Darzalex Faspro

1 INDICATIONS AND USAGE DARZALEX FASPRO is a combination of daratumumab, a CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with: multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant multiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor multiple myeloma in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy multiple myeloma as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent high-risk smoldering multiple myeloma as monotherapy light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone in newly diagnosed patients. Limitations of Use: DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials ( 1.3 ) 1.1 Multiple Myeloma DARZALEX FASPRO is indicated for the treatment of adult patients with [see Clinical Studies (14) ] : multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant. multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy. multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor. multiple myeloma in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. multiple myeloma as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. 1.2 High-Risk Smoldering Multiple Myeloma DARZALEX FASPRO as monotherapy is indicated for the treatment of adult patients with high-risk smoldering multiple myeloma. 1.3 Light Chain Amyloidosis DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. Limitations of Use DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials [see Warnings and Precautions (5.2) ] .

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. Pre-medicate with a corticosteroid, acetaminophen and a histamine-1 receptor antagonist. ( 2.6 ) The recommended dosage of DARZALEX FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to recommended schedule. ( 2.2 , 2.3 , 2.4 ) Administer post-medications as recommended. ( 2.6 ) 2.1 Important Dosing Information DARZALEX FASPRO is for subcutaneous use only. Administer medications before and after administration of DARZALEX FASPRO to minimize administration-related reactions [see Dosage and Administration (2.6) ] . Type and screen patients prior to starting DARZALEX FASPRO. 2.2 Recommended Dosage for Multiple Myeloma The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Tables 1, 2, 3, 4, 5, and 6 provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of a combination therapy. Monotherapy and In Combination with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd), Pomalidomide and Dexamethasone (DARZALEX FASPRO-Pd) or Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) Use the dosing schedule provided in Table 1 when DARZALEX FASPRO is administered: in combination with lenalidomide and dexamethasone (4-week cycle) OR in combination with pomalidomide and dexamethasone (4-week cycle) OR in combination with carfilzomib and dexamethasone (4-week cycle) OR as monotherapy. Table 1: DARZALEX FASPRO dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) and for monotherapy Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) Use the dosing schedule provided in Table 2 when DARZALEX FASPRO is administered in combination with bortezomib, melphalan and prednisone (6-week cycle). Table 2: DARZALEX FASPRO dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 54 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 16 doses) Week 55 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 55 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Thalidomide, and Dexamethasone (DARZALEX FASPRO-VTd) Use the dosing schedule in Table 3 when DARZALEX FASPRO is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle). Table 3: DARZALEX FASPRO dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Eligible for Autologous Stem Cell Transplant (ASCT) Use the dosing schedule in Table 4 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT. Table 4: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Who Are Ineligible for ASCT Use the dosing schedule in Table 5 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (3-week cycle) for treatment of newly diagnosed multiple myeloma patients who are ineligible for ASCT. Table 5: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (3-week cycle) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 24 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 6 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib and Dexamethasone (DARZALEX FASPRO-Vd) Use the dosing schedule in Table 6 when DARZALEX FASPRO is administered in combination with bortezomib and dexamethasone (3-week cycle). Table 6: DARZALEX FASPRO dosing schedule in combination with bortezomib and dexamethasone (3-week cycle) Weeks Schedule Weeks 1 to 9 weekly (total of 9 doses) Weeks 10 to 24 First dose of the every-3-week dosing schedule is given at Week 10 every three weeks (total of 5 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. 2.3 Recommended Dosage for High-Risk Smoldering Multiple Myeloma The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Use the dosing schedule provided in Table 7 when DARZALEX FASPRO is administered as monotherapy in high-risk smoldering multiple myeloma patients (4-week cycle). Table 7: DARZALEX FASPRO dosing schedule for monotherapy (4-week cycle) Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until diagnosis of multiple myeloma or a maximum of 3 years First dose of the every-4-week dosing schedule is given at Week 25 every four weeks 2.4 Recommended Dosage for Light Chain Amyloidosis In Combination with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Use the dosing schedule provided in Table 8 when DARZALEX FASPRO is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle). Table 8: DARZALEX FASPRO dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle) Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progression or a maximum of 2 years First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.4) and the prescribing information for dosage recommendations for the other drugs. 2.5 Missed DARZALEX FASPRO Doses If a dose of DARZALEX FASPRO is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval. 2.6 Recommended Concomitant Medications Pre-medication Administer the following pre-medications 1 to 3 hours before each dose of DARZALEX FASPRO: Acetaminophen 650 mg to 1,000 mg orally Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously Corticosteroid (long- or intermediate-acting) Monotherapy Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO. In Combination Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO administration. When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX FASPRO administration days [see Clinical Studies (14) ] . Do not administer background regimen-specific corticosteroids (e.g., prednisone) on DARZALEX FASPRO administration days when patients have received dexamethasone (or equivalent) as a pre-medication. Post-medication Administer the following post-medications: Monotherapy Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX FASPRO. In Combination Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) on the day after administration of DARZALEX FASPRO. If a background regimen-specific corticosteroid (e.g., dexamethasone, prednisone) is administered the day after the administration of DARZALEX FASPRO, additional corticosteroids may not be needed [see Clinical Studies (14) ] . If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid). For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 doses of DARZALEX FASPRO, consider discontinuing these additional post-medications, if the patient does not experience a major systemic administration-related reaction. Prophylaxis for Herpes Zoster Reactivation Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX FASPRO and continue for 3 months following the end of treatment [see Adverse Reactions (6.1) ]. 2.7 Dosage Modifications for Adverse Reactions No dose reductions of DARZALEX FASPRO are recommended. Consider withholding DARZALEX FASPRO to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.4 , 5.5) ] . 2.8 Preparation and Administration DARZALEX FASPRO should be administered by a healthcare provider. To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DARZALEX FASPRO for subcutaneous use. Do not administer DARZALEX FASPRO intravenously . DARZALEX FASPRO is ready to use. Preparation Remove the DARZALEX FASPRO vial from refrigerated storage [2°C to 8°C (36°F to 46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)]. Store the unpunctured vial at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake. Withdraw 15 mL from the vial into a syringe using an 18G to 22G transfer needle with a regular bevel. Insert the needle into the vial at a 90° angle within the ring of the stopper. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present. DARZALEX FASPRO is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately. After the solution of DARZALEX FASPRO is withdrawn into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe appropriately to include the route of administration per institutional standards. Label the syringe with the peel-off label. To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection. Storage If the syringe containing DARZALEX FASPRO is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours and/or at room temperature at 15°C to 25°C (59°F to 77°F) for up to 12 hours under ambient light. Discard if storage time exceeds these limits. If stored in the refrigerator, allow the solution to come to room temperature before administration. Administration Inject 15 mL of DARZALEX FASPRO into the subcutaneous tissue of the abdomen approximately 3 inches [7.5 cm] to the right or left of the navel over approximately 3 to 5 minutes. No data are available on performing the injection at other sites of the body. Rotate injection sites for successive injections. Never inject DARZALEX FASPRO into areas where the skin is red, bruised, tender, hard or areas where there are scars. Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose. During treatment with DARZALEX FASPRO, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO.

