive either intravenous (IV) Rituximab or a subcutaneous (SC) combination of Rituximab and Hyaluronidase human, combined with standard chemotherapy.
The primary endpoint of the overall response rate was assessed, and it was found that the SC formulation of Rituximab and Hyaluronidase human demonstrated non-inferiority to the IV formulation, with response rates of 84.4 percent and 84.9 percent, respectively. Additionally, the study analyzed pharmacokinetic data, revealing that the geometric mean serum trough concentrations of Rituximab were higher with the SC administration (134.58 µg/mL) compared to the IV formulation (83.13 µg/mL), supporting the effectiveness of the SC product.
Regarding safety, there were few clinically significant differences in rates of adverse events between the two groups, except for slightly higher rates of neutropenia (26 percent vs. 21 percent) and administration-related reactions (48% vs. 35 percent) in the SC Rituximab and Hyaluronidase human group. These administration-related reactions were predominantly grade 1 or 2 local injection site reactions.
