Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Daratumumab is an antineoplastic agent belonging to the pharmacological class of monoclonal antibodies, specifically anti-CD38 monoclonal antibodies.
Daratumumab is FDA-approved for treating various stages of Multiple Myeloma in adults.
Daratumumab is administered intravenously for complete bioavailability, and its monoclonal antibody distributes systemically, reaching blood and tissues and undergoing minimal metabolism. Elimination primarily occurs through tissue catabolism, with minimal renal or hepatic involvement.
Infusion reactions such as swollen face, lips, mouth, tongue or throat and difficulty swallowing or breathing are the most common side effects of Daratumumab.
Daratumumab is available as an injectable solution.
The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Daratumumab is an antineoplastic agent belonging to the pharmacological class of monoclonal antibodies, specifically anti-CD38 monoclonal antibodies.
Hematopoietic cells have the glycoprotein CD38 on their surface, and CD38 is involved in several aspects of cell signalling. An immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that targets explicitly CD38 is called daratumumab. Daratumumab has a greater affinity for cells that overexpress CD38 in cancers such as multiple myeloma. Daratumumab is able to cause apoptosis, complement- and antibody-dependent cytotoxicity, and antibody-dependent cellular phagocytosis thanks to this binding. The antibody's Fc region triggers phagocytes like macrophages to undergo antibody-dependent cellular phagocytosis; the antibody's Fc region triggers effector cells like natural killer cells to undergo antibody-dependent cellular cytotoxicity; and the antibody's FC region binds to complement protein and triggers complement-dependent cytotoxicity.
Peak plasma concentration of Daratumumab reaches 915 mcg/mL with weekly dosing.
The trough concentration of Daratumumab is 573 mcg/mL in monotherapy and 502 mcg/mL in combination therapy.
Steady state for Daratumumab monotherapy is achieved over five months.
Daratumumab is available as an injection solution.
Injection solutions: To be administered parenterally as applicable.
As the physician recommends, the medication can usually be taken once every week or every 3 weeks.
In treating Multiple myeloma: In multiple myeloma, the body rapidly breaks down bone, causing weakness and pain, making bones more susceptible to fractures. Doctors prescribe Daratumumab in addition to chemotherapy to eradicate cancer cells, stop them from growing, and prevent them from spreading to other areas of the body. Direct tumour cell death is induced by daratumumab, which also strengthens the immune system and stops the growth of cancer cells. This FDA-approved treatment improves overall response rates, lowers the risk of disease progression or death, and prolongs progression-free survival in various stages, including newly diagnosed and relapsed/refractory cases.
Daratumumab is indicated for the following health conditions:
- In patients who are not eligible for an autologous stem cell transplant (ASCT), a combination of bortezomib, melphalan, and prednisone is indicated to treat newly diagnosed multiple myeloma.
- When lenalidomide and low-dose dexamethasone are combined, patients who are not eligible for ASCT can receive treatment for newly diagnosed multiple myeloma.
- Combination with prednisone, thalidomide, and bortezomib: Suitable for patients who are eligible for ASCT and who have recently been diagnosed with multiple myeloma.
- Monotherapy targets multiple myeloma in patients who are double-refractory to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) or have received at least three lines of therapy.
- Combination with low-dose dexamethasone and bortezomib: Beneficial for multiple myeloma patients with at least one previous therapy.
- For patients with multiple myeloma who have had at least one previous therapy, a combination of lenalidomide and low-dose dexamethasone is appropriate.
- In patients with multiple myeloma who have received at least two previous therapies, such as lenalidomide and a proteasome inhibitor, the combination of pomalidomide and low-dose dexamethasone responds to the disease.
- Combination of dexamethasone and carfilzomib: Treats patients with multiple myeloma who have had one to three previous lines of therapy and have relapsed or are refractory.
Parenterally: Daratumumab is given by intravenous (IV) infusion, which usually takes 15 hours to complete and ensures precise dosage under controlled conditions. Pre-infusion and post-infusion medications are given one to three hours before each injection to reduce infusion reactions. Only in the absence of previous infusion reactions is incremental escalation considered. Regardless of the degree or severity of the infusion reaction, it is immediately stopped, and the symptoms are treated. Additional measures might be required to treat infusion reactions, like lowering the infusion rate or stopping the treatment. If a scheduled dose is missed, it should be administered immediately, and the dosing schedule should be modified to maintain the treatment interval.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
100mg/5mL (20mg/mL) single-use vial
400mg/20mL (20mg/mL)single-use vial
Daratumumab is available as an injectable solution.
Dose Adjustment in Adult Patients:
- Multiple Myeloma
Newly diagnosed multiple myeloma
Combination treatment comprising prednisone, melphalan, and bortezomib
Weeks 1-6: One weekly IV infusion at a dose of 16 mg/kg (total of 6 doses)
Weeks 7–54: Administer IV infusion of 16 mg/kg every three weeks (16 doses); the first dose of the dosing schedule every three weeks is administered at Week 7.
Week 55 and after, until the disease advances: Every four weeks, an IV infusion of 16 mg/kg is given; the first dose of this dosing schedule is administered at Week 55.
Combination treatment comprising dexamethasone and lenalidomide.
Weeks 1-8: Weekly IV infusion of 16 mg/kg (total of 8 doses)
Weeks 9-24: First dose of a two-weekly dosing schedule that consists of 16 mg/kg IV infusions spaced two weeks apart (a total of eight doses).
Until the disease progresses, starting in Week 25, a 16 mg/kg IV infusion is administered every 4 weeks. The first dose of this dosing schedule is given at Week 25.
Combination treatment comprising dexamethasone, thalidomide, and bortezomib
Phase of induction (Weeks 1-8): weekly IV infusion of 16 mg/kg (total of 8 doses)
Phase of induction (Weeks 9–16): IV infusion of 16 mg/kg every two weeks (total of four doses); the first dosage of the dosing regimen every two weeks is administered at Week 9
Stop high-dose chemotherapy treatment and ASCT consolidation (Week 1–8): 16 mg/kg IV infusion every 2 weeks (total of 4 doses); the first dose of the dosing schedule, which is administered every 2 weeks, is given at Week 1 when treatment is resumed after ASCT.
- Refractory or relapsed multiple myeloma
Monotherapy
Weeks 1 to 8: a weekly IV infusion of 16 mg/kg (8 doses total)
Weeks 9 to 24: 16 mg/kg IV infusion every two weeks (eight doses total); Week 9 is the first dose of the every two weeks dosing schedule.
Weeks 25–and afterwards, until disease progression: 16 mg/kg IV infusion every four weeks; Week 25 is the first dose of the every four weeks dosing schedule.
Combination treatment comprising dexamethasone and bortezomib
Weeks 1 to 9: a weekly IV infusion of 16 mg/kg (a total of 9 doses)
Weeks 10 to 24: 16 mg/kg IV infusion every three weeks (total of five doses); Week 10 is the first dose of the every three weeks dosing schedule. Weeks 25–and beyond, until disease progression: 16 mg/kg IV infusion every four weeks; Week 25 is the first dose of the every four weeks dosing schedule.
Combination treatment comprising dexamethasone and lenalidomide
Weeks 1 to 8: a weekly IV infusion of 16 mg/kg (8 doses total)
Weeks 9 to 24: 16 mg/kg IV infusion every two weeks (8 doses total); Week 9 is the first dose of every two weeks dosing schedule.
Weeks 25–and afterwards, until disease progression: 16 mg/kg IV infusion every four weeks; Week 25 is the first dose of every four weeks dosing schedule.
Combination therapy with pomalidomide and dexamethasone
Weeks 1 to 8: weekly IV infusion at a dose of 16 mg/kg
Weeks 9 to 24: an IV infusion of 16 mg/kg every two weeks (8 doses total); Week 9 is the first week of the two-weekly dosing schedule.
Week 25 afterwards until the disease progresses: an IV infusion of 16 mg/kg every 4 weeks is administered; the first dose of this dosing schedule is given at Week 25.
Combination treatment comprising dexamethasone and carfilzomib
Week 1: Two doses of 8 mg/kg IV administered on Days 1 and 2
Weeks 2–8: IV (16 mg/kg, 7 doses total)
Weeks 9–24: 8 doses of 16 mg/kg IV given every two weeks.
Week 25 and beyond IV 16 mg/kg every 4 weeks; continue until toxicity or disease progression occurs.
Considerations for Dosing
Inform blood transfusion facilities when serological testing is being interfered with.
Inform blood banks of the patient's daratumumab use.
Before starting treatment, identify and screen patients.
While on Daratumumab, managing side effects is possible through dietary adjustments. Consume green leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, broccoli, cauliflower, and cabbage with beans and herbs. Avoid taking alcohol and tobacco. Refusing processed meats, fast food, fried foods, refined carbs, or added sugars is advisable.
The dietary restriction should be individualized as per patient requirements.
- Reactions Related to Infusion: If there are any infusion-related reactions, stop the daratumumab infusion immediately. In cases of anaphylactic responses or other potentially fatal events connected to the infusion, stop the injection permanently and provide the necessary emergency treatment.
- Interference with Red Blood Cell Antibody Screening and Cross-Matching: Perform type and screen evaluations on patients before starting medication. Inform blood banks of a patient's use of Daratumumab to avoid interfering with red blood cell antibody screening and cross-matching.
- Neutropenia: To detect neutropenia, regularly measure the total blood cell count while receiving therapy. Monitor for any symptoms of infection in neutropenic individuals. Consider waiting for the dose to decrease to allow the neutrophil counts to return to normal.
- Thrombocytopenia: Throughout therapy, check complete blood cell counts often to look for thrombocytopenia. To encourage platelet recovery, defer the dosage if required.
- Prenatal and Fetal Toxicity: Daratumumab may be harmful to unborn children. Inform expectant mothers about possible fetal risks. Encourage women who are capable of becoming pregnant to utilize reliable contraception to avoid getting pregnant while receiving Daratumumab medication.
Alcohol Warning
Breast Feeding Warning
Pregnancy Warning
Food Warning
The adverse reactions related to Daratumumab can be categorized as:
- Common Adverse Effects: Upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhoea, cough, insomnia, vomiting, and back pain.
- Less Common Adverse Effects: Neutropenia, interference with cross-matching and red blood cell antibody screening and thrombocytopenia
- Rare Adverse Effects: Embryo-fetal toxicity and Infusion-related reactions (IRRs) severity.
Reports on Postmarketing
An allergic response
Pancreatitis
Listeria and cytomegalovirus infections
The clinically relevant drug interactions of Daratumumab are briefly summarized here.
Effects of Daratumumab on Laboratory Tests
- Indirect Antiglobulin Tests (Indirect Coombs Test): Compatibility testing can be affected by daratumumab's binding to CD38 on RBCs. Reagent RBCs can be genotyped or treated with dithiothreitol (DTT) as a kind of mitigation. ABO/RhD-compatible non-cross-matched RBCs can be given in an emergency transfusion by following local blood bank protocols.
- Serum Protein Electrophoresis and Immunofixation Tests: Monoclonal immunoglobulins may detect Daratumumab in serum protein electrophoresis (SPE) and immunofixation (IFE) tests used to monitor illness, leading to false positive findings for patients with IgG kappa myeloma protein. This affects the International Myeloma Working Group's (IMWG) preliminary evaluation of comprehensive replies. Alternative techniques for assessing the depth of response should be taken into consideration for patients who consistently exhibit extremely good partial responses.
- Pregnancy
Pregnancy Category C (FDA): Use caution if the benefits outweigh the risks.
There is no human data to suggest a risk associated with daratumumab use during pregnancy, and no studies have been done on animals.
The placenta facilitates the passage of immunoglobulin G1 (IgG1) monoclonal antibodies.
Daratumumab's mode of action suggests that it could reduce bone density and deplete fetal myeloid or lymphoid cells.
Lenalidomide, pomalidomide, and thalidomide are only available through REMS programs, so take them together with other medications. At the same time, pregnancy is not advised due to the possibility of congenital disabilities and the death of the fetus. For more information, see the individual prescribing information for these medications.
Allow until a hematology assessment is finished before giving live vaccinations to newborns and infants exposed to daratumumab while still in utero.
Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. The medication may deplete fetal CD38-positive immune cells and reduce bone density due to its mechanism of action.
contraception
During treatment and for three months following treatment termination, women who are capable of becoming pregnant should use an effective form of birth control.
- Nursing Mothers
The excretion of daratumumab into human or animal milk and its impact on milk production are unknown. No research has been done to evaluate daratumumab's impact on breastfed infants.
Although maternal IgG is expelled in human milk, newborns and infants do not take it in significant quantities due to its breakdown in the gastrointestinal system. Considering the advantages of both breastfeeding and therapy for the mother, a choice should be taken on whether to stop Daratumumab treatment or stop breastfeeding because the hazards of the medication to the newborn via oral intake are unclear.
- Pediatric Use
As per FDA, the safety and effectiveness of Daratumumab in pediatric patients have not been established.
- Geriatrics (> 65 years old) Use
It has been established that daratumumab is safe and effective for older adults 65 years and older. Yet, variations based on age could occur. Monitor elderly citizens cautiously for adverse reactions.
Dose Adjustment in Kidney Impairment Patients:
Mild-Moderate-severe (CrCl 15-89 mL/min): No dose modification is necessary.
Dose Adjustment in Hepatic Impairment Patients:
There is no need to change the dosage in mild cases (total bilirubin [TB] ULN or TB 1.5–3x ULN with any AST).
Unknown for severe (TB >3x ULN and any AST).
In human clinical studies, overdosage has never occurred once. A clinical trial used intravenous doses up to 24 mg/kg without exceeding the maximum tolerated dosage.
Management: The specific antidote for daratumumab overdose is unknown. If the patient overdoses, the proper symptomatic treatment should be started immediately, and they should be closely watched for any indications of adverse outcomes.
Pharmacodynamics:
The monoclonal antibody daratumumab targets and causes apoptosis in cells, such as multiple myeloma cells, that express CD38 highly. Administering it every 1-4 weeks allows for a prolonged period of action. Patients should be informed about the possibility of thrombocytopenia, cross-matching toxicity, hypersensitivity, neutropenia, and interference with red blood cell antibody screening.
Pharmacokinetics:
- Absorption: Daratumumab is administered intravenously, ensuring complete and direct absorption into the bloodstream, bypassing the gastrointestinal tract.
- Volume of Distribution: In intravenous monotherapy, Daratumumab has a volume distribution of 4.7 ± 1.3L; in combination therapy, it is 4.4 ± 1.5L. Subcutaneous Daratumab has a distribution volume of 5.2L in the central compartment and 3.8L in the peripheral compartment.
- Metabolism: Monoclonal antibodies like Daratumumab are anticipated to undergo metabolism into smaller proteins and amino acids through proteolytic enzymes.
- Elimination: Monoclonal antibodies are metabolized into amino acids to synthesize new proteins or eliminated by the kidneys. The half-life is 18 days for monotherapy and 22-23 days for combination therapy. Intravenous Daratumumab exhibits a clearance of 171.4 ± 95.3mL/day, while subcutaneous Daratumumab has a clearance of 119mL/day. Daratumumab achieves a clearance of 171.4 mL/day at steady-state.
- Raedler LA. Darzalex (Daratumumab): First Anti-CD38 Monoclonal Antibody Approved for Patients with Relapsed Multiple Myeloma. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):70-3. PMID: 27668047; PMCID: PMC5013856.
- Arnall JR, Maples KT, Harvey RD, Moore DC. Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations. Ann Pharmacother. 2022 Aug;56(8):927-940. doi: 10.1177/10600280211058754. Epub 2021 Dec 28. PMID: 34963325.
- Kumar L, Melinkeri S, Ganesan P, Kumar J, Biswas G, Kilara N, Pathalingappa H, Prasad S, Jain M, Mishra SK, Prasad S, Boyella PK, Sahoo RK, Bondarde S, Shah S, Rege M, Deb U, Korde T, Dixit J. Daratumumab in Indian patients with relapsed and refractory multiple myeloma: a prospective, multicenter, phase IV study. Future Oncol. 2023 Dec 20. doi: 10.2217/fon-2023-0842. Epub ahead of print. PMID: 38116642.
- Huang ZY, Jin XQ, Liang QL, Zhang DY, Han H, Wang ZW. Efficacy and safety of daratumumab in the treatment of relapsed/refractory multiple myeloma: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2023 Sep 22;102(38):e35319. doi: 10.1097/MD.0000000000035319. PMID: 37747011; PMCID: PMC10519573.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761036s041lbl.pdf
- https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf
- https://www.ncbi.nlm.nih.gov/books/NBK548759/
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