4 CONTRAINDICATIONS DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ]. Patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions : Permanently discontinue DARZALEX FASPRO for life-threatening reactions. ( 5.1 ) Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis : Monitor patients with cardiac involvement more frequently for cardiac adverse reactions and administer supportive care as appropriate. ( 5.2 ) Infections : DARZALEX FASPRO can cause serious and fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.3 ) Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO to allow recovery of neutrophils. ( 5.4 ) Thrombocytopenia : Monitor complete blood cell counts periodically during treatment. Consider withholding DARZALEX FASPRO to allow recovery of platelets. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception. ( 5.6 , 8.1 , 8.3 ) Interference with cross-matching and red blood cell antibody screening : Type and screen patients prior to starting treatment. Inform blood banks that a patient has received DARZALEX FASPRO. ( 5.7 , 7.1 ) 5.1 Hypersensitivity and Other Administration Reactions Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO [see Adverse Reactions (6.2) ] . Systemic Reactions In a pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3%, Grade 3: 0.8%, Grade 4: 0.1%). In patients with high-risk smoldering multiple myeloma (N=193), systemic administration-related reactions occurred in 17% of patients in AQUILA (Grade 2: 7%, Grade 3: 1%). In all patients (N=1639), systemic administration-related reactions occurred in 7% of patients with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 283 systemic administration-related reactions that occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients. Severe reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision. Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.6) ] . Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.6) ] . Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO. Local Reactions In this pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193), injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 1.1%. The most frequent (>1%) injection-site reactions were injection site erythema and injection site rash. In patients with high-risk smoldering multiple myeloma (N=193), injection-site reactions occurred in 28% of patients, including Grade 2 reactions in 3%. These local reactions occurred a median of 6 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management. 5.2 Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions (6.1) ] . Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate. 5.3 Infections DARZALEX FASPRO can cause serious, life-threatening, or fatal infections. In patients who received DARZALEX FASPRO in a pooled safety population including patients with smoldering multiple myeloma and light chain (AL) amyloidosis (N=1639), serious infections, including opportunistic infections, occurred in 24% of patients, Grade 3 or 4 infections occurred in 22%, and fatal infections occurred in 2.5%. The most common type of serious infection reported was pneumonia (8.5%). Monitor patients for signs and symptoms of infection prior to and during treatment with DARZALEX FASPRO and treat appropriately. Administer prophylactic antimicrobials according to guidelines [see Dosage and Administration (2.6) ] . 5.4 Neutropenia Daratumumab may increase neutropenia induced by background therapy [see Adverse Reactions (6.1) ] . Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3–4 neutropenia were observed. 5.5 Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1) ] . Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets. 5.6 Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . The combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy. 5.7 Interference with Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum [see References (15) ] . The determination of a patient's ABO and Rh blood type are not impacted [see Drug Interactions (7.1) ] . Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO [see Dosage and Administration (2.1) ] . 5.8 Interference with Determination of Complete Response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.1) ] . This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.

7 DRUG INTERACTIONS 7.1 Effects of Daratumumab on Laboratory Tests Interference with Indirect Antiglobulin Tests (Indirect Coombs Test) Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References (15) ] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices. Interference with Serum Protein Electrophoresis and Immunofixation Tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO-treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity and Other Administration Reactions [see Warnings and Precautions (5.1) ] . Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Warnings and Precautions (5.2) ] . Infections [see Warnings and Precautions (5.3) ] . Neutropenia [see Warnings and Precautions (5.4) ] . Thrombocytopenia [see Warnings and Precautions (5.5) ] . The most common adverse reactions (≥20%) in patients with multiple myeloma eligible for autologous stem cell transplant who received DARZALEX FASPRO-VRd are peripheral neuropathy, fatigue, upper respiratory infection, constipation, musculoskeletal pain, insomnia, rash, diarrhea, edema, and pyrexia. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who were ineligible for autologous stem cell transplant who received DARZALEX FASPRO-VRd are upper respiratory tract infection, sensory neuropathy, musculoskeletal pain, diarrhea, fatigue, edema, rash, motor dysfunction, COVID-19, constipation, sleep disorder, cough, pneumonia, renal impairment, dizziness, nausea, urinary tract infection, pyrexia, abdominal pain, dyspnea, decreased appetite, and bruising. ( 6.1 ) The most common adverse reaction (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO monotherapy is upper respiratory tract infection. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-Pd are fatigue, pneumonia, upper respiratory tract infection, and diarrhea. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-Kd are upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral. ( 6.1 ) The most common adverse reactions (≥20%) in patients with high-risk smoldering multiple myeloma who received DARZALEX FASPRO monotherapy are upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions. ( 6.1 ) The most common adverse reactions (≥20%) in patients with light chain (AL) amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. ( 6.1 ) The most common (≥40%) hematology laboratory abnormalities with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone (n=351) from the start of induction to the end of consolidation compared to bortezomib, lenalidomide and dexamethasone (VRd) (n=347) was evaluated in PERSEUS [see Clinical Studies (14.1) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8 and once every 2 weeks from weeks 9 to 16 during induction in combination with VRd or VRd alone. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT. Within 12 weeks of ASCT, and when engraftment was complete, patients received DARZALEX FASPRO once every 2 weeks from weeks 1 to 8 during consolidation in combination with VRd or VRd alone. The median duration of treatment for induction and consolidation was 9.9 months (0.5 to 18.5 months) for DARZALEX FASPRO-VRd. Serious adverse reactions occurred in 37% of patients who received DARZALEX FASPRO-VRd. The most frequent serious adverse reaction in >5% of patients who received DARZALEX FASPRO-VRd was pneumonia (6%). Fatal adverse reactions occurred in 1.7% of patients who received DARZALEX FASPRO-VRd. Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-VRd. An adverse reaction which resulted in permanent discontinuation of DARZALEX FASPRO-VRd in more than 1 patient included sepsis. The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, upper respiratory infection, constipation, musculoskeletal pain, insomnia, rash, diarrhea, edema, and pyrexia. Table 9 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PERSEUS. Table 9: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO-VRd through the End of Consolidation in PERSEUS Adverse Reaction DARZALEX FASPRO-VRd (N=351) VRd (N=347) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Key: VRd=bortezomib-lenalidomide-dexamethasone Nervous system disorders Peripheral neuropathy Peripheral neuropathy includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. 52 5 54 4 Paresthesia 11 <1 Only Grade 3 adverse reactions occurred. 11 <1 General disorders and administration site conditions Fatigue Includes other related terms. 35 3 37 5 Edema 22 1 21 1 Pyrexia 21 2 22 3 Infections Upper respiratory tract infection Upper respiratory tract infection includes fungal pharyngitis, h1n1 influenza, influenza, influenza like illness, laryngitis, nasopharyngitis, oral candidiasis, oropharyngeal candidiasis, parainfluenzae virus infection, pharyngitis, respiratory moniliasis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, upper respiratory tract infection, viral tonsillitis, and viral upper respiratory tract infection. 32 1 26 2 Pneumonia Pneumonia includes bronchopulmonary aspergillosis, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, and pneumonia streptococcal. 14 9 10 6 Fatal adverse reactions included Pneumonia: n=1 (0.3%) in the VRd arm. Gastrointestinal disorders Constipation 31 2 30 2 Diarrhea 23 3 25 5 Nausea 16 1 12 1 Abdominal pain 11 0 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 26 1 23 1 Muscle spasm 12 0 9 <1 Psychiatric disorders Insomnia 26 2 16 2 Skin and subcutaneous tissue disorders Rash 25 3 31 5 Hepatobiliary disorders Hepatotoxicity Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic cytolysis, hepatic failure, hepatic function abnormal, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, and liver disorder 16 6 16 5 Respiratory, thoracic and mediastinal disorders Cough 12 <1 8 0 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, lenalidomide and dexamethasone include: Gastrointestinal disorders: vomiting, hemorrhoids Musculoskeletal and connective tissue disorders: arthralgia Infections: bronchitis, sepsis, urinary tract infection, herpes zoster, Covid-19, cytomegalovirus infection Respiratory, thoracic, and mediastinal disorders: dyspnea, pulmonary edema Metabolism and nutrition disorders: hypocalcemia, decreased appetite, hyperglycemia, dehydration Vascular disorders: hypotension, hypertension, orthostatic hypotension General disorders and administration site conditions: infusion reactions, injection site reaction, chills Nervous system disorders: dizziness, headache, syncope Cardiac disorders: thrombosis, atrial fibrillation, tachycardia Skin and subcutaneous tissue disorders: pruritus Table 10 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PERSEUS. Table 10: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline in Patients Who Received DARZALEX FASPRO-VRd through the End of Consolidation in PERSEUS