DARZALEX
Clinical safety rating
cautionComprehensive clinical and safety monograph for DARZALEX (DARZALEX).
Comprehensive clinical and safety monograph for DARZALEX (DARZALEX).
FDA-approved: Treatment of adult patients with multiple myeloma: in combination with lenalidomide and dexamethasone for newly diagnosed patients who are ineligible for autologous stem cell transplant; in combination with bortezomib, melphalan, and prednisone for newly diagnosed patients who are ineligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone for previously treated patients; in combination with bortezomib and dexamethasone for previously treated patients; in combination with pomalidomide and dexamethasone for previously treated patients; as monotherapy for patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent.Off-label: Approved indications also include light chain amyloidosis (in combination with bortezomib, cyclophosphamide, and dexamethasone) based on trial data but not yet FDA-labeled; off-label use in POEMS syndrome, primary plasma cell leukemia, and autoimmune hemolytic anemia (limited evidence).
Back pain, Constipation, Decreased white blood cell count (neutrophils), Diarrhea, Dizziness, Fatigue, Fever, Infusion reaction, Insomnia (difficulty in sleeping), Joint pain, Low blood platelets, Nausea, Breathlessness, Upper respiratory tract infection, Vomiting
Daratumumab is an IgG1κ human monoclonal antibody that binds to CD38, a transmembrane glycoprotein highly expressed on the surface of multiple myeloma cells. Binding to CD38 induces apoptosis via immune-mediated mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).
| Metabolism | Daratumumab is a monoclonal antibody, eliminated primarily through intracellular catabolism via the reticuloendothelial system (RES) and target-mediated clearance. It is not metabolized by hepatic CYP450 enzymes or excreted renally. The exact catabolic pathways are not fully characterized, but involve proteolysis into small peptides and amino acids. |
| Excretion | Daratumumab is eliminated primarily via intracellular catabolism and proteolytic degradation. No significant renal or biliary excretion occurs. Less than 1% of the dose is excreted unchanged in urine. |
| Half-life | Mean terminal half-life is approximately 18 days (range 12–28 days) after the last dose, supporting an every-4-week maintenance dosing interval. |
| Protein binding | Approximately 60–70% bound to plasma proteins; specifically to IgG and albumin via non-specific interactions. |
| Volume of Distribution | Mean volume of distribution is approximately 0.1–0.2 L/kg, indicating limited distribution beyond plasma and interstitial fluid. |
| Bioavailability | Subcutaneous administration (with recombinant human hyaluronidase) yields an absolute bioavailability of approximately 60–70% relative to IV; the SC formulation provides comparable exposure with a 15–20% lower mean trough concentration. |
| Onset of Action | Following intravenous infusion, clinical response (reduction in M-protein) is typically observed within 1–2 months (after 2–4 cycles). Subcutaneous administration has a similar onset. |
| Duration of Action | Duration of response varies; median progression-free survival in clinical trials ranges from 12–20 months depending on line of therapy. Daratumumab continues to exert effects for several weeks after last dose due to long half-life. |
| Molecular Weight | 148000 |
16 mg/kg intravenously once weekly for weeks 1-8, then every 2 weeks for weeks 9-24, then every 4 weeks starting week 25 until disease progression. Subcutaneous formulation: 1800 mg subcutaneously once weekly for weeks 1-8, then every 2 weeks for weeks 9-24, then every 4 weeks starting week 25.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl >=30 mL/min). Insufficient data for severe renal impairment (CrCl <30 mL/min) or hemodialysis; use with caution. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not studied in severe hepatic impairment (Child-Pugh C); use with caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years. No approved dosing. |
| Geriatric use | No specific dose adjustment required. Clinical studies included patients up to 85 years; overall safety and efficacy similar to younger adults, but monitor for increased adverse reactions. |
| 1st trimester | Daratumumab is a human IgG1 monoclonal antibody. IgG antibodies cross the placenta; the risk of fetal harm during the first trimester is unknown but anticipated due to potential FcRn-mediated transfer. Animal studies have not been conducted. Use only if potential benefit justifies potential risk. |
| 2nd trimester | IgG antibodies cross the placenta in increasing amounts throughout pregnancy, with highest transfer in the third trimester. Fetal immune modulation may occur. Avoid use unless clearly needed. |
| 3rd trimester | IgG antibodies cross the placenta readily; daratumumab may cause fetal B-cell depletion and immunosuppression. Use during third trimester should be avoided unless essential. |
Clinical note
Comprehensive clinical and safety monograph for DARZALEX (DARZALEX).
| Placental transfer | As a human IgG1 monoclonal antibody, daratumumab is expected to cross the placenta, especially in the second and third trimesters, via neonatal Fc receptor (FcRn)-mediated transport. The extent of transfer has not been studied but is anticipated to be significant in late pregnancy. |
| Breastfeeding | Daratumumab is a large protein molecule (approximate molecular weight 148 kDa) and is likely to be present in human milk in low amounts. However, because of the potential for adverse reactions including immunosuppression in the breastfed infant, breastfeeding is not recommended during treatment and for at least 3 months after the last dose (based on the drug's half-life of approximately 18 days). |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Daratumumab is an IgG1 monoclonal antibody. As IgG molecules cross the placenta, especially during the third trimester, there is potential for fetal exposure. There are no adequate and well-controlled studies in pregnant women. Based on its mechanism of action, daratumumab may cause fetal harm, including B-cell depletion in the fetus. Advise pregnant women of the potential risk to a fetus. |
| Fetal Monitoring | Monitor for infusion reactions during and after administration. Assess complete blood counts regularly due to potential neutropenia and thrombocytopenia. In pregnancy, consider fetal monitoring (ultrasound) for growth and development if exposure occurs. Monitor for signs of infection in the newborn if maternal exposure near delivery. |
| Fertility Effects | No dedicated fertility studies have been conducted. Based on animal studies, daratumumab may impair fertility due to effects on immune function and potential impact on reproductive organs. The clinical relevance in humans is unknown. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
History of severe hypersensitivity reactions to daratumumab or any of its excipients
| Precautions | Infusion reactions: Severe, including anaphylactic reactions, bronchospasm, hypotension, and hypoxia. Premedicate with corticosteroids, antihistamines, and antipyretics., Hematologic toxicity: Neutropenia, thrombocytopenia, and anemia; monitor blood counts regularly., Interference with blood compatibility testing (indirect antiglobulin test): Daratumumab binds to CD38 on red blood cells, causing pan-reactivity in antibody screening tests. Type and screen must be performed prior to starting therapy., Increased risk of infections: Bacterial, viral (including herpes zoster reactivation), and fungal infections; consider antiviral prophylaxis., Embryo-fetal toxicity: May cause fetal harm; advise females of reproductive potential to use effective contraception., Cardiac toxicity: Cases of cardiac arrest, arrhythmias, and heart failure; monitor patients with cardiac history., Second primary malignancies: Increased risk of non-melanoma skin cancer and other malignancies. |
| Food/Dietary | No specific food interactions are known. Maintain adequate hydration unless otherwise directed. |
| Clinical Pearls | Premedicate with antihistamines, antipyretics, and corticosteroids to reduce infusion reactions. Monitor for thrombocytopenia and neutropenia. Consider herpes zoster prophylaxis due to increased risk of reactivation. Infusion rate escalation should follow standard protocol to mitigate reactions. |
| Patient Advice | You may experience infusion reactions such as fever, chills, or shortness of breath during or after the infusion; report these immediately. · This drug lowers your platelet and white blood cell counts, increasing risk of bleeding and infection. Monitor for signs like easy bruising or fever. · You will need frequent blood tests to monitor blood counts and liver function. · Avoid live vaccines while on this medication. · Inform your healthcare provider if you have a history of shingles (herpes zoster) as preventive antiviral therapy may be needed. |
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