rituximab-hyaluronidase

Action and Spectrum

Actions and Spectrum: 

rituximab-hyaluronidase is a combination medication that consists of rituximab and hyaluronidase. rituximab is a monoclonal antibody, while hyaluronidase is an enzyme. When combined, they form a subcutaneous (under the skin) injection used for the treatment of certain types of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). 

• Mechanism of Action: rituximab targets and binds to a specific protein called CD20, found on the surface of B lymphocytes. By binding to CD20, rituximab activates the body’s immune system to attack and destroy these CD20-positive B cells. This action helps reduce the number of abnormal B cells and suppress the immune response. 

On the other hand, hyaluronidase is an enzyme that temporarily breaks down the connective tissue barrier under the skin, allowing the dispersion and absorption of rituximab. By facilitating the subcutaneous delivery of rituximab, hyaluronidase enhances the drug’s bioavailability and allows for a more convenient and faster administration than the traditional intravenous infusion of rituximab. 

• Spectrum of Use: rituximab-hyaluronidase is primarily indicated for the treatment of the following conditions: 
• Non-Hodgkin lymphoma (NHL): It is used in combination with chemotherapy as a 1st  line treatment for previously untreated diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). 
• Chronic lymphocytic leukemia (CLL): It is combined with chemotherapy to treat previously untreated CLL. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Follicular Lymphoma 

Abdominal pain (14%) 

Fatigue (20%) 

Neutropenia (32%) 

Paresthesia (16%) 

Nausea (31%) 

Arthralgia (13%) 

Cough (23%) 

Dyspnea (11%) 

Alopecia (14%) 

Constipation (25%) 

Diarrhea (18%) 

Anemia (15%) 

Injection site erythema (13%) 

Pneumonia (11%) 

Vomiting (14%) 

Pyrexia (15%) 

Peripheral neuropathy (12%) 

Diffuse Large B-Cell Lymphoma 

Cough (11%) 

Fatigue (19%) 

Pyrexia (13%) 

Nausea (22%) 

Febrile neutropenia (14%) 

Lopecia (24%) 

Vomiting (11%) 

Constipation (15%) 

Diarrhea (14%) 

Asthenia (11%) 

Decreased neutrophil count (14%) 

Neutropenia (31%) 

Peripheral neuropathy (12%) 

Chronic Lymphocytic Leukemia 

Neutropenia (65%) 

Chills (13%) 

Injection site erythema (26%) 

Injection site pain (16%) 

Erythema (15%) 

Nausea (38%) 

Diarrhea (12%) 

Anemia (13%) 

Rash (12%) 

Thrombocytopenia (24%) 

Vomiting (21%) 

Pyrexia (32%) 

Leukopenia (19%) 

Cough (13%) 

Febrile neutropenia (11%) 

Upper respiratory tract infection (13%) 

1-10% 

Follicular Lymphoma 

Back pain (9%) 

Asthenia 

Dizziness (7%) 

Hypertension (6%) 

Dyspnea, Grade 3-4 (1%) 

Injection site pain (8%) 

Pruritus (10%) 

Peripheral edema (5%) 

Dyspepsia (8%) 

Chest pain 

Urinary tract infection (8%) 

Insomnia (7%) 

Conjunctivitis (5%) 

Myalgia (8%) 

Stomatitis (6%) 

Rash (10%) 

Peripheral neuropathy 

Sinusitis (7%) 

Chills (8%) 

Erythema (9%) 

Upper abdominal pain (5%) 

Extremity pain (10%) 

Influenza (4%) 

Influenza-like illness (3%) 

Oropharyngeal pain (9%) 

Mucosal inflammation (5%) 

Diarrhea 

Muscles spasms (8%) 

Infection site pain (8%) 

Hypertension 

Diffuse Large B-Cell Lymphoma 

Peripheral edema (8%) 

Stomatitis (6%) 

Decreased appetite (8%) 

Dyspepsia (5%) 

Insomnia (7%) 

Decreased weight (8%) 

Lymphopenia (5%) 

Mucosal inflammation (8%) 

Abdominal pain (7%) 

Decreased lymphocyte count (5%) 

Headache (6%) 

Leukopenia (7%) 

Dyspnea (6%) 

Decreased WBC count (7%) 

Paresthesia (9%) 

Headache (6%) 

Chronic Lymphocytic Leukemia 

Oropharyngeal pain (6%) 

Asthenia (8%) 

Arthralgia (9%) 

Dyspnea (4%) 

Respiratory tract infection (8%) 

Constipation (8%) 

Pruritus (8%) 

Bronchitis (7%) 

Abdominal pain (9%) 

Urinary tract infection (2%) 

Pneumonia (2%) 

Headache (7%) 

Extremity pain (7%) 

Hypotension (1%) 

Insomnia (1%) 

Black Box Warning

Black Box Warning: 