Laboratory Abnormality DARZALEX FASPRO-VRd Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=351 for DARZALEX FASPRO-VRd and N=346 for VRd. VRd All Grades (%) Grade 3 or4 (%) All Grades (%) Grade 3 or 4 (%) Key: VRd=bortezomib-lenalidomide-dexamethasone Hematology Decreased platelets 89 34 78 25 Decreased lymphocytes 87 69 69 43 Decreased leukocytes 78 47 56 22 Decreased neutrophils 67 52 47 34 Decreased hemoglobin 39 7 43 6 Chemistry Increased alanine aminotransferase (ALT) 52 7 48 5 Decreased sodium 40 5 25 5 Increased alkaline phosphatase 39 0 36 1 Decreased potassium 30 6 24 3 Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone compared to bortezomib, lenalidomide and dexamethasone (VRd) was evaluated in CEPHEUS in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial therapy [see Clinical Studies (14.1) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity in combination with VRd (n=197) or VRd alone (n=195). The median duration of treatment was 56.3 months (0.1 to 64.6 months) for DARZALEX FASPRO-VRd and 34.3 months (0.5 to 63.8 months) for VRd. Serious adverse reactions occurred in 72% of patients who received DARZALEX FASPRO-VRd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO-VRd were pneumonia (19%), COVID-19 (12%), thromboembolism (7%), and diarrhea (6%). Fatal adverse reactions occurred in 16.8% of patients who received DARZALEX FASPRO-VRd. Fatal adverse reactions that occurred in more than 1 patient included pneumonia (4%), COVID-19 (4%), and myocardial infarction (2%). Permanent treatment discontinuation due to an adverse reaction occurred in 8% of patients who received DARZALEX FASPRO-VRd. An adverse reaction which resulted in permanent discontinuation of DARZALEX FASPRO-VRd in more than 1 patient included pneumonia. The most common adverse reactions (≥20%) were upper respiratory tract infection, sensory neuropathy, musculoskeletal pain, diarrhea, fatigue, edema, rash, motor dysfunction, COVID-19, constipation, sleep disorder, cough, pneumonia, renal impairment, dizziness, nausea, urinary tract infection, pyrexia, abdominal pain, dyspnea, decreased appetite, and bruising. Table 11 summarized the adverse reactions in patients who received DARZALEX FASPRO in CEPHEUS. Table 11: Adverse Reactions Reported in ≥20% of Patients Who Received DARZALEX FASPRO-VRd in CEPHEUS Adverse Reaction DARZALEX FASPRO-VRd (N=197) VRd (N=195) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Key: VRd=bortezomib-lenalidomide dexamethasone Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, influenza, influenza like illness, laryngitis, nasal congestion, nasopharyngitis, parainfluenzae virus infection, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection bacterial, respiratory tract infection viral, rhinitis, rhinovirus infection, sinus congestion, sinus disorder, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract inflammation, and viral upper respiratory tract infection. 75 4 Only Grade 3 adverse reactions occurred. 63 3 COVID-19 Includes other related terms. 39 Fatal adverse reactions occurred for Abdominal pain: n=1 (1%) in the DARZALEX FASPRO-VRd arm; COVID-19: n=7 (4%) in the DARZALEX FASPRO-VRd arm and n=5 (3%) in the VRd arm; Pneumonia: n=8 (4%) in the DARZALEX FASPRO-VRd arm and n=5 (3%) in the VRd arm; Dyspnea: n=1 (1%) in the DARZALEX FASPRO-VRd arm. 9 25 3 Pneumonia Pneumonia includes bronchopulmonary aspergillosis, covid-19 pneumonia, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia cryptococcal, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia viral, and tuberculosis. 31 16 26 15 Urinary tract infection 24 4 17 3 Nervous system disorders Sensory neuropathy Sensory neuropathy includes anosmia, burning sensation, dysesthesia, hyperesthesia, hyperesthesia teeth, hypoesthesia, hypoesthesia oral, neuralgia, neuropathy peripheral, oral dysesthesia, palmar-plantar erythrodysesthesia syndrome, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, and skin burning sensation. 72 12 72 10 Motor dysfunction Motor dysfunction includes balance disorder, essential tremor, extrapyramidal disorder, facial paralysis, gait disturbance, hypotonia, mobility decreased, motor dysfunction, muscle contractions involuntary, muscle contracture, muscle spasms, muscular weakness, myopathy, paraparesis, peripheral motor neuropathy, peroneal nerve palsy, pharyngeal paresthesia, and tremor. 44 11 37 7 Dizziness 26 2 26 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 62 9 61 7 Gastrointestinal disorders Diarrhea 57 12 59 9 Constipation 38 2 42 3 Nausea 25 0 25 2 Abdominal pain 23 1 17 2 General disorders and administration site conditions Fatigue 56 14 53 11 Edema 54 4 46 2 Pyrexia 24 1 16 1 Skin and subcutaneous tissue disorders Rash 50 8 47 7 Psychiatric disorders Sleep disorder 33 3 33 2 Respiratory, thoracic and mediastinal disorders Cough 32 1 21 1 Dyspnea 21 2 17 1 Renal and urinary disorders Renal impairment Renal impairment includes acute kidney injury, blood creatinine increased, chronic kidney disease, creatinine renal clearance decreased, glomerular filtration rate decreased, prerenal failure, renal failure, renal impairment, and renal injury. 26 7 25 6 Metabolism and nutrition disorders Decreased appetite 21 1 20 3 Injury, poisoning and procedural complications Bruising 20 0 12 0 Clinically relevant adverse reactions in <20% of patients who received DARZALEX FASPRO with bortezomib, lenalidomide and dexamethasone include: Infections: bronchitis, sepsis, herpes zoster, hepatitis B reactivation Gastrointestinal disorders: vomiting, pancreatitis Metabolism and nutrition disorders: hyperglycemia Vascular disorders: hypertension, hypotension, thromboembolism, hemorrhage Nervous system disorders: headache, syncope General disorders and administration site conditions: chills, infusion reactions, injection site reactions Cardiac disorders: atrial fibrillation Skin and subcutaneous tissue disorders: pruritus Table 12 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in CEPHEUS. Table 12: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline in Patients Who Received DARZALEX FASPRO-VRd in CEPHEUS Laboratory Abnormality DARZALEX FASPRO-VRd Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=197 for DARZALEX FASPRO-VRd and N=194 for VRd. VRd All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Key: VRd=bortezomib-lenalidomide-dexamethasone Hematology Decreased leukocytes 93 39 77 15 Decreased neutrophils 89 49 75 35 Decreased lymphocytes 87 55 72 38 Decreased platelets 81 31 73 23 Decreased hemoglobin 53 14 52 16 Chemistry Increased alanine aminotransferase (ALT) 66 7 61 3 Increased creatinine 54 5 56 3 Decreased potassium 53 19 36 12 Decreased sodium 48 16 40 13 Increased aspartate aminotransferase (AST) 43 3 46 3 Increased alkaline phosphatase 43 2 31 1 Decreased corrected calcium 32 5 26 5 Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Melphalan and Prednisone The safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.1) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity (N=67) in combination with bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for 6 months or longer and 19% were exposed for greater than one year. Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients. Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient was neutropenic sepsis. Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia. The most common adverse reactions (≥20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. Table 13 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES. Table 13: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADES Adverse Reaction DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (N=67) All Grades (%) Grades ≥3 (%) Infections Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. 39 0 Bronchitis 16 0 Pneumonia Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. 15 7 Only Grade 3 adverse reactions occurred. Gastrointestinal disorders Constipation 37 0 Nausea 36 0 Diarrhea 33 3 Vomiting 21 0 Abdominal pain Abdominal pain includes abdominal pain, and abdominal pain upper. 13 0 General disorders and administration site conditions Fatigue Fatigue includes asthenia, and fatigue. 36 3 Pyrexia 34 0 Edema peripheral Edema peripheral includes edema, edema peripheral, and peripheral swelling. 13 1 Nervous system disorders Peripheral sensory neuropathy 34 1 Dizziness 10 0 Respiratory, thoracic and mediastinal disorders Cough Cough includes cough, and productive cough. 24 0 Psychiatric disorders Insomnia 22 3 Musculoskeletal and connective tissue disorders Back pain 21 3 Musculoskeletal chest pain 12 0 Metabolism and nutrition disorders Decreased appetite 15 1 Skin and subcutaneous tissue disorders Rash 13 0 Pruritus 12 0 Vascular disorders Hypertension 13 6 Hypotension 10 3 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone included: General disorders and administration site conditions: infusion reaction, injection site reaction, chills Infections: herpes zoster, urinary tract infection, influenza, sepsis Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms Nervous system disorders: headache, paresthesia Metabolism and nutrition disorders: hypocalcemia, hyperglycemia Respiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edema Cardiac disorders: atrial fibrillation Table 14 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES. Table 14: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADES Laboratory Abnormality DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone Denominator is based on the safety population treated with DARZALEX FASPRO-VMP (N=67). All Grades (%) Grades 3–4 (%) Decreased leukocytes 96 52 Decreased lymphocytes 93 84 Decreased platelets 93 42 Decreased neutrophils 88 49 Decreased hemoglobin 48 19 Relapsed/Refractory Multiple Myeloma In Combination with Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO with lenalidomide and dexamethasone was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2) ]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for 6 months or longer and 20% were exposed for greater than one year. Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients. Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient were pneumonia and anemia. Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased. The most common adverse reactions (≥20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. Table 15 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES. Table 15: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADES Adverse Reaction DARZALEX FASPRO with Lenalidomide and Dexamethasone (N=65) All Grades (%) Grades ≥3 (%) General disorders and administration site conditions Fatigue Fatigue includes asthenia, and fatigue. 52 5 Only Grade 3 adverse reactions occurred. Pyrexia 23 2 Edema peripheral 18 3 Gastrointestinal disorders Diarrhea 45 5 Constipation 26 2 Nausea 12 0 Vomiting 11 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 43 3 Pneumonia Pneumonia includes lower respiratory tract infection, lung infection, and pneumonia. 23 17 Bronchitis Bronchitis includes bronchitis, and bronchitis viral. 14 2 Urinary tract infection 11 0 Musculoskeletal and connective tissue disorders Muscle spasms 31 2 Back pain 14 0 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. 22 3 Cough Cough includes cough, and productive cough. 14 0 Nervous system disorders Peripheral sensory neuropathy 17 2 Psychiatric disorders Insomnia 17 5 Metabolism and nutrition disorders Hyperglycemia 12 9 Hypocalcemia 11 0 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with lenalidomide and dexamethasone included: Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain Nervous system disorders: dizziness, headache, paresthesia Skin and subcutaneous tissue disorders: rash, pruritus Gastrointestinal disorders: abdominal pain Infections: influenza, sepsis, herpes zoster Metabolism and nutrition disorders: decreased appetite Cardiac disorders: atrial fibrillation General disorders and administration site conditions: chills, infusion reaction, injection site reaction Vascular disorders: hypotension, hypertension Table 16 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES. Table 16: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADES Laboratory Abnormality DARZALEX FASPRO with Lenalidomide and Dexamethasone Denominator is based on the safety population treated with DARZALEX FASPRO-Rd (N=65). All Grades (%) Grades 3–4 (%) Decreased leukocytes 94 34 Decreased lymphocytes 82 58 Decreased platelets 86 9 Decreased neutrophils 89 52 Decreased hemoglobin 45 8 In Combination with Pomalidomide and Dexamethasone The safety of DARZALEX FASPRO with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone (Pd) in patients who had received at least one prior line of therapy with lenalidomide and a proteasome inhibitor (PI) was evaluated in APOLLO [see Clinical Studies (14.2) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity in combination with pomalidomide and dexamethasone (n=149) or pomalidomide and dexamethasone (n=150). Among patients receiving DARZALEX FASPRO-Pd, 71% were exposed for 6 months or longer and 50% were exposed for greater than one year. Serious adverse reactions occurred in 50% of patients who received DARZALEX FASPRO-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO-Pd were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients who received DARZALEX FASPRO-Pd. Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-Pd. The most common adverse reactions (≥20%) were fatigue, pneumonia, upper respiratory tract infection, and diarrhea. Table 17 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO. Table 17: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DARZALEX FASPRO-Pd Arm in APOLLO Adverse Reaction DARZALEX FASPRO-Pd (N=149) Pd (N=150) All Grades (%) Grades ≥3 (%) All Grades (%) Grades ≥3 (%) Key: Pd=pomalidomide-dexamethasone General disorders and administration site conditions Fatigue Fatigue includes asthenia, and fatigue. 46 13 39 5 Only Grade 3 adverse reactions occurred. Pyrexia 19 0 14 0 Edema peripheral Edema peripheral includes edema, edema peripheral and peripheral swelling. 15 0 9 0 Infections Pneumonia Pneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. 38 23 Grade 5 adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO-Pd arm and n=2 (1.3%) in the Pd arm. 27 17 Upper respiratory infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection. 36 1 22 2 Gastrointestinal disorders Diarrhea 22 5 14 1 Respiratory, thoracic and mediastinal disorders Cough Cough includes cough, and productive cough. 13 0 8 0 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with pomalidomide and dexamethasone include: Metabolism and nutrition disorders: hypocalcemia, hypokalemia, decreased appetite, dehydration Nervous system disorders: peripheral sensory neuropathy, syncope, headache, paresthesia, dizziness Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia Psychiatric disorders: insomnia Gastrointestinal disorders: nausea, abdominal pain, vomiting Skin and subcutaneous tissue disorders: rash, pruritus Cardiac disorders: atrial fibrillation General disorders and administration site conditions: infusion reactions, chills, injection site reaction Infections: urinary tract infection, influenza, hepatitis B reactivation, herpes zoster, sepsis Vascular disorders: hypertension, hypotension Table 18 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in APOLLO. Table 18: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Pd or Pd in APOLLO Laboratory Abnormality DARZALEX FASPRO-Pd Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=148 for DARZALEX FASPRO-Pd and N=149 for Pd. Pd All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Key: Pd=pomalidomide-dexamethasone Decreased neutrophils 97 84 84 63 Decreased leukocytes 95 64 82 40 Decreased lymphocytes 93 59 79 33 Decreased platelets 75 19 60 19 Decreased hemoglobin 51 16 57 15 In Combination with Carfilzomib and Dexamethasone The safety of DARZALEX FASPRO with carfilzomib and dexamethasone was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2) ]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity (N=66) in combination with carfilzomib and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year. Serious adverse reactions occurred in 27% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone. Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO. Dosage interruptions due to an adverse reaction occurred in 46% of patients who received DARZALEX FASPRO. The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral. Table 19 summarizes the adverse reactions in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES. Table 19: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES Adverse Reaction DARZALEX FASPRO-Kd (N=66) All Grades (%) Grade ≥3 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. 52 0 Bronchitis Bronchitis includes bronchitis, and bronchitis viral. 12 2 Only Grade 3 adverse reactions occurred. General disorders and administration site conditions Fatigue Fatigue includes asthenia, and fatigue. 39 2 Pyrexia 21 2 Edema peripheral Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling. 20 0 Psychiatric disorders Insomnia 33 6 Vascular disorders Hypertension Hypertension includes blood pressure increased, and hypertension. 32 21 Gastrointestinal disorders Diarrhea 29 0 Nausea 21 0 Vomiting 15 0 Respiratory, thoracic and mediastinal disorders Cough Cough includes cough, and productive cough. 24 0 Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. 23 2 Nervous system disorders Headache 23 0 Peripheral sensory neuropathy 11 0 Musculoskeletal and connective tissue disorders Back pain 17 2 Musculoskeletal chest pain 11 0 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with carfilzomib and dexamethasone include: Gastrointestinal disorders: abdominal pain, constipation, pancreatitis Infection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsis Metabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemia Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia Nervous system disorders: paresthesia, dizziness, syncope General disorders and administration site conditions: injection site reaction, infusion reactions, chills Skin and subcutaneous tissue disorders: rash, pruritus Cardiac disorders: cardiac failure Vascular disorders: hypotension Table 20 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone in PLEIADES. Table 20: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADES Laboratory Abnormality DARZALEX FASPRO-Kd Denominator is based on the safety population treated with DARZALEX FASPRO-Kd (N=66). All Grades (%) Grades 3–4 (%) Decreased platelets 88 18 Decreased lymphocytes 83 50 Decreased leukocytes 68 18 Decreased neutrophils 55 15 Decreased hemoglobin 47 6 Decreased corrected calcium 45 2 Increased alanine aminotransferase (ALT) 35 5 Monotherapy The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see Clinical Studies (14.2) ]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO, 37% were exposed for 6 months or longer and 1% were exposed for greater than one year. Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than 1 patient were general physical health deterioration, septic shock, and respiratory failure. Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 2 patients were thrombocytopenia and hypercalcemia. Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia. The most common adverse reaction (≥20%) was upper respiratory tract infection. Table 21 summarizes the adverse reactions in COLUMBA. Table 21: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA Adverse Reaction DARZALEX FASPRO (N=260) Intravenous Daratumumab (N=258) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection. 24 1 Only Grade 3 adverse reactions occurred. 22 1 Pneumonia Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. 8 5 10 6 Grade 5 adverse reactions occurred. Gastrointestinal disorders Diarrhea 15 1 11 0.4 Nausea 8 0.4 11 0.4 General disorders and administration site conditions Fatigue Fatigue includes asthenia, and fatigue. 15 1 16 2 Infusion reactions Infusion reactions includes terms determined by investigators to be related to infusion. 13 2 34 5 Pyrexia 13 0 13 1 Chills 6 0.4 12 1 Musculoskeletal and connective tissue disorders Back pain 10 2 12 3 Respiratory, thoracic and mediastinal disorders Cough Cough includes cough, and productive cough. 9 1 14 0 Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. 6 1 11 1 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included: General disorders and administration site conditions: injection site reaction, peripheral edema Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasms Gastrointestinal disorders: constipation, vomiting, abdominal pain Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration Psychiatric disorders: insomnia Vascular disorders: hypertension, hypotension Nervous system disorders: dizziness, peripheral sensory neuropathy, paresthesia Infections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis B virus reactivation Skin and subcutaneous tissue disorders: pruritus, rash Cardiac disorders: atrial fibrillation Respiratory, thoracic and mediastinal disorders: pulmonary edema Table 22 summarizes the laboratory abnormalities in COLUMBA. Table 22: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA Laboratory Abnormality DARZALEX FASPRO Denominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258). Intravenous Daratumumab All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Decreased leukocytes 65 19 57 14 Decreased lymphocytes 59 36 56 36 Decreased neutrophils 55 19 43 11 Decreased platelets 43 16 45 14 Decreased hemoglobin 42 14 39 16 High-Risk Smoldering Multiple Myeloma The safety of DARZALEX FASPRO as monotherapy in patients with high-risk smoldering multiple myeloma was evaluated in AQUILA [see Clinical Studies (14.3) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until 39 cycles or up to 36 months or until diagnosis of multiple myeloma or unacceptable toxicity. The median duration of treatment for patients receiving DARZALEX FASPRO was 35 months (0 to 36 months). Serious adverse reactions occurred in 29% of patients who received DARZALEX FASPRO. The most frequent serious adverse reactions in ≥2% of patients who received DARZALEX FASPRO were pneumonia (7%), fracture (3%), sepsis (2%), and upper respiratory tract infection (2%). Fatal adverse reactions occurred in 1% of patients who received DARZALEX FASPRO, including COVID-19 (0.5%) and pneumonia (0.5%). Permanent treatment discontinuation due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO. Adverse reactions which resulted in permanent discontinuation of DARZALEX FASPRO in more than 1 patient included fatigue, anxiety, and dyspnea. Dosage interruptions of DARZALEX FASPRO due to an adverse reaction occurred in 47% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included upper respiratory infection, pneumonia, and COVID-19. The most common adverse reactions (≥20%) were upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions. Table 23 summarizes the adverse reactions in patients who received DARZALEX FASPRO in AQUILA. Table 23: Adverse Reactions Reported in ≥10% of Patients with High-Risk Smoldering Multiple Myeloma and with at Least a 5% Greater Frequency in the DARZALEX FASPRO Arm in AQUILA DARZALEX FASPRO (N=193) ACTM (N=196) Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Key: ACTM=active monitoring Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, adenoviral upper respiratory infection, catarrh, influenza, influenza like illness, laryngitis, metapneumovirus infection, nasal congestion, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract congestion, respiratory tract infection, respiratory tract infection viral, sinus congestion, sinusitis, throat irritation, tonsillitis, tracheitis, upper respiratory tract congestion, upper respiratory tract infection, upper respiratory tract infection bacterial, upper-airway cough syndrome, and viral upper respiratory tract infection. 66 1 Only Grade 3 adverse reactions occurred. 27 0 Pneumonia Pneumonia includes covid-19 pneumonia, lower respiratory tract infection, organizing pneumonia, pneumonia, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, and pneumonia viral. 16 7 Fatal adverse reactions occurred for Pneumonia: n=1 (1%) in the DARZALEX FASPRO arm. 8 3 Rhinitis Rhinitis includes rhinitis, rhinitis atrophic, rhinorrhea, rhinovirus infection, and viral rhinitis. 10 0 2 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes arthralgia, axillary pain, back pain, breast pain, chest pain, facial spasm, fibromyalgia, flank pain, groin pain, muscle fatigue, muscle rupture, muscle spasms, muscle strain, muscle tightness, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, pain in jaw, periarthritis, radicular pain, rotator cuff syndrome, spinal pain, spinal stenosis, and tendon pain. 59 1 42 3 General disorders and administration site conditions Fatigue Fatigue includes asthenia, fatigue, and malaise. 42 3 21 1 Injection site reactions Injection site reaction includes injection site discoloration, injection site erythema, injection site hemorrhage, injection site induration, injection site edema, injection site pain, injection site pruritus, injection site rash, injection site swelling, injection site urticaria, injection site vesicles, and injection site warmth. 20 0 0 0 Infusion-related reactions Infusion-related reactions includes terms determined by investigators to be related to infusion. 17 1 0 0 Pyrexia 17 0 3 1 Edema Edema includes brain edema, eye swelling, eyelid edema, generalized edema, joint swelling, laryngeal edema, localized edema, edema, edema peripheral, peripheral swelling, post procedural edema, post procedural swelling, swelling face, and swelling of eyelid. 15 1 5 1 Gastrointestinal disorders Diarrhea 27 2 5 1 Nausea 19 0 5 0 Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain. 17 1 7 2 Skin and subcutaneous tissue disorders Rash Rash includes acne, dermatitis, dermatitis allergic, dermatitis bullous, dermatitis contact, drug eruption, drug hypersensitivity, eczema, eczema asteatotic, eczema infected, erysipelas, erythema, erythema multiforme, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, seborrheic dermatitis, seborrheic keratosis, skin lesion, skin reaction, skin ulcer, and urticaria. 27 1 6 1 Psychiatric disorders Sleep disorder Sleep disorder includes insomnia, restless legs syndrome, sleep apnea syndrome, sleep deficit, and sleep disorder. 24 1 5 0 Nervous system disorders Sensory neuropathy Sensory neuropathy includes allodynia, anosmia, burning sensation, carpal tunnel syndrome, cervical radiculopathy, cervicobrachial syndrome, dysesthesia, hypoesthesia, hypoesthesia oral, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, pharyngeal paresthesia, polyneuropathy, and sensory disturbance. 20 0 8 0 Headache Headache includes headache, migraine, and vascular headache. 18 1 8 0 Dizziness Dizziness includes dizziness, and dizziness postural. 12 0 5 0 Respiratory, thoracic and mediastinal disorders Cough Cough includes cough, and productive cough. 19 0 7 0 Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. 18 1 6 1 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included: Gastrointestinal disorders: constipation, vomiting Skin and subcutaneous tissue disorders: pruritus Infections: bronchitis, urinary tract infection, herpes zoster, sepsis General disorders and administration site conditions: chills Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration Nervous system disorders: syncope Vascular disorders: hypotension Table 24 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in AQUILA. Table 24: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with High-Risk Smoldering Multiple Myeloma Who Received DARZALEX FASPRO in AQUILA DARZALEX FASPRO Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=191 for DARZALEX FASPRO and N=191 for ACTM. ACTM Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Key: ACTM=active monitoring Hematology Decreased lymphocytes 47 6 12 3 Decreased hemoglobin 42 0 44 2 Decreased leukocytes 34 3 27 2 Decreased neutrophils 34 6 29 4 Decreased platelets 19 1 9 1 Chemistry Decreased albumin 28 0 15 1 Increased alanine aminotransferase (ALT) 25 1 13 1 Decreased sodium 24 3 19 2 Increased creatinine 20 0 13 1 Increased aspartate aminotransferase (AST) 20 0 12 1 Light Chain Amyloidosis In Combination with Bortezomib, Cyclophosphamide and Dexamethasone The safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (DARZALEX FASPRO-VCd) was evaluated in ANDROMEDA [see Clinical Studies (14.4) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received DARZALEX FASPRO-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year. Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX FASPRO-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%). Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure. Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required a dosage interruption in ≥3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%). The most common adverse reactions (≥20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. Table 25 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA. Table 25: Adverse Reactions (≥10%) in Patients with AL Amyloidosis Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) with a Difference Between Arms of >5% Compared to VCd in ANDROMEDA Adverse Reaction DARZALEX FASPRO-VCd (N=193) VCd (N=188) All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Infections Upper respiratory tract infection Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. 40 1 Only Grade 3 adverse reactions occurred. 21 1 Pneumonia Pneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. 15 10 9 5 Gastrointestinal disorders Diarrhea 36 6 30 4 Constipation 34 2 29 0 Nervous system disorders Peripheral sensory neuropathy 31 3 20 2 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. 26 4 20 4 Cough Cough includes cough, and productive cough. 20 1 11 0 Musculoskeletal and connective tissue disorders Back pain 12 2 6 0 Arthralgia 10 0 5 0 Muscle spasms 10 1 5 0 Cardiac disorders Arrhythmia Arrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia 11 4 5 2 General disorders and administration site conditions Injection site reactions Injection site reactions includes terms determined by investigators to be related to daratumumab injection. 11 0 0 0 Clinically relevant adverse reactions not included in Table 25 and occurred in patients who received DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone included: Skin and subcutaneous tissue disorders: rash, pruritus Nervous system disorders: paresthesia General disorders and administration site conditions: infusion reaction, chills Cardiac disorders: cardiac failure Cardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients. , cardiac arrest Metabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydration Infections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenza Vascular disorders: hypertension Musculoskeletal and connective tissue disorders: musculoskeletal chest pain Gastrointestinal disorders: pancreatitis Respiratory, thoracic and mediastinal disorders: pulmonary edema Table 26 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in ANDROMEDA. Table 26: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) in ANDROMEDA Laboratory Abnormality DARZALEX FASPRO-VCd VCd All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Denominator is based on the number of patients with a baseline and post-baseline laboratory value for each laboratory test, N=188 for DARZALEX FASPRO-VCd and N=186 for VCd. Decreased lymphocytes 81 54 71 46 Decreased hemoglobin 66 6 70 6 Decreased leukocytes 60 7 46 4 Decreased platelets 46 3 40 4 Decreased neutrophils 30 6 18 4 Cardiac Adverse Reactions in Light Chain (AL) Amyloidosis Among patients who received DARZALEX FASPRO in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3%), Stage II (46%) and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage I and II and 28% of patients with Stage III). Serious cardiac disorders in >2% of patients included cardiac failure (8%), cardiac arrest (4%) and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage I and II and 19% of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the DARZALEX FASPRO-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%). 6.2 Postmarketing Experience The following adverse reactions have been identified with post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System : Anaphylactic reaction, Systemic administration reactions (including death) Gastrointestinal: Pancreatitis Infections: Cytomegalovirus, Listeriosis

8.1 Pregnancy Risk Summary DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data ) . There are no available data on the use of DARZALEX FASPRO in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The combination of DARZALEX FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available through a REMS program. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy. Clinical Considerations Fetal/Neonatal Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. Data Animal Data DARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase . Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs). No systemic exposure of hyaluronidase was detected in monkeys given 220,000 U/kg subcutaneously (440 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 360,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 720 times higher than the human dose. There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 1,100,000 U/kg hyaluronidase subcutaneously, which is 2,200 times higher than the human doses.