Darzalex

1 INDICATIONS AND USAGE DARZALEX is indicated for the treatment of adult patients with 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. in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant. in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. 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. DARZALEX is a CD38-directed cytolytic antibody indicated for the treatment of adult patients with 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 in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor 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 DOSAGE AND ADMINISTRATION Pre-medicate with corticosteroids, antipyretics and antihistamines. ( 2.3 ) Dilute and administer as an intravenous infusion. ( 2.5 ) Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule. ( 2.2 ) Administer post-infusion medications. ( 2.3 ) 2.1 Important Dosing Information Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.3) ] . Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection [see Dosage and Administration (2.5) ]. DARZALEX should be administered by a healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur [see Warnings and Precautions (5.1) ]. Type and screen patients prior to starting DARZALEX [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage Monotherapy and In Combination with Lenalidomide (D-Rd) or Pomalidomide (D-Pd) and Dexamethasone The DARZALEX dosing schedule in Table 1 is for combination therapy (4-week cycle regimens) and monotherapy as follows: - combination therapy with lenalidomide and low-dose dexamethasone for newly diagnosed patients ineligible for autologous stem cell transplant (ASCT) and in patients with relapsed/refractory multiple myeloma - combination therapy with pomalidomide and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma - monotherapy for patients with relapsed/refractory multiple myeloma. The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule: Table 1: DARZALEX Dosing Schedule in Combination With Lenalidomide or Pomalidomide (4-Week Cycle) and Low-Dose Dexamethasone 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 For dosing instructions of combination agents administered with DARZALEX, see Clinical Studies (14) and manufacturer's prescribing information. In Combination with Bortezomib, Melphalan and Prednisone (D-VMP) The DARZALEX dosing schedule in Table 2 is for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma ineligible for ASCT. The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule: Table 2: DARZALEX Dosing Schedule in Combination With Bortezomib, Melphalan and Prednisone ([VMP], 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 For dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.1) . In Combination with Bortezomib, Thalidomide and Dexamethasone (D-VTd) The DARZALEX dosing schedule in Table 3 is for combination therapy with bortezomib, thalidomide, and dexamethasone (4-week cycle regimen) for patients with newly diagnosed multiple myeloma eligible for ASCT. The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule: Table 3: DARZALEX Dosing Schedule in Combination With Bortezomib, Thalidomide and Dexamethasone ([VTd]; 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) For dosing instructions of combination agents administered with DARZALEX, see Clinical Studies (14.1) and the manufacturer's prescribing information. In Combination with Bortezomib and Dexamethasone (D-Vd) The DARZALEX dosing schedule in Table 4 is for combination therapy with bortezomib and dexamethasone (3-week cycle) for patients with relapsed/refractory multiple myeloma. The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule: Table 4: DARZALEX Dosing Schedule 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 For dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.2) and manufacturer's prescribing information . In Combination with Carfilzomib and Dexamethasone (DKd) The recommended dosage for DARZALEX when administered in combination with carfilzomib and dexamethasone (4-week cycle) for patients with relapsed/refractory multiple myeloma is provided in Table 5. Table 5: DARZALEX Dosing Schedule With Carfilzomib and Dexamethasone (4-Week Cycle) Weeks DARZALEX Dose Based on actual body weight Schedule Week 1 8 mg/kg days 1 and 2 (total 2 doses) Weeks 2 to 8 16 mg/kg weekly (total of 7 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 16 mg/kg 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 16 mg/kg every four weeks For dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.2) and manufacturer's prescribing information . Infusion Rates Administer DARZALEX intravenously at the infusion rate described below in Table 6. Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions. The recommended dose of 16 mg/kg to be administered on Day 1 when DARZALEX is administered as monotherapy or in combination may be split over two consecutive days, such that an 8 mg/kg dose is administered on Day 1 and Day 2, respectively. Table 6: Infusion Rates for DARZALEX (16 mg/kg) Administration Dilution volume Initial rate (first hour) Rate increment Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions. Maximum rate Week 1 Infusion Option 1 (Single dose infusion) Week 1 Day 1 (16 mg/kg) 1,000 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Option 2 (Split dose infusion) Week 1 Day 1 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Week 1 Day 2 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Week 2 (16 mg/kg) Use a dilution volume of 500 mL for the 16 mg/kg dose only if there were no infusion-related reactions the previous week. Otherwise, use a dilution volume of 1,000 mL. 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Week 3 onwards (16 mg/kg) Use a modified initial rate (100 mL/hour) for subsequent infusions (i.e. Week 3 onwards) only if there were no infusion-related reactions during the previous infusion. Otherwise, continue to use instructions indicated in the table for the Week 2 infusion rate. 500 mL 100 mL/hour 50 mL/hour every hour 200 mL/hour Missed DARZALEX Doses If a dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval. 2.3 Recommended Concomitant Medications Pre-infusion Medication Administer the following pre-infusion medications 1 hour to 3 hours before every DARZALEX infusion: Corticosteroid (long- or intermediate-acting) Monotherapy: Administer methylprednisolone 100 mg (or equivalent) intravenously. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally or intravenously. In Combination: Administer dexamethasone 20 mg (or equivalent) orally or intravenously. 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 infusion days [see Clinical Studies (14) ]. Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as a pre-medication. Acetaminophen 650 mg to 1,000 mg orally Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously. Post-infusion Medication Administer the following post-infusion 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. 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) beginning the day after the administration of a DARZALEX infusion. If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed [see Clinical Studies (14) ]. For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major infusion-related reaction. Prophylaxis for Herpes Zoster Reactivation Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following the end of treatment [see Adverse Reactions (6.1) ]. 2.4 Dosage Modifications for Adverse Reactions No dose reductions of DARZALEX are recommended. Consider withholding DARZALEX to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.3 , 5.4) ] . For information concerning drugs given in combination with DARZALEX, see manufacturer's prescribing information. Infusion-Related Reactions For infusion-related reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion-related reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below [see Warnings and Precautions (5.1) ] . Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6). Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion-related reaction. Grade 4 (life-threatening): Permanently discontinue DARZALEX. 2.5 Preparation and Administration Preparation DARZALEX is for single dose only. Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight. DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag [see Description (11) , How Supplied/Storage and Handling (16) ] . Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present. Remove a volume of 0.9% Sodium Chloride Injection from the infusion bag/container that is equal to the required volume of DARZALEX solution. Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection as specified in Table 6 [see Dosage and Administration (2.2) ] . Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial. Gently invert the bag/container to mix the solution. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed. If not used immediately, store the diluted solution refrigerated for up to 24 hours at 2°C to 8°C (36°F to 46°F) and/or at room temperature up to 15 hours at 15°C to 25°C (59°F to 77°F). The room temperature storage includes infusion time. Protect from light during storage. Do not freeze. Administration If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 micrometer or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE. 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 DARZALEX concomitantly in the same intravenous line with other agents.

4 CONTRAINDICATIONS DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation [see Warnings and Precautions (5.1) ] . Patients with a history of severe hypersensitivity to daratumumab or any of the components of the formulation. ( 4 )

5 WARNINGS AND PRECAUTIONS Infusion-related reactions : Interrupt DARZALEX infusion for infusion-related reactions of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening infusion-related reactions and institute appropriate emergency care. ( 2.4 , 5.1 ) 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. ( 5.2 , 7.1 ) Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Dose delay may be required to allow recovery of neutrophils. ( 5.3 ) Thrombocytopenia : Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets. ( 5.4 ) 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 ) 5.1 Infusion-Related Reactions DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported [see Adverse Reactions (6.2) ] . In clinical trials (monotherapy and combination: N=2,066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). The incidence of infusion modification due to reactions was 36%. Median durations of 16 mg/kg infusions for the Week 1, Week 2, and subsequent infusions were approximately 7, 4, and 3 hours respectively. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion-related reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision [see Adverse Reactions (6.1) ] . When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption for ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 hours for Week 1-Day 1, 4.2 hours for Week 1-Day 2, and 3.4 hours for the subsequent infusions. Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion [see Dosage and Administration (2.3) ] . Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.4) ] . To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions [see Dosage and Administration (2.3) ] . Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease [see Dosage and Administration (2.3) ] . 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 DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX. 5.2 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 infusion. 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. Type and screen patients prior to starting DARZALEX [see Dosage and Administration (2.1) ] . 5.3 Neutropenia DARZALEX 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 until recovery of neutrophils. 5.4 Thrombocytopenia DARZALEX 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 until recovery of platelets. 5.5 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 patients with IgG kappa myeloma protein. 5.6 Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX 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 and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

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 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: Infusion-related reactions [see Warnings and Precautions (5.1) ] . Neutropenia [see Warnings and Precautions (5.3) ] . Thrombocytopenia [see Warnings and Precautions (5.4) ] . The most frequently reported adverse reactions (incidence ≥20%) are: upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. ( 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. The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant Combination Treatment with Lenalidomide and Dexamethasone (DRd) The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies (14.1) ]. Adverse reactions described in Table 7 reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd). Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%). Table 7: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in MAIA Body System Adverse Reaction DRd (N=364) Rd (N=365) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Rd=lenalidomide-dexamethasone. Gastrointestinal disorders Diarrhea 57 7 0 46 4 0 Constipation 41 1 <1 36 <1 0 Nausea 32 1 0 23 1 0 Vomiting 17 1 0 12 <1 0 Infections Upper respiratory tract infection Acute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 52 2 <1 36 2 <1 Bronchitis Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis 29 3 0 21 1 0 Pneumonia Atypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis 26 14 1 14 7 1 Urinary tract infection 18 2 0 10 2 0 General disorders and administration site conditions Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 41 2 <1 0 0 0 Peripheral edema Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling 41 2 0 33 1 0 Fatigue 40 8 0 28 4 0 Asthenia 32 4 0 25 3 <1 Pyrexia 23 2 0 18 2 0 Chills 13 0 0 2 0 0 Musculoskeletal and connective tissue disorders Back pain 34 3 <1 26 3 <1 Muscle spasms 29 1 0 22 1 0 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea, Dyspnea exertional 32 3 <1 20 1 0 Cough Cough, Productive cough 30 <1 0 18 0 0 Nervous system disorders Peripheral sensory neuropathy 24 1 0 15 0 0 Headache 19 1 0 11 0 0 Paresthesia 16 0 0 8 0 0 Metabolism and nutrition disorders Decreased appetite 22 1 0 15 <1 <1 Hyperglycemia 14 6 1 8 3 1 Hypocalcemia 14 1 <1 9 1 1 Vascular disorders Hypertension Blood pressure increased, Hypertension 13 6 <1 7 4 0 Laboratory abnormalities worsening during treatment from baseline listed in Table 8. Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA DRd (N=364) Rd (N=365) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Rd=lenalidomide-dexamethasone. Leukopenia 90 30 5 82 20 4 Neutropenia 91 39 17 77 28 11 Lymphopenia 84 41 11 75 36 6 Thrombocytopenia 67 6 3 58 7 4 Anemia 47 13 0 57 24 0 Combination Treatment with Bortezomib, Melphalan and Prednisone The safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies (14.1) ]. Adverse reactions described in Table 9 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP. Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%). Table 9: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the D-VMP Arm in ALCYONE Body System Adverse Reaction D-VMP (N=346) VMP (N=354) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone. Infections Upper respiratory tract infection upper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection 48 5 0 28 3 0 Pneumonia pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis 16 12 < 1 6 5 < 1 General disorders and administration site conditions Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 28 4 1 0 0 0 Peripheral edema edema peripheral, generalized edema, peripheral swelling 21 1 < 1 14 1 0 Respiratory, thoracic and mediastinal disorders Cough cough, productive cough 16 < 1 0 8 < 1 0 Dyspnea dyspnea, dyspnea exertional 13 2 1 5 1 0 Vascular disorders Hypertension hypertension, blood pressure increased 10 4 < 1 3 2 0 Laboratory abnormalities worsening during treatment from baseline listed in Table 10. Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE D-VMP (N=346) VMP (N=354) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone. Thrombocytopenia 88 27 11 88 26 16 Neutropenia 86 34 10 87 32 11 Lymphopenia 85 46 12 83 44 9 Anemia 47 18 0 50 21 0 Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd) The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies (14.1) ]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd. Serious adverse reactions with a 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%). Table 11: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DVTd Arm in CASSIOPEIA Body System Adverse Reaction DVTd (N=536) VTd (N=538) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone. Note: Hematology laboratory related toxicities were excluded and reported separately in the table below. General disorders and administration site conditions Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 35 3 <1 0 0 0 Pyrexia 26 2 <1 21 2 0 Gastrointestinal disorders Nausea 30 4 0 24 2 <1 Vomiting 16 2 0 10 2 0 Infections Upper respiratory tract infection Laryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 27 1 0 17 1 0 Bronchitis Bronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis 20 1 0 13 1 0 Respiratory, thoracic and mediastinal disorders Cough Cough, Productive cough 17 0 0 9 0 0 Vascular disorders Hypertension 10 4 0 5 2 0 Table 12: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA DVTd (N=536) VTd (N=538) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone. Lymphopenia 95 44 15 91 37 10 Leukopenia 82 14 10 57 6 9 Thrombocytopenia 81 9 5 58 8 3 Neutropenia 63 19 14 41 10 9 Anemia 36 4 0 35 5 0 Relapsed/Refractory Multiple Myeloma Combination Treatment with Lenalidomide and Dexamethasone The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Clinical Studies (14.2) ]. Adverse reactions described in Table 13 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd). Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each). Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm. Table 13: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in POLLUX Adverse Reaction DRd (N=283) Rd (N=281) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Rd=lenalidomide-dexamethasone. Infections Upper respiratory tract infection upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection 65 6 < 1 51 4 0 General disorders and administration site conditions Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 48 5 0 0 0 0 Fatigue 35 6 < 1 28 2 0 Pyrexia 20 2 0 11 1 0 Gastrointestinal disorders Diarrhea 43 5 0 25 3 0 Nausea 24 1 0 14 0 0 Vomiting 17 1 0 5 1 0 Respiratory, thoracic and mediastinal disorders Cough cough, productive cough, allergic cough 30 0 0 15 0 0 Dyspnea dyspnea, dyspnea exertional 21 3 < 1 12 1 0 Musculoskeletal and connective tissue disorders Muscle spasms 26 1 0 19 2 0 Nervous system disorders Headache 13 0 0 7 0 0 Laboratory abnormalities worsening during treatment from baseline listed in Table 14. Table 14: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUX DRd (N=283) Rd (N=281) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Rd=lenalidomide-dexamethasone. Lymphopenia 95 42 10 87 32 6 Neutropenia 92 36 17 87 32 8 Thrombocytopenia 73 7 6 67 10 5 Anemia 52 13 0 57 19 0 Combination Treatment with Bortezomib and Dexamethasone The safety of DARZALEX in combination with bortezomib and dexamethasone was evaluated in CASTOR [see Clinical Studies (14.2) ]. Adverse reactions described in Table 15 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm. Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each). Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm. Table 15: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DVd Arm CASTOR Adverse Reaction DVd (N=243) Vd (N=237) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Vd=bortezomib-dexamethasone. Nervous system disorders Peripheral sensory neuropathy 47 5 0 38 6 < 1 General disorders and administration site conditions Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 45 9 0 0 0 0 Peripheral edema edema peripheral, edema, generalized edema, peripheral swelling 22 1 0 13 0 0 Pyrexia 16 1 0 11 1 0 Infections Upper respiratory tract infection upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection 44 6 0 30 3 < 1 Gastrointestinal disorders Diarrhea 32 3 < 1 22 1 0 Vomiting 11 0 0 4 0 0 Respiratory, thoracic and mediastinal disorders Cough cough, productive cough, allergic cough 27 0 0 14 0 0 Dyspnea dyspnea, dyspnea exertional 21 4 0 11 1 0 Laboratory abnormalities worsening during treatment are listed in Table 16. Table 16: Treatment-Emergent Hematology Laboratory Abnormalities in CASTOR DVd (N=243) Vd (N=237) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Vd=bortezomib-dexamethasone. Thrombocytopenia 90 28 19 85 22 13 Lymphopenia 89 41 7 81 24 3 Neutropenia 58 12 3 40 5 < 1 Anemia 48 13 0 56 14 0 Combination Treatment with Twice-Weekly (20/56 mg/m 2 ) Carfilzomib and Dexamethasone The safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Clinical Studies (14.2) ] . Adverse reactions described in Table 17 reflect exposure to DARZALEX for a median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd). Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%). Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia. Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%. Table 17: Adverse Reactions (≥15%) in Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone (DKd) in CANDOR Adverse Reaction DKd (N=308) Kd (N=153) All Grades Grades 3 or 4 All Grades Grades 3 or 4 (%) (%) (%) (%) Key: D=daratumumab; Kd=carfilzomib-dexamethasone. General Disorders and Administration Site Conditions Infusion-related reactions The incidence of infusion-related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration. 41 12 28 5 Fatigue Fatigue includes fatigue and asthenia. 32 11 28 8 Pyrexia 20 1.9 15 0.7 Infections Respiratory tract infection Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 40 Includes fatal adverse reactions. 7 29 3.3 Pneumonia 18 13 12 9 Bronchitis 17 2.6 12 1.3 Blood and lymphatic system disorders Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia. 37 25 30 16 Anemia Anemia includes anemia, hematocrit decreased and hemoglobin decreased. 33 17 31 14 Gastrointestinal disorders Diarrhea 32 3.9 14 0.7 Nausea 18 0 13 0.7 Vascular Disorders Hypertension 31 18 28 13 Respiratory, Thoracic and Mediastinal Disorders Cough Cough includes productive cough and cough. 21 0 21 0 Dyspnea 20 3.9 22 2.6 Psychiatric disorders Insomnia 18 3.9 11 2 Musculoskeletal and connective tissue disorders Back pain 16 1.9 10 1.3 Adverse Reactions Occurring at a Frequency of < 15% Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia Cardiac disorders: atrial fibrillation Gastrointestinal disorders: vomiting, constipation General disorders and administration site conditions: peripheral edema, asthenia, chills Infections: influenza, urinary tract infection, sepsis, septic shock Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndrome Respiratory, thoracic and mediastinal disorders: pulmonary edema Skin and subcutaneous tissue disorders: rash, pruritus Combination Treatment with Once-Weekly (20/70 mg/m 2 ) Carfilzomib and Dexamethasone The safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2) ] . Adverse reactions described in Table 18 reflect exposure to DARZALEX for a median treatment duration of 19.8 months (range: 0.3 to 34.5 months). Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression. Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient. Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively. Table 18: Adverse Reactions (≥15%) of Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone in EQUULEUS Adverse Reaction DKd (N=85) All Grades (%) Grades 3 or 4 (%) Key: D=daratumumab; Kd=carfilzomib-dexamethasone. Blood and lymphatic system disorders Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia. 68 32 Anemia Anemia includes anemia, hematocrit decreased and hemoglobin decreased. 52 21 Neutropenia Neutropenia includes neutrophil count decreased and neutropenia. 31 21 Lymphopenia Lymphopenia includes lymphocyte count decreased and lymphopenia 29 25 General disorder and administration site conditions Fatigue Fatigue includes fatigue and asthenia. 54 18 Infusion-related reactions The incidence of infusion-related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration. 53 12 Pyrexia 37 1.2 Infections Respiratory tract infection Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 53 3.5 Bronchitis 19 0 Nasopharyngitis 18 0 Influenza 17 3.5 Gastrointestinal disorders Nausea 42 1.2 Vomiting 40 1.2 Diarrhea 38 2.4 Constipation 17 0 Respiratory, thoracic and mediastinal disorders Dyspnea 35 3.5 Cough Cough includes productive cough and cough. 33 0 Vascular disorders Hypertension 33 20 Psychiatric disorders Insomnia 33 4.7 Nervous system disorders Headache 27 1.2 Musculoskeletal and connective tissue disorders Back pain 25 0 Pain in extremity 15 0 Adverse Reactions Occurring at a Frequency of < 15% Blood and lymphatic system disorders: leukopenia, febrile neutropenia Cardiac disorders: atrial fibrillation Gastrointestinal disorders: pancreatitis General disorders and administration site conditions: peripheral edema, chills Infections: pneumonia, urinary tract infection, sepsis, septic shock Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia Nervous system disorders: dizziness, paresthesia, peripheral sensory neuropathy Skin and subcutaneous tissue disorders: pruritus, rash Combination Treatment with Pomalidomide and Dexamethasone The safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2) ] . Adverse reactions described in Table 19 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients. Table 19: Adverse Reactions With Incidence ≥10% Reported in EQUULEUS Adverse Reaction DPd (N=103) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Pd=pomalidomide-dexamethasone. General disorders and administration site conditions Fatigue 50 10 0 Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 50 4 0 Pyrexia 25 1 0 Chills 20 0 0 Edema peripheral edema, edema peripheral, peripheral swelling 17 4 0 Asthenia 15 0 0 Non-cardiac chest pain 15 0 0 Pain 11 0 0 Infections Upper respiratory tract infection acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection 50 4 1 Pneumonia lung infection, pneumonia, pneumonia aspiration 15 8 2 Respiratory, thoracic and mediastinal disorders Cough cough, productive cough, allergic cough 43 1 0 Dyspnea dyspnea, dyspnea exertional 33 6 1 Nasal congestion 16 0 0 Gastrointestinal disorders Diarrhea 38 3 0 Constipation 33 0 0 Nausea 30 0 0 Vomiting 21 2 0 Musculoskeletal and connective tissue disorders Muscle spasms 26 1 0 Back pain 25 6 0 Arthralgia 22 2 0 Pain in extremity 15 0 0 Bone pain 13 4 0 Musculoskeletal chest pain 13 2 0 Psychiatric disorders Insomnia 23 2 0 Anxiety 13 0 0 Nervous system disorders Dizziness 21 2 0 Tremor 19 3 0 Headache 17 0 0 Metabolism and nutrition disorders Hypokalemia 16 3 0 Hyperglycemia 13 5 1 Decreased appetite 11 0 0 Laboratory abnormalities worsening during treatment are listed in Table 20. Table 20: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUS DPd (N=103) All Grades (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, Pd=pomalidomide-dexamethasone. Neutropenia 95 36 46 Lymphopenia 94 45 26 Thrombocytopenia 75 10 10 Anemia 57 30 0 Monotherapy The safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients. Adverse reactions occurring in at least 10% of patients are presented in Table 21. Table 22 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%. Table 21: Adverse Reactions With Incidence ≥10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg Adverse Reaction DARZALEX (N=156) All Grades (%) Grade 3 (%) Grade 4 (%) General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes terms determined by investigators to be related to infusion 48 3 0 Fatigue 39 2 0 Pyrexia 21 1 0 Chills 10 0 0 Gastrointestinal disorders Nausea 27 0 0 Diarrhea 16 1 0 Constipation 15 0 0 Vomiting 14 0 0 Musculoskeletal and connective tissue disorders Back pain 23 2 0 Arthralgia 17 0 0 Pain in extremity 15 1 0 Musculoskeletal chest pain 12 1 0 Respiratory, thoracic and mediastinal disorders Cough 21 0 0 Nasal congestion 17 0 0 Dyspnea 15 1 0 Infections Upper respiratory tract infection 20 1 0 Nasopharyngitis 15 0 0 Pneumonia Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. 11 6 0 Metabolism and nutrition disorders Decreased appetite 15 1 0 Nervous system disorders Headache 12 1 0 Vascular disorders Hypertension 10 5 0 Table 22: Treatment-Emergent Grade 3–4 Laboratory Abnormalities (≥10%) Daratumumab 16 mg/kg (N=156) All Grades (%) Grade 3 (%) Grade 4 (%) Lymphopenia 72 30 10 Neutropenia 60 17 3 Thrombocytopenia 48 10 8 Anemia 45 19 0 Herpes Zoster Virus Reactivation Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2–5% of patients receiving DARZALEX. Infections Grade 3 or 4 infections were reported as follows: Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKd where carfilzomib 20/56 mg/m 2 was administered twice-weekly : 37%, Kd : 29%; DKd where carfilzomib 20/70 mg/m 2 was administered once-weekly : 21% Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%. Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1–4% of patients. Fatal infections (Grade 5) were reported as follows: Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd : 5%, Kd : 3%; DKd : 0% Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%. Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis. Hepatitis B Virus (HBV) Reactivation Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials. Other Clinical Trials Experience The following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection: Nervous System disorders: Syncope 6.2 Postmarketing Experience The following adverse reactions have been identified during 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 disorders: Anaphylactic reaction, IRR (including deaths) Gastrointestinal disorders: Pancreatitis Infections: Cytomegalovirus, Listeriosis

8.1 Pregnancy Risk Summary DARZALEX 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 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 and lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Lenalidomide, pomalidomide, and thalidomide are only available through a REMS program. Refer to the lenalidomide, pomalidomide, or thalidomide 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 may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until a hematology evaluation is completed. Data Animal Data 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 regulating humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).