DARZALEX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DARZALEX (DARZALEX).
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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DARZALEX (DARZALEX).
| Breastfeeding | No data on the presence of daratumumab in human milk, effects on the breastfed infant, or effects on milk production. Human IgG is present in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 3 months after the last dose. M/P ratio is unknown. |
| 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. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
["Absolute: history of severe hypersensitivity (e.g., anaphylaxis) to daratumumab or any of its excipients.","Relative: None specifically listed; however, caution is advised in patients with active infections, pre-existing cardiac disease, or severe renal impairment (due to limited data)."]
| 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."] |
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| 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. |