The black box warning for this medication combination includes the following information: 

• Severe Mucocutaneous Reactions: Rituxan Hycela can cause severe and life-threatening mucocutaneous reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These reactions can occur during or after treatment and may lead to death. Patients should be monitored for skin reactions; if severe mucocutaneous reactions occur, treatment should be discontinued. 
• Progressive Multifocal Leukoencephalopathy (PML): Rituxan Hycela, like other rituximab-containing products, risks developing PML, a rare and potentially fatal brain infection which is caused by the JC virus. PML can result in severe disability/death. Signs and symptoms of PML may include clumsiness of limbs, progressive weakness on one side of the body, confusion, or difficulties with thinking, vision, or speech. If PML is suspected, treatment with Rituxan Hycela should be discontinued. 
• Reactivation of Hepatitis B: Rituxan Hycela can cause the reactivation of hepatitis B virus (HBV) in patients who are carriers of the virus. HBV reactivation can lead to severe liver damage, including liver failure and death. Before starting treatment with Rituxan Hycela, patients should be screened for HBV infection markers. Patients with evidence of current or previous HBV infection should be monitored for HBV reactivation during and after treatment. 
• If HBV reactivation occurs, rituximab/hyaluronidase treatment should be immediately discontinued, and appropriate antiviral therapy should be initiated. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

rituximab-hyaluronidase has a few contraindications, meaning circumstances or medical conditions in which its use is not recommended. Contraindications for rituximab-hyaluronidase may include: 

• Hypersensitivity: The medication should not be used in individuals with known hypersensitivity or severe allergic reactions to rituximab, hyaluronidase, or other product components. 
• Severe active infections: rituximab-hyaluronidase should not be administered to individuals with severe active infections. The medication can further compromise the immune system, making it strenuous for the body to fight infections. 
• Hepatitis B virus (HBV) infection: rituximab-hyaluronidase is contraindicated in patients with active hepatitis B infection. The medication can potentially reactivate the hepatitis B virus and cause severe liver problems. 

Caution 

Specific cautions associated with rituximab-hyaluronidase may include: 

• Infusion-related reactions: rituximab-hyaluronidase can cause infusion-related reactions, including fever, chills, rash, itching, and difficulty breathing. These reactions can occur during or shortly after the administration of the medication. Close monitoring is necessary during the infusion, and healthcare providers should be prepared to manage any potential reactions. 
• Immunization: Live vaccines should be avoided during treatment with rituximab-hyaluronidase. The drug can debilitate the immune system, and administering live vaccines may result in an inadequate response. It is recommended to complete all necessary immunizations before starting rituximab-hyaluronidase treatment. 
• Infections: rituximab-hyaluronidase may increase the risk of developing infections. Before starting treatment, it is important to screen patients for any underlying infections, including hepatitis B virus (HBV) and tuberculosis (TB). Close monitoring for signs and symptoms of infection during and after treatment is essential. 
• Cardiac side effects: rituximab-hyaluronidase may have cardiac side effects, including arrhythmias, angina, and myocardial infarction. Patients with pre-existing cardiac conditions should be closely monitored during treatment. 
• Tumor lysis syndrome: In patients with a high tumor burden, rituximab-hyaluronidase treatment may lead to tumor lysis syndrome, characterized by the rapid breakdown of tumor cells. Close monitoring and appropriate preventive measures should be taken to minimize the risk of this syndrome. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk is Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

rituximab-hyaluronidase is a combination medication that consists of rituximab, a monoclonal antibody, and hyaluronidase, an enzyme.  

• rituximab is a chimeric monoclonal antibody that specifically targets the CD20 antigen present on surface of B lymphocytes. It exerts its pharmacological effects through multiple mechanisms: 
• Antibody-dependent cellular cytotoxicity (ADCC): rituximab binds to CD20 on B cells, leading to the activation of the immune system, particularly natural killer (NK) cells, which can recognize and destroy the rituximab-bound B cells. 
• Complement-dependent cytotoxicity (CDC): rituximab can also activate the complement system, which triggers a cascade of reactions destroying CD20-positive B cells. 
• Induction of apoptosis: rituximab promotes programmed cell death (apoptosis) in CD20-positive B cells, eliminating them. 
• hyaluronidase: hyaluronidase is an enzyme that catalyzes the breakdown of hyaluronic acid, a natural component of the extracellular matrix. It temporarily breaks down the hyaluronic acid barrier, facilitating the dispersion and absorption of co-administered medications, such as rituximab. 

Adding hyaluronidase to rituximab allows the subcutaneous administration of the medication, providing an alternative to intravenous infusion. By enhancing the absorption of rituximab, hyaluronidase improves bioavailability and enables more convenient and faster administration. 

Pharmacodynamics: 

Mechanism of action: The action of rituximab-hyaluronidase is primarily driven by the action of rituximab, the monoclonal antibody component of the medication. hyaluronidase, the enzyme, is co-administered to facilitate the subcutaneous delivery of rituximab. Let’s delve into the mechanism of action of rituximab: 

rituximab is a chimeric monoclonal antibody targeting a specific antigen called CD20, found on the surface of B lymphocytes. The action of rituximab involves the following: 

• Binding to CD20: rituximab binds specifically to CD20 antigens on the surface of B cells. CD20 is expressed during most stages of B cell development, except for the early pre-B cells and plasma cells. 
• Antibody-dependent cellular cytotoxicity (ADCC): Upon binding to CD20, rituximab can trigger immune effector functions, such as antibody-dependent cellular cytotoxicity (ADCC). ADCC involves activating immune cells, particularly natural killer (NK) cells, which recognize the rituximab-bound B cells and destroy them through various mechanisms. 
• Complement-dependent cytotoxicity (CDC): rituximab can also activate the complement system, that helps destroy foreign substances. Activation of complement through rituximab binding to CD20 leads to forming a membrane attack complex, causing lysis of CD20-positive B cells. 
• Induction of apoptosis: rituximab can induce programmed cell death, known as apoptosis, in CD20-positive B cells. This process helps eliminate the targeted B cells. 

The combination of these mechanisms leads to the depletion of CD20-positive B cells, which are involved in various disease processes, including certain types of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). 

hyaluronidase, as a co-administered enzyme, assists in the subcutaneous delivery of rituximab by temporarily breaking down the hyaluronic acid barrier in the subcutaneous tissue. This enhances the dispersion and absorption of rituximab, allowing for subcutaneous medication administration. 

Pharmacokinetics: 

Absorption 

rituximab is administered intravenously, typically as an infusion. Following intravenous administration, rituximab is wholly and immediately available in the systemic circulation. 

hyaluronidase is co-administered with rituximab to facilitate the dispersion and absorption of the medication. hyaluronidase is not typically absorbed systemically as it acts locally at the injection site to break down the connective tissue barrier temporarily. 

Distribution 

rituximab distributes throughout the body, including the blood, lymphoid tissue, and other tissues. It binds specifically to CD20 antigen on B cells, leading to its localization in lymphoid tissue where B cells reside. 

hyaluronidase is distributed locally at the injection site, breaking down hyaluronic acid and increasing the subcutaneous tissue’s permeability. 

Metabolism 

rituximab is a large protein and is not metabolized in the same way as small molecules. It undergoes proteolytic degradation into smaller peptides and amino acids. 

hyaluronidase is endogenous to the body and is naturally metabolized. 

Elimination and Excretion 

The elimination of rituximab occurs primarily via catabolism and clearance by the reticuloendothelial system, including liver and spleen cells. It is eliminated slowly from the body, with a long half-life ranging from several days to several weeks. 

It is primarily broken down by proteolytic enzymes and excreted through normal metabolic processes. 

Adminstartion

Administration: 

Subcutaneous administration 

rituximab-hyaluronidase is administered as a subcutaneous injection, which is injected under the skin. The administration of rituximab-hyaluronidase involves the following steps: 

• Preparation: The healthcare professional prepares the medication by reconstituting rituximab and hyaluronidase. This involves mixing the lyophilized powder of rituximab with the provided diluent and then combining it with the hyaluronidase solution. The resulting mixture is drawn into a syringe. 
• Injection site selection: The injection site is typically in the abdomen (except for a 2-inch area around the navel), upper thigh, or outer area of the upper arm. The site should be clean, dry, and without lesions or irritation. 
• Administration: The healthcare professional injects the prepared rituximab-hyaluronidase subcutaneously into the selected site. The exact technique may vary, but it generally involves pinching the skin and inserting the needle at a 45 to 90-degree angle. The needle is then fully inserted, and the medication is slowly injected. 
• Monitoring: The healthcare professional monitors the patient for any immediate adverse reactions or infusion-related side effects following the injection. The patient may be observed for a certain period to ensure no complications. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: rituximab-hyaluronidase 

Why do we use rituximab-hyaluronidase? 

rituximab-hyaluronidase treats certain types of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It is a combination medication that consists of rituximab, a monoclonal antibody, and hyaluronidase, an enzyme. The use of rituximab-hyaluronidase is indicated in the following situations: 

• Diffuse Large B-cell Lymphoma (DLBCL): rituximab-hyaluronidase, in combination with chemotherapy, is used as a 1st line treatment for previously untreated DLBCL, which is the most common type of aggressive NHL. 
• Follicular Lymphoma (FL): rituximab-hyaluronidase, in combination with chemotherapy, is used as a first-line treatment for previously untreated FL, which is a slow-growing form of NHL. 
• Chronic Lymphocytic Leukemia (CLL): rituximab-hyaluronidase, combined with chemotherapy, is used to treat previously untreated CLL.