Label: DARZALEX- daratumumab injection, solution, concentrate

  • NDC Code(s): 57894-502-05, 57894-502-20
  • Packager: Janssen Biotech, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated July 9, 2020

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use DARZALEX® safely and effectively. See full prescribing information for DARZALEX.

    DARZALEX (daratumumab) injection, for intravenous use
    Initial U.S. Approval: 2015

    RECENT MAJOR CHANGES

    Indications and Usage (1)09/2019
    Dosage and Administration (2)06/2020
    Warnings and Precautions (5.1, 5.6)06/2020

    INDICATIONS AND USAGE

    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 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)

    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)

    DOSAGE FORMS AND STRENGTHS

    Injection:

    • 100 mg/5 mL solution in a single-dose vial (3)
    • 400 mg/20 mL solution in a single-dose vial (3)

    CONTRAINDICATIONS

    Patients with a history of severe hypersensitivity to daratumumab or any of the components of the formulation. (4)

    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).

    ADVERSE REACTIONS

    The most frequently reported adverse reactions (incidence ≥20%) were: infusion-related reactions, neutropenia, thrombocytopenia, fatigue, asthenia, nausea, diarrhea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, bronchitis, pneumonia and upper respiratory tract infection. (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.

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 6/2020

  • Table of Contents
  • 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 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.
  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Dosing Information

    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 Dosing Regimens) and Low-Dose Dexamethasone and for Monotherapy
    WeeksSchedule
    *
    First dose of the every-2-week dosing schedule is given at Week 9
    First dose of the every-4-week dosing schedule is given at Week 25
    Weeks 1 to 8weekly (total of 8 doses)
    Weeks 9 to 24*every two weeks (total of 8 doses)
    Week 25 onwards until disease progressionevery 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 Dosing Regimen)
    WeeksSchedule
    *
    First dose of the every-3-week dosing schedule is given at Week 7
    First dose of the every-4-week dosing schedule is given at Week 55
    Weeks 1 to 6weekly (total of 6 doses)
    Weeks 7 to 54*every three weeks (total of 16 doses)
    Week 55 onwards until disease progressionevery 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 Dosing Regimen)
    Treatment phaseWeeksSchedule
    *
    First dose of the every-2-week dosing schedule is given at Week 9
    First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT
    InductionWeeks 1 to 8weekly (total of 8 doses)
    Weeks 9 to 16*every two weeks (total of 4 doses)
    Stop for high dose chemotherapy and ASCT
    ConsolidationWeeks 1 to 8every 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 regimen) 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 Dosing Regimen)
    WeeksSchedule
    *
    First dose of the every-3-week dosing schedule is given at Week 10
    First dose of the every-4-week dosing schedule is given at Week 25
    Weeks 1 to 9weekly (total of 9 doses)
    Weeks 10 to 24*every three weeks (total of 5 doses)
    Week 25 onwards until disease progressionevery 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 5. Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions.

    To facilitate administration, the first prescribed 16 mg/kg dose at Week 1 may be split over two consecutive days i.e. 8 mg/kg on Day 1 and Day 2 respectively, see Table 5 below.

    Table 5: Infusion Rates for DARZALEX (16 mg/kg) Administration
    Dilution volume Initial rate
    (first hour)
    Rate increment*Maximum rate
    *
    Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions.
    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.
    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.
    Week 1 Infusion
    Option 1 (Single dose infusion)
      Week 1 Day 1 (16 mg/kg) 1,000 mL50 mL/hour50 mL/hour every hour200 mL/hour
    Option 2 (Split dose infusion)
      Week 1 Day 1 (8 mg/kg) 500 mL50 mL/hour50 mL/hour every hour200 mL/hour
      Week 1 Day 2 (8 mg/kg) 500 mL50 mL/hour50 mL/hour every hour200 mL/hour
    Week 2 (16 mg/kg) infusion500 mL50 mL/hour50 mL/hour every hour200 mL/hour
    Subsequent (Week 3 onwards, 16 mg/kg) infusions500 mL100 mL/hour50 mL/hour every hour200 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 1–3 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 to 1,000 mg orally
    • Diphenhydramine 25 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 5).
    • 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 5. 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 use 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.
    • 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, USP 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, USP as specified in Table 5 [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.
    • Since DARZALEX does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time).
    • If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C–8°C (36°F–46°F) and protected from light. 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 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.
  • 3 DOSAGE FORMS AND STRENGTHS

    DARZALEX is a colorless to pale yellow, preservative-free solution available as:

    Injection:

    • 100 mg/5 mL (20 mg/mL) in a single-dose vial.
    • 400 mg/20 mL (20 mg/mL) in a single-dose vial.
  • 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)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Infusion-Related Reactions

    DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. In clinical trials (monotherapy and combination treatments: 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 72.8 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, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension [see Adverse Reactions (6.1)].

    When DARZALEX dosing was interrupted in the setting of ASCT (Study CASSIOPEIA) for a median of 3.75 months (range: 2.4; 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 h for Week 1-Day 1, 4.2 h 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)].

    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.

  • 6 ADVERSE REACTIONS

    The following clinically significant adverse reactions are described elsewhere in the labeling:

    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 2,066 patients with multiple myeloma including 1,910 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy.

    Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant

    Combination Treatment with Lenalidomide and Dexamethasone (DRd)

    Adverse reactions described in the table below reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for the daratumumab-lenalidomide-dexamethasone (DRd) group and median treatment duration of 21.3 months (range: 0.03 to 40.64 months) for the lenalidomide-dexamethasone group (Rd) in a Phase 3 active-controlled study MAIA. The most frequent (≥20%) adverse reactions were infusion-related reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea and cough. 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 6: 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)
    Any Grade (%)Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling
    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
    §
    Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis
    Atypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis
    #
    Dyspnea, Dyspnea exertional
    Þ
    Cough, Productive cough
    ß
    Blood pressure increased, Hypertension
    Infusion-related reactions*412<1000
    Gastrointestinal disorders
      Diarrhea57704640
      Constipation411<136<10
      Nausea32102310
      Vomiting171012<10
    General disorders and administration site conditions
      Peripheral edema41203310
      Fatigue40802840
      Asthenia3240253<1
      Pyrexia23201820
      Chills1300200
    Infections and infestations
      Upper respiratory tract infection522<1362<1
      Bronchitis§29302110
      Pneumonia261411471
      Urinary tract infection18201020
    Metabolism and nutrition disorders
      Decreased appetite221015<1<1
      Hyperglycemia1461831
      Hypocalcemia141<1911
    Musculoskeletal and connective tissue disorders
      Back pain343<1263<1
      Muscle spasms29102210
    Nervous system disorders
      Peripheral sensory neuropathy24101500
      Headache19101100
      Paresthesia1600800
    Respiratory, thoracic and mediastinal disorders
      Dyspnea#323<12010
      CoughÞ30<101800
    Vascular disorders
      Hypertensionß136<1740

    Laboratory abnormalities worsening during treatment from baseline listed in Table 7.

    Table 7: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA
    DRd (N=364)Rd (N=365)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
    Anemia4713057240
    Thrombocytopenia67635874
    Leukopenia9030582204
    Neutropenia913917772811
    Lymphopenia84411175366

    Combination Treatment with Bortezomib, Melphalan and Prednisone

    Adverse reactions described in Table 8 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for the daratumumab, bortezomib, melphalan and prednisone (D-VMP) group, and median treatment duration of 12 months (range: 0.1 to 14.9 months) for the VMP group in a Phase 3 active-controlled study ALCYONE. The most frequent adverse reactions (≥20% with at least 5% greater frequency in the D-VMP arm) were infusion-related reactions, upper respiratory tract infection and edema peripheral. 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 8: 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)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    edema peripheral, generalized edema, peripheral swelling
    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.
    §
    pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis
    cough, productive cough
    #
    dyspnea, dyspnea exertional
    Þ
    hypertension, blood pressure increased
    Infusion-related reactions*2841000
    General disorders and administration site conditions
      Edema peripheral211< 11410
    Infections and infestations
      Upper respiratory tract infection48502830
      Pneumonia§1612< 165< 1
    Respiratory, thoracic and mediastinal disorders
      Cough16< 108< 10
      Dyspnea#1321510
    Vascular disorders
      HypertensionÞ104< 1320

    Laboratory abnormalities worsening during treatment from baseline listed in Table 9.

    Table 9: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE
    D-VMP (N=346)VMP (N=354)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone
    Anemia4718050210
    Thrombocytopenia882711882616
    Neutropenia863410873211
    Lymphopenia85461283449

    Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant

    Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)

    Adverse reactions described in Table 10 reflect exposure to DARZALEX up to day 100 post-transplant in a Phase 3 active-controlled study CASSIOPEIA [see Clinical Studies (14.1)]. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for the DVTd group and 8.7 months (range: 6.4 to 11.5 months) for the VTd group. The most frequent adverse reactions (>20% with at least 5% greater frequency in the DVTd group) were infusion-related reactions, nausea, pyrexia, upper respiratory tract infection and bronchitis. 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 10: 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)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    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
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    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
    Bronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis
    §
    Cough, Productive cough
    Infusion-related reactions*353<1000
    Gastrointestinal disorders
      Nausea3040242<1
      Vomiting16201020
    General disorders and administration site conditions
      Pyrexia262<12120
    Infections and infestations
      Upper respiratory tract infection27101710
      Bronchitis20101310
    Respiratory, thoracic and mediastinal disorders
      Cough§1700900
    Vascular disorders
      Hypertension1040520
    Table 11: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA
    DVTd (N=536)VTd (N=538)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.
    Anemia36403550
    Thrombocytopenia81955883
    Leukopenia8214105769
    Neutropenia63191441109
    Lymphopenia954415913710

    Relapsed/Refractory Multiple Myeloma

    Combination Treatment with Lenalidomide and Dexamethasone

    Adverse reactions described in Table 12 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for the daratumumab-lenalidomide-dexamethasone (DRd) group and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide-dexamethasone (Rd) group in a Phase 3 active-controlled study POLLUX. The most frequent adverse reactions (≥20%) were infusion-related reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea. The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group. 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 12: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in POLLUX
    Adverse ReactionDRd (N=283)Rd (N=281)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    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
    cough, productive cough, allergic cough
    §
    dyspnea, dyspnea exertional
    Infusion-related reactions*4850000
    Gastrointestinal disorders
      Diarrhea43502530
      Nausea24101400
      Vomiting1710510
    General disorders and administration site conditions
      Fatigue356< 12820
      Pyrexia20201110
    Infections and infestations
      Upper respiratory tract infection656< 15140
    Musculoskeletal and connective tissue disorders
      Muscle spasms26101920
    Nervous system disorders
      Headache1300700
    Respiratory, thoracic and mediastinal disorders
      Cough30001500
      Dyspnea§213< 11210

    Laboratory abnormalities worsening during treatment from baseline listed in Table 13.

    Table 13: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUX
    DRd (N=283)Rd (N=281)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grades
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=Daratumumab, Rd=lenalidomide-dexamethasone.
    Anemia5213057190
    Thrombocytopenia737667105
    Neutropenia92361787328
    Lymphopenia95421087326

    Combination Treatment with Bortezomib and Dexamethasone

    Adverse reactions described in Table 14 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) in the daratumumab-bortezomib-dexamethasone (DVd) group and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib-dexamethasone (Vd) group in a Phase 3 active-controlled study CASTOR. The most frequent adverse reactions (>20%) were infusion-related reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group. 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 14: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DVd Arm CASTOR
    Adverse ReactionDVd (N=243)Vd (N=237)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=daratumumab, Vd=bortezomib-dexamethasone.
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    edema peripheral, edema, generalized edema, peripheral swelling
    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
    §
    cough, productive cough, allergic cough
    dyspnea, dyspnea exertional
    Infusion-related reactions*4590000
    Gastrointestinal disorders
      Diarrhea323< 12210
      Vomiting1100400
    General disorders and administration site conditions
      Edema peripheral22101300
      Pyrexia16101110
    Infections and infestations
      Upper respiratory tract infection4460303< 1
    Nervous system disorders
      Peripheral sensory neuropathy4750386< 1
    Respiratory, thoracic and mediastinal disorders
      Cough§27001400
      Dyspnea21401110

    Laboratory abnormalities worsening during treatment are listed in Table 15.

    Table 15: Treatment-Emergent Hematology Laboratory Abnormalities in CASTOR
    DVd (N=243)Vd (N=237)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=Daratumumab, Vd=bortezomib-dexamethasone.
    Anemia4813056140
    Thrombocytopenia902819852213
    Neutropenia58123405< 1
    Lymphopenia8941781243

    Combination Treatment with Pomalidomide and Dexamethasone

    Adverse reactions described in Table 16 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in EQUULEUS. The most frequent adverse reactions (>20%) were infusion-related reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough and dyspnea. 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 16: Adverse Reactions With Incidence ≥10% Reported in EQUULEUS
    Body SystemDPd (N=103)
      Adverse ReactionAny Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    edema, edema peripheral, peripheral swelling.
    acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection
    §
    lung infection, pneumonia, pneumonia aspiration
    cough, productive cough, allergic cough
    #
    dyspnea, dyspnea exertional
      Infusion-related reactions*5040
    Gastrointestinal disorders
      Diarrhea3830
      Constipation3300
      Nausea3000
      Vomiting2120
    General disorders and administration site conditions
      Fatigue50100
      Pyrexia2510
      Chills2000
      Edema peripheral1740
      Asthenia1500
      Non-cardiac chest pain1500
      Pain1100
    Infections and infestations
      Upper respiratory tract infection5041
      Pneumonia§1582
    Metabolism and nutrition disorders
      Hypokalemia1630
      Hyperglycemia1351
      Decreased appetite1100
    Musculoskeletal and connective tissue disorders
      Muscle spasms2610
      Back pain2560
      Arthralgia2220
      Pain in extremity1500
      Bone pain1340
      Musculoskeletal chest pain1320
    Nervous system disorders
      Dizziness2120
      Tremor1930
      Headache1700
    Psychiatric disorders
      Insomnia2320
      Anxiety1300
    Respiratory, thoracic and mediastinal disorders
      Cough4310
      Dyspnea#3361
      Nasal congestion1600

    Laboratory abnormalities worsening during treatment are listed in Table 17.

    Table 17: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUS
    DPd (N=103)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.
    Anemia57300
    Thrombocytopenia751010
    Neutropenia953646
    Lymphopenia944526

    Monotherapy

    The safety data reflect exposure to DARZALEX in 156 adult patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg in three open-label, clinical trials. 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 18. Table 19 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.

    Table 18: Adverse Reactions With Incidence ≥10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg
    DARZALEX
    (N=156)
      Adverse ReactionAny Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    *
    Infusion-related reaction includes terms determined by investigators to be related to infusion
    Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.
      Infusion-related reaction*4830
    General disorders and administration site conditions
      Fatigue3920
      Pyrexia2110
      Chills1000
    Respiratory, thoracic and mediastinal disorders
      Cough2100
      Nasal congestion1700
      Dyspnea1510
    Musculoskeletal and connective tissue disorders
      Back pain2320
      Arthralgia1700
      Pain in extremity1510
      Musculoskeletal chest pain1210
    Infections and infestations
      Upper respiratory tract infection2010
      Nasopharyngitis1500
      Pneumonia1160
    Gastrointestinal disorders
      Nausea2700
      Diarrhea1610
      Constipation1500
      Vomiting1400
    Metabolism and nutrition disorders
      Decreased appetite1510
    Nervous system disorders
      Headache1210
    Vascular disorders
      Hypertension1050
    Table 19: Treatment-Emergent Grade 3-4 Laboratory Abnormalities (≥10%)
    Daratumumab 16 mg/kg (N=156)
    Any Grade
    (%)
    Grade 3
    (%)
    Grade 4
    (%)
    Anemia45190
    Thrombocytopenia48108
    Neutropenia60173
    Lymphopenia723010

    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: 27% vs. Rd: 23%; DPd: 28%

    Newly diagnosed patient studies: D-VMP: 23% vs. VMP: 15%; DRd: 32% vs. Rd: 23%; DVTd: 22% vs. VTd 20%.

    Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1–4%) and 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.

    6.2 Immunogenicity

    As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products may be misleading.

    In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 of the 1,050 evaluable combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

    6.3 Postmarketing Experience

    The following adverse reactions have been identified during postapproval use of DARZALEX. 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

    Gastrointestinal disorders: Pancreatitis

  • 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.

  • 8 USE IN SPECIFIC POPULATIONS

    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).

    8.2 Lactation

    Risk Summary

    There is no data on the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX is administered with lenalidomide, pomalidomide, or thalidomide, advise women not to breastfeed during treatment with DARZALEX. Refer to lenalidomide, pomalidomide, or thalidomide prescribing information for additional information.

    8.3 Females and Males of Reproductive Potential

    DARZALEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

    Pregnancy Testing

    With the combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide, refer to the lenalidomide, pomalidomide, or thalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.

    Contraception

    Advise females of reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose. Additionally, refer to the lenalidomide, pomalidomide, or thalidomide labeling for additional recommendations for contraception.

    8.4 Pediatric Use

    Safety and effectiveness of DARZALEX in pediatric patients have not been established.

    8.5 Geriatric Use

    Of the 2,066 patients that received DARZALEX at the recommended dose, 37% were 65 to 75 years of age, and 16% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14)].

  • 11 DESCRIPTION

    Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody that binds to CD38 antigen. It is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.

    DARZALEX (daratumumab) injection is supplied as a colorless to pale yellow preservative-free solution for intravenous use in a single-dose vial. The pH is 5.5.

    Each DARZALEX 20 mL single-dose vial contains 400 mg daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and Water for Injection, USP.

    Each DARZALEX 5 mL single-dose vial contains 100 mg daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and Water for Injection, USP.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab.

    12.2 Pharmacodynamics

    NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.

    Exposure-Response Relationship

    The exposure-response relationship and time course of pharmacodynamics of DARZALEX have not been fully characterized.

    Cardiac Electrophysiology

    DARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

    12.3 Pharmacokinetics

    Daratumumab area under the concentration-time curve (AUC) increases more than proportionally over a dosage range from 1 to 24 mg/kg (0.06 to 1.5 times the approved recommended dosage) as monotherapy or 1 to 16 mg/kg (0.06 to 1 time the approved recommended dosage) as combination therapy.

    Following administration of the approved recommended dosage of DARZALEX as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) was approximately 2.7 to 3-fold higher at the end of weekly dosing compared to the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 ± 332 µg/mL when DARZALEX was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when DARZALEX was administered as combination therapy. Split dosing of the first dose resulted in a different PK profile in the first day compared to single dosing; however, similar Cmax and Cmin concentrations were both predicted and observed following the administration of the second split dose on Week 1 Day 2.

    When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion). At steady state, daratumumab mean ± SD accumulation ratio for Cmax was 1.6 ± 0.5.

    Distribution

    Daratumumab volume of distribution was 4.7 ± 1.3 L as monotherapy and 4.4 ± 1.5 L as combination therapy following administration of the approved dosage.

    Elimination

    Daratumumab clearance decreased with increasing dose and with multiple dosing. The mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day and the mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days following administration of the approved recommended dosage of DARZALEX as monotherapy. Terminal half-life was similar when DARZALEX was administered as combination therapy.

    Specific Populations

    No clinically significant differences in the pharmacokinetics of daratumumab as monotherapy or as combination therapy were observed based on sex, age (31 to 93 years), mild [total bilirubin 1 to 1.5 times upper limit of normal (ULN) or aspartate aminotransaminase (AST)>ULN] and moderate (total bilirubin 1.5 to 3 times ULN and any AST) hepatic impairment, or renal impairment [Creatinine clearance (CLcr) 15 –89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on daratumumab pharmacokinetics is unknown.

    Body Weight

    The central volume of distribution and clearance of daratumumab increased with increasing body weight.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

  • 14 CLINICAL STUDIES

    14.1 Newly Diagnosed Multiple Myeloma

    Combination Treatment with Lenalidomide and Dexamethasone in Patients Ineligible for Autologous Stem Cell Transplant

    MAIA (NCT02252172), an open-label, randomized, active-controlled Phase 3 study, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.

    A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45–90) years, with 44% of the patients ≥75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

    MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd.

    Figure 1: Kaplan-Meier Curve of PFS in MAIA

    Figure 1

    Additional efficacy results from MAIA are presented in Table 20 below.

    Table 20: Additional Efficacy Results From MAIA*
    DRd (N=368)Rd (N=369)
    DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval
    *
    Based on intent-to-treat population
    p-value from Cochran Mantel-Haenszel Chi-Squared test.
    Based on threshold of 10-5 using a next-generation sequencing assay (clonoSEQ).
    §
    p-value from Fisherʼs exact test
    Overall response (sCR+CR+VGPR+PR) n(%)*342 (92.9%)300 (81.3%)
    p-value<0.0001
      Stringent complete response (sCR)112 (30.4%)46 (12.5%)
      Complete response (CR)63 (17.1%)46 (12.5%)
      Very good partial response (VGPR)117 (31.8%)104 (28.2%)
      Partial response (PR)50 (13.6%)104 (28.2%)
    CR or better (sCR + CR)175 (47.6%)92 (24.9%)
      p-value<0.0001
    VGPR or better (sCR + CR + VGPR)292 (79.3%)196 (53.1%)
      p-value<0.0001
    MRD negativity rate*, n(%)89 (24.2%)27 (7.3%)
      95% CI (%)(19.9%, 28.9%)(4.9%, 10.5%)
      p-value§<0.0001
    MRD negativity rate in patients with CR or better
      Number of patients with CR or betterN=175N=92
      MRD negativity rate n(%)89 (50.9%)27 (29.3%)
      95% CI (%)(43.2%, 58.5%)(20.3%, 39.8%)

    In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.

    Combination Treatment with Bortezomib, Melphalan and Prednisone (VMP) in Patients Ineligible for Autologous Stem Cell Transplant

    ALCYONE (NCT02195479), an open-label, randomized, active-controlled Phase 3 study, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m2 body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2–9; 4 doses per cycle). Melphalan at 9 mg/m2, and prednisone at 60 mg/m2 were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1–9). DARZALEX treatment was continued until disease progression or unacceptable toxicity.

    A total of 706 patients were randomized: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40–93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Nineteen percent of patients had ISS Stage I, 42% had ISS Stage II and 38% had ISS Stage III disease. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).

    ALCYONE demonstrated an improvement in PFS in the D-VMP arm as compared to the VMP arm (HR=0.50; 95% CI: 0.38, 0.65; p<0.0001), representing a 50% reduction in the risk of disease progression or death in patients treated with D-VMP. After a median follow-up of 40 months, the median PFS was 36.4 months (95% CI: 32.1, 45.9) in the D-VMP arm and 19.3 months (95% CI: 18.0, 20.4) in the VMP arm.

    *
    PFS median follow-up of 16.5 months
    Figure 2: Kaplan-Meier Curve of PFS in ALCYONE*

    Figure 2

    After a median follow-up of 40 months, ALCYONE demonstrated an improvement in overall survival (OS) in the D-VMP arm as compared to the VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the D-VMP arm. Median OS was not reached for either arm.

    Figure 3: Kaplan-Meier Curve of OS in ALCYONE

    Figure 3

    Additional efficacy results from ALCYONE are presented in Table 21 below.

    Table 21: Additional Efficacy Results From ALCYONE
    D-VMP (N=350)VMP (N=356)
    D-VMP = daratumumab-bortezomib-melphalan-prednisone; VMP = bortezomib-melphalan-prednisone; MRD = minimal residual disease; CI = confidence interval
    *
    Based on intent-to-treat population
    p-value from Cochran Mantel-Haenszel Chi-Squared test.
    Based on threshold of 10-5 using a next-generation sequencing assay (clonoSEQ).
    §
    p-value from Fisherʼs exact test.
    Overall response (sCR+CR+VGPR+PR) n(%)*318 (90.9%)263 (73.9%)
      p-value<0.0001
      Stringent complete response (sCR)63 (18.0%)25 (7.0%)
      Complete response (CR)86 (24.6%)62 (17.4%)
      Very good partial response (VGPR)100 (28.6%)90 (25.3%)
      Partial response (PR)69 (19.7%)86 (24.2%)
    MRD negativity rate*, n(%)78 (22.3%)22 (6.2%)
      95% CI (%)(18.0, 27.0)(3.9, 9.2)
      p-value§<0.0001
    MRD negativity rate in patients with CR or better
      Number of patients with CR or betterN=149N=87
      MRD negativity rate n(%)74 (49.7%)22 (25.3%)
      95% CI (%)(41.4, 58.0)(16.6, 35.7)

    In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median duration of response had not been reached in the D-VMP group and was 21.3 months (range: 0.5+, 23.7+) in the VMP group.

    Combination Treatment with Bortezomib, Thalidomide and Dexamethasone in Patients Eligible for Autologous Stem Cell Transplant (ASCT)

    CASSIOPEIA (NCT02541383), an open-label, randomized, active-controlled Phase 3 study compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. The trial was limited to patients 65 years of age and younger.

    Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1–4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1–2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3–4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer's prescribing information.

    A total of 1,085 patients were randomized: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 years (range: 22 to 65 years). The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.

    Efficacy was evaluated by stringent Complete Response (sCR) rate at Day 100 post-transplant, Complete Response Rate (CR) at Day 100 post-transplant, and Progression-Free Survival (PFS).

    Table 22: Efficacy Results From CASSIOPEIA at Day 100 Post-Transplant
    DVTd (N=543)VTd (N=542)
    D-VTd = daratumumab-bortezomib-thalidomide-dexamethasone; VTd = bortezomib-thalidomide-dexamethasone
    *
    Based on intent-to-treat population
    p-value from Cochran Mantel-Haenszel Chi-Squared test.
    Overall response (sCR+CR+VGPR+PR) n(%)*503 (92.6%)487 (89.9%)
      Stringent complete response (sCR)157 (28.9%)110 (20.3%)
        p-value0.0010
      Complete response (CR)54 (9.9%)31 (5.7%)
      Very good partial response (VGPR)242 (44.6%)282 (52.0%)
      Partial response (PR)50 (9.2%)64 (11.8%)

    CASSIOPEIA demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; with a median follow up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001).

    Figure 4: Kaplan-Meier Curve of PFS in CASSIOPEIA*
    *
    based on interim analysis and the boundary for PFS was crossed.

    Figure 4

    14.2 Relapsed/Refractory Multiple Myeloma

    Combination Treatment with Lenalidomide and Dexamethasone

    POLLUX (NCT02076009), an open-label, randomized, active-controlled Phase 3 trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.

    A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% White, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by PFS based on IMWG criteria.

    POLLUX demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing a 63% reduction in the risk of disease progression or death in patients treated with DRd. After a median follow-up of 55 months, the median PFS was 45.0 months (95% CI: 34.1, 53.9) in the DRd arm and was 17.5 months (95% CI: 13.9, 20.8) in the Rd arm.

    *
    PFS median follow-up of 13.5 months
    Figure 5: Kaplan-Meier Curve of PFS in POLLUX*

    Figure 5

    Additional efficacy results from POLLUX are presented in Table 23 below.

    Table 23: Additional Efficacy Results From POLLUX*
    DRd (N=286)Rd (N=283)
    DRd = daratumumab- lenalidomide-dexamethasone; Rd = lenalidomide-dexamethasone
    *
    Based on Intent-to-treat population
    p-value from Cochran Mantel-Haenszel Chi-Squared test.
    Overall response (sCR+CR+VGPR+PR)261 (91.3%)211 (74.6%)
      p-value<0.0001
      Stringent complete response (sCR)51 (17.8%)20 (7.1%)
      Complete response (CR)70 (24.5%)33 (11.7%)
      Very good partial response (VGPR)92 (32.2%)69 (24.4%)
      Partial response (PR)48 (16.8%)89 (31.4%)

    In responders, the median time to response was 1 month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group.

    With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group.

    Combination Treatment with Bortezomib and Dexamethasone

    CASTOR (NCT02136134), an open-label, randomized, active-controlled Phase 3 trial, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had received at least one prior therapy. Bortezomib was administered by SC injection or IV infusion at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of DARZALEX infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas DARZALEX was given until disease progression. However, dexamethasone 20 mg was continued as a DARZALEX pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information.

    A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% were male; 87% White, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an immunomodulatory agent (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were in general well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd arm respectively refractory to lenalidomide. Efficacy was evaluated by PFS based on IMWG criteria.

    CASTOR demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm