daratumumab/hyaluronidase

Action and Spectrum

Actions and Spectrum: 

daratumumab/hyaluronidase is a medication used to treat certain types of cancer, specifically multiple myeloma. It is a combination therapy that consists of daratumumab, a monoclonal antibody, and hyaluronidase, an enzyme. 

• Action of daratumumab: daratumumab is a monoclonal antibody that targets and binds to a protein called CD38, found on multiple myeloma cells’ surfaces. By binding to CD38, daratumumab helps to mark the cancer cells for destruction by the immune system. It can also induce direct cell death of the cancer cells and has been shown to have immunomodulatory effects. 
• Action of hyaluronidase: hyaluronidase is an enzyme that helps break down hyaluronic acid, a substance in the extracellular matrix surrounding cells. By breaking down hyaluronic acid, hyaluronidase improves the dispersion and absorption of other injected substances, such as daratumumab, into the tissues. This enzyme enhances the delivery of daratumumab into the subcutaneous tissue, allowing for a more rapid and convenient administration than intravenous infusion. 

The combination of daratumumab and hyaluronidase allows for the subcutaneous administration of daratumumab instead of the traditional intravenous infusion. This subcutaneous formulation provides an alternative route of administration that offers shorter infusion times and reduces the treatment burden for patients. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Multiple myeloma newly diagnosed 

Combination with melphalan, bortezomib, prednisone 

Peripheral sensory neuropathy (34%) 

Constipation (37%) 

Nausea (36%) 

Musculoskeletal chest pain (12%) 

Diarrhea (33%) 

Decreased neutrophils (88%) 

Hypertension (13%) 

Rash (13%) 

Back pain (21%) 

Decreased lymphocytes (93%) 

Peripheral edema (13%) 

Pneumonia (15%) 

Decreased leukocytes (96%) 

Insomnia (22%) 

Cough (24%) 

Abdominal pain (13%) 

Fatigue (36%) 

Bronchitis (16%) 

Pruritus (12%) 

Decreased hemoglobin (48%) 

Vomiting (21%) 

Upper respiratory tract infection (39%) 

Pyrexia (34%) 

Diminished platelets (93%) 

Diminished appetite (15%) 

Diminished leukocytes (52%) 

Diminished hemoglobin (19%) 

Diminished lymphocytes (84%) 

Diminished platelets (42%) 

Diminished neutrophils (49%) 

Combination with dexamethasone, lenalidomide 

Dyspnea (22%) 

Hyperglycemia (12%) 

Decreased lymphocytes (82%) 

Fatigue (52%) 

Decreased platelets (86%) 

Insomnia (17%) 

Bronchitis (14%) 

Peripheral sensory neuropathy (17%) 

Pneumonia (23%) 

Diarrhea (45%) 

Constipation (26%) 

Decreased leukocytes (94%) 

Nausea (12%) 

Back pain (14%) 

Pyrexia (23%) 

Decreased neutrophils (89%) 

Muscle spasm (31%) 

Hypocalcemia (11%) 

Cough (14%) 

Upper respiratory tract infection (43%) 

Vomiting (11%) 

Peripheral edema (18%) 

Decreased hemoglobin (45%) 

Urinary tract infection (11%) 

Monotherapy 

Pyrexia (13%) 

Decreased hemoglobin (42%) 

Fatigue (15%) 

Decreased leukocytes (65%) 

Decreased neutrophils (55%) 

Diarrhea (15%) 

Infusion reactions (13%) 

Decreased platelets (43%) 

Upper respiratory tract infection (24%) 

Decreased lymphocytes (59%) 

Light chain amyloidosis 

Dyspnea (26%) 

Diarrhea (36%) 

Decreased neutrophils (30%) 

Peripheral sensory neuropathy (31%) 

Upper respiratory tract infection (40%) 

Decreased platelets (46%) 

Injection site reactions (11%) 

Decreased leukocytes (60%) 

Pneumonia (15%) 

Constipation (34%) 

Decreased lymphocytes (81%) 

Back pain (12%) 

Cough (20%) 

Decreased hemoglobin (66%) 

Arrhythmia (11%) 

1-10% 

Multiple myeloma newly diagnosed 

Combination with melphalan, bortezomib, prednisone 

Chills (<10%) 

Paresthesia (<10%) 

Hypotension (3%) 

Influenza (<10%) 

Dizziness (10%) 

Pulmonary edema (<10%) 

Infusion reaction (<10%) 

Fatigue (3%) 

Headache (<10%) 

Urinary tract infection (<10%) 

Arthralgia (<10%) 

Diarrhea (3%) 

Herpes zoster (<10%) 

Insomnia (3%) 

Injection site reaction (<10%) 

Back pain (3%) 

Hypertension (6%) 

Sepsis (<10%) 

Muscle spasms (<10%) 

Atrial fibrillation (<10%) 

Peripheral sensory neuropathy (1%) 

Decreased appetite (1%) 

Dyspnea (<10%) 

Peripheral edema (1%) 

Pneumonia (7%) 

Combination with dexamethasone, lenalidomide 

Hyperglycemia (9%) 

Paresthesia (<10%) 

Grade 3 or 4 

Bronchitis (2%) 

Peripheral sensory neuropathy (2%) 

Rash (<10%) 

Pruritus (<10%) 

Fatigue (5%) 

Upper respiratory tract infection (3%) 

Hypertension (<10%) 

Insomnia (5%) 

Chills (<10%) 

Diarrhea (5%) 

Decreased platelets (9%) 

Abdominal pain (<10%) 

Infusion reaction (<10%) 

Injection site reaction (<10%) 

Herpes zoster (<10%) 

Atrial fibrillation (<10%) 

Musculoskeletal chest pain (<10%) 

Decreased appetite (<10%) 

Dizziness (<10%) 

Dyspnea (3%) 

Sepsis (<10%) 

Headache (<10%) 

Decreased hemoglobin (8%) 

Constipation (2%) 

Muscles spasms (2%) 

Pyrexia (2%) 

Peripheral edema (3%) 

Monotherapy 

Infusion reactions (2%) 

Bronchitis (<10%) 

Pneumonia (5%) 

Constipation (<10%) 

Dyspnea (1%) 

Peripheral sensory neuropathy (<10%) 

Insomnia (<10%) 

Hyperglycemia (<10%) 

Hypotension (<10%) 

Hepatitis B reactivation (<10%) 

Pruritus (<10%) 

Nausea (8%) 

Peripheral edema (<10%) 

Cough (9%) 

Dizziness (<10%) 

Muscle spasm (<10%) 

Sepsis (<10%) 

Hypertension (<10%) 

Rash (<10%) 

Urinary tract infection (<10%) 

Chills (6%) 

Back pain (2%) 

Decreased appetite (<10%) 

Pulmonary edema (<10%) 

Vomiting (<10%) 

Atrial fibrillation (<10%) 

Dehydration (<10%) 

Influenza (<10%) 

Pneumonia (8%) 

Dyspnea (6%) 

Hypocalcemia (<10%) 

Rash (<10%) 

Arthralgia (<10%) 

Diarrhea (1%) 

Musculoskeletal chest pain (<10%) 

Fatigue (1%) 

Herpes zoster (<10%) 

Peripheral edema (<10%) 

Cough (1%) 

Decreased appetite (<10%) 

Insomnia (<10%) 

Hypotension (<10%) 

Paresthesia (<10%) 

Light chain amyloidosis 

Arrhythmia (4%) 

Decreased neutrophils (6%) 

Diarrhea, Grade 3 (6%) 

Muscle spasm (1%) 

Dyspnea (4%) 

Cough, Grade 3 (1%) 

Back pain (2%) 

Constipation, Grade 3 (2%) 

Decreased leukocytes (7%) 

Decreased platelets (3%) 

Pneumonia (10%) 

Decreased hemoglobin (6%) 

<1% 

Multiple Myeloma 

Nausea (0.4%) 

Chills (0.4%) 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

The contraindications for daratumumab/hyaluronidase (Darzalex Faspro) include: 

• Known severe hypersensitivity reaction: daratumumab/hyaluronidase should not be administered to individuals with a prior history of severe hypersensitivity (e.g., anaphylactic reaction) to daratumumab, hyaluronidase, or any of the other components of the medication. 
• Infusion-related reactions: daratumumab/hyaluronidase can cause infusion-related reactions, including fever, chills, nausea, vomiting, fatigue, headache, cough, throat irritation, and breathing difficulties.  

Caution 

There were several cautions associated with daratumumab/hyaluronidase (Darzalex Faspro). These cautions include: 

• Infusion-related reactions: Although not a contraindication, daratumumab/hyaluronidase can still cause infusion-related reactions, which may include symptoms such as fever, chills, nausea, vomiting, fatigue, headache, cough, throat irritation, and breathing difficulties. Healthcare providers should closely monitor patients during and after the infusion and take appropriate measures to manage any reactions that may occur. 
• Interference with serological testing: daratumumab, the monoclonal antibody component of daratumumab/hyaluronidase, binds to CD38 on red blood cells and can interfere with specific blood tests, such as indirect antiglobulin test (indirect Coombs test) and antibody screening tests. This interference can lead to false-positive results. It’s crucial to inform laboratories of daratumumab/hyaluronidase treatment before undergoing blood testing to ensure an accurate interpretation of results. 
• Infections: daratumumab/hyaluronidase can increase the risk of infections, including respiratory tract infections (RTI), urinary tract infections, and pneumonia. Before initiating treatment, healthcare providers should assess patients for any active or prior infections and take appropriate measures to manage and monitor for infections during treatment. 
• Hepatitis B reactivation: In individuals with a history of hepatitis B virus (HBV) infection, reactivation of HBV can occur during or after treatment with daratumumab/hyaluronidase. Close monitoring of HBV markers is necessary for patients with a history of HBV infection, and antiviral prophylaxis may be required. 
• Pregnancy and breastfeeding: Using daratumumab/hyaluronidase during pregnancy may cause harm to the developing fetus. I am avoiding pregnancy during treatment and for 3 months after the last dose is recommended. It is unknown whether daratumumab/hyaluronidase is excreted in human milk, and the potential risks to the infant are unclear.

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: 

daratumumab/hyaluronidase combines the pharmacological properties of daratumumab, a monoclonal antibody, and hyaluronidase, an enzyme.  

daratumumab is a monoclonal antibody that specifically targets and binds to CD38, a protein expressed on the surface of multiple myeloma cells. By binding to CD38, daratumumab induces several anti-cancer effects, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptosis of CD38-expressing cells. 

Immunomodulatory Effects: daratumumab has demonstrated immunomodulatory effects, such as enhancing the activation and proliferation of natural killer (NK) cells and reducing the immune suppressive activity of regulatory T cells. These effects contribute to its anti-tumor activity. 

Pharmacodynamics: 

Mechanism of action: daratumumab/hyaluronidase involves the combined effects of daratumumab, a monoclonal antibody, and hyaluronidase, an enzyme.  

• daratumumab: daratumumab is a monoclonal antibody that specifically targets and binds to CD38, a protein expressed on surface of the multiple myeloma cells and other immune system cells. The mechanism of action of daratumumab includes the following: 
• Antibody-Dependent Cellular Cytotoxicity (ADCC): daratumumab binds to CD38 on multiple myeloma cells, leading to the activation of immune cells, like the natural killer cells and macrophages, through the Fc domain of the antibody. These activated immune cells recognize the daratumumab-bound CD38 on the cancer cells and induce their destruction through various mechanisms, including releasing cytotoxic granules and producing pro-inflammatory cytokines. 
• Complement-Dependent Cytotoxicity (CDC): daratumumab can also activate the complement system, which helps in cell lysis. The binding of daratumumab to CD38 on multiple myeloma cells triggers the activation of the complement system, leading to the formation of membrane attack complexes that cause cell lysis. 
• Antibody-Dependent Cellular Phagocytosis (ADCP): daratumumab-coated multiple myeloma cells can be recognized and engulfed by immune cells, such as macrophages, through ADCP. This process aids in the clearance of cancer cells from the body. 
• Direct Apoptosis: daratumumab can directly induce programmed cell death (apoptosis) in CD38-expressing multiple myeloma cells, destroying them. 
• hyaluronidase: hyaluronidase is an enzyme that facilitates the dispersion and absorption of injected substances, such as daratumumab, by breaking down hyaluronic acid, a component of the extracellular matrix. The presence of hyaluronidase in the daratumumab/hyaluronidase formulation allows for subcutaneous administration of daratumumab, enhancing its absorption into the subcutaneous tissue. 

By combining daratumumab with hyaluronidase, the subcutaneous administration of daratumumab is made possible, providing an alternative route of administration to the traditional intravenous infusion. 

Pharmacokinetics: 

Absorption 

daratumumab is administered intravenously or subcutaneously. When administered intravenously, the absorption is instantaneous and complete. Subcutaneous administration allows for slower and sustained absorption. 

hyaluronidase is typically administered as an enzyme preparation for subcutaneous administration, facilitating the dispersion and absorption of other injected substances. The absorption of hyaluronidase itself after subcutaneous administration is generally minimal. 

Distribution 

After systemic absorption, daratumumab is distributed throughout the body, including the extravascular compartments. The volume of distribution is generally consistent with the plasma volume. 

hyaluronidase is not extensively distributed systemically and primarily acts at the injection site, degrading hyaluronic acid. 

Metabolism 

daratumumab is an immunoglobulin G (IgG) monoclonal antibody and is expected to undergo catabolism into smaller peptides and amino acids. 

hyaluronidase is primarily metabolized locally at the injection site, where it enzymatically degrades hyaluronic acid. 

Elimination and Excretion 

The exact details of the excretion of daratumumab need to be well-documented. However, as an antibody, it is expected to undergo elimination primarily via catabolism and bodily clearance. 

The exact details of the excretion of hyaluronidase are not well-documented, but as an enzyme, it is expected to undergo degradation and clearance from the body. 

Adminstartion

Administration: 

Subcutaneous administration 

daratumumab/hyaluronidase is administered as a subcutaneous injection. Here are some key points regarding the administration of daratumumab/hyaluronidase: 

• Preparation: The medication is a single-dose vial containing daratumumab and hyaluronidase. Before administration, the vial should be visually inspected for any particulate matter or discoloration. The solution should appear clear to slightly opalescent. If any abnormalities are observed, the vial should not be used. 
• Dosing: The dosing regimen for daratumumab/hyaluronidase may vary depending on the individual’s specific medical condition and treatment plan. The healthcare provider will determine the recommended starting dose and subsequent doses. 
• Administration Site: daratumumab/hyaluronidase is administered as an SC injection into the abdomen, thigh/upper arm. The injection site should be rotated with each dose to minimize the risk of injection site reactions. 
• Preparation and Administration Technique: The healthcare provider will prepare the injection by attaching a single-use needle to the vial and withdrawing the appropriate daratumumab/hyaluronidase solution. The injection should be administered using an aseptic technique. 
• Injection Volume: The volume of daratumumab/hyaluronidase to be injected per dose may vary depending on the prescribed dose. The healthcare provider will determine the appropriate volume based on the individual’s dose. 
• Injection Speed: The injection should be administered over a duration of approximately 3 to 5 minutes for a total dose. The exact duration may vary based on the volume being injected. 
• Monitoring: Patients should be monitored for any signs of infusion-related or hypersensitivity reactions following the injection. Healthcare providers should be prepared to manage any reactions that may occur. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: daratumumab/hyaluronidase 

Pronounced: [ DAR-a-TOOM-ue-mab-and-HYE-al-ure-ON-i-dase-o ] 

Why do we use daratumumab/hyaluronidase? 

daratumumab/hyaluronidase is primarily used to treat multiple myeloma, affecting plasma cells in the bone marrow. Here are the primary uses of daratumumab/hyaluronidase: 

• Newly Diagnosed Multiple Myeloma: daratumumab/hyaluronidase, in combination with other types of drugs, is used for the therapy of newly diagnosed multiple myeloma in adult patients who are eligible for autologous stem cell transplant (ASCT). It is typically administered before and after ASCT to improve response rates and extend progression-free survival. 
• Relapsed or Refractory Multiple Myeloma: daratumumab/hyaluronidase is a viable treatment choice for adult patients who are dealing with relapsed or refractory multiple myeloma and have undergone at least one prior therapy. This medication can be administered either as a standalone treatment/combination with other medications, such as bortezomib, lenalidomide, or dexamethasone. 
• Smoldering Multiple Myeloma: daratumumab/hyaluronidase is also indicated for treating smoldering multiple myeloma, a precursor condition that may progress to active multiple myeloma.  

The use of daratumumab/hyaluronidase may be determined based on several factors, including the individual’s specific disease characteristics, previous treatments, and overall health condition. A healthcare professional specializing in managing multiple myeloma usually determines the treatment plan.