Daratumumab

Daratumumab is used for: Multiple Myeloma

Multiple Myeloma Newly diagnosed multiple myeloma Combination therapy with bortezomib, melphalan and prednisone Indicated in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT) Weeks 1-6: 16 mg/kg IV infusion once weekly (total of 6 doses) Weeks 7-54: 16 mg/kg IV infusion every 3 weeks (total of 16 doses) Week 55 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks Relapsed/refractory multiple myeloma Monotherapy Indicated as monotherapy for multiple myeloma in patients who have received at least 3 lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMiD Weeks 1-8: 16 mg/kg IV infusion once weekly (total of 8 doses) Weeks 9-24: 16 mg/kg IV infusion every 2 weeks (total of 8 doses) Week 25 onward until disease progression: 16 mg/kg IV infusion every 4 weeks Combination therapy with bortezomib and dexamethasone Indicated in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy Weeks 1-9: 16 mg/kg IV infusion once weekly (total of 9 doses) Weeks 10-24: 16 mg/kg IV infusion every 3 weeks (total of 5 doses) Week 25 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks Combination therapy with lenalidomide and dexamethasone Indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at 1 prior therapy Weeks 1-8: 16 mg/kg IV infusion once weekly (total of 8 doses) Weeks 9-24: 16 mg/kg IV infusion every 2 weeks (total of 8 doses) Week 25 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks Combination therapy with pomalidomide and dexamethasone Indicated in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor Weeks 1-8: 16 mg/kg IV infusion once weekly Weeks 9-24: 16 mg/kg IV infusion every 2 weeks Week 25 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks Hepatic impairment Mild (total bilirubin [TB] ULN, or TB 1.5-3x ULN and any AST): No dose adjustment required Severe (TB >3x ULN and any AST): Not studied

Renal impairment No dosage adjustment required

IV Preparation Vials are single-use only Calculate the dose (mg), total volume (mL) of solution required and the number of vials needed Check solution is colorless to pale yellow; do not use if opaque particles, discoloration, or other foreign particles are present Using aseptic technique, remove a volume of 0.9% NaCl from the infusion bag/container equivalent to the required volume of daratumumab solution Withdraw the daratumumab dose from the vial(s) and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% NaCl (first infusion 1000 mL; second and subsequent infusions 500 mL) Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE) Discard any unused portion left in the vial Gently invert the bag/container to mix the solution Do not shake Following dilution, store infusion bag/container for up to 24 hr in a refrigerator at 2-8ºC (36-46ºF); protect from light and do not freeze After allowing the bag/container to come to room temperature, use immediately since the solution does not contain a preservative Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit Do not use if visibly opaque particles, discoloration, or foreign particles are observed IV Administration Should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur Administer diluted solution by IV infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, nonpyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer) Polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE administration sets must be used Infusion should be completed within 15 hr Do not store any unused portion of the infusion solution for reuse Any unused product or waste material should be disposed of in accordance with local requirements Do not infuse concomitantly in the same IV line with other agents Infusion rate Consider incremental escalation only in the absence of infusion reactions with the previous infusion First infusion (1000 mL dilution) 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr Second infusion (500 mL dilution) 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr Use a dilution volume of 500 mL only if there were no infusion reactions during the first 3 hr of the first infusion; otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion Subsequent infusions (500 mL dilution) 100 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr If there were no infusion reactions during a final infusion rate of ?100 mL/hr in the first 2 infusions, then use a modified initial rate for subsequent infusions (eg, third infusion onward); otherwise to follow rate for the second infusion

Hypersensitivity.

Monitor for CBC periodically during treatment, infusion-related reactions (IRR), & patients w/ neutropenia for signs of infections. Pre-medicate w/ antihistamines, antipyretics & corticosteroids prior to treatment; administer oral corticosteroids following Darzalex infusions. Consider post-infusion medications eg, inhaled corticosteroids, short & long-acting bronchodilators in patients w/ history of COPD. Immediately interrupt for any grade/severity of IRRs. Permanently discontinue if life-threatening IRR occurs. May cause to result positive indirect Coombs test & may persist for up to 6 mth after last dose. Consider phenotyping prior to initiation of therapy. Interference of complete response & of disease progression in some patients w/ IgG kappa myeloma protein. Patients on controlled Na diet. Pregnancy & lactation. Childn <18 yr. Lactation Unknown if distributed in human breast milk Human IgG is known to be present in human milk; published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy There are no human data to inform a risk with use of daratumumab during pregnancy and animal studies have not been conducted Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta Based on its mechanism of action, daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone density Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed Contraception Women of reproductive potential should use effective contraception during treatment and for 3 months after discontinuing treatment Lactation Unknown if distributed in human breast milk Human IgG is known to be present in human milk; published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Side effects of Daratumumab : >10% (Monotherapy) Lymphopenia (72%) Neutropenia (60%) Infusion reaction (48%) Thrombocytopenia (48%) Anemia (45%) Fatigue (39%) Lymphopenia, Grade 3 (30%) Nausea (27%) Back pain (23%) Pyrexia (21%) Cough (21%) Upper respiratory tract infection (20%) Anemia, Grade 3 (19%) Neutropenia, Grade 3 (17%) Nasal congestion (17%) Arthralgia (17%) Diarrhea (16%) Constipation (15%) Pain in extremity (15%) Dyspnea (15%) Nasopharyngitis (15%) Decreased appetite (15%) Vomiting (14%) Musculoskeletal chest pain (12%) Headache (12%) Pneumonia (11%) 1-10% (Monotherapy) Thrombocytopenia, Grade 3 (10%) Lymphopenia, Grade 4 (10%) Hypertension (10%) Chills (10%) Thrombocytopenia, Grade 4 (8%) Pneumonia, Grade 3 (6%) Hypertension, Grade 3 (5%) Neutropenia, Grade 4 (3%) Infusion reaction, Grade 3 (3%) Fatigue, Grade 3 (2%) Back pain, Grade 3 (2%) Pyrexia, Grade 3 (1%) Dyspnea, Grade 3 (1%) Pain in extremity, Grade 3 (1%) Musculoskeletal chest pain, Grade 3 (1%) Upper respiratory tract infection, Grade 3 (1%) Diarrhea, Grade 3 (1%) Decreased appetite, Grade 3 (1%) Headache, Grade 3 (1%)

Monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells The binding to CD38 is believed to induce rapid tumor cell death through programmed cell death, or apoptosis, and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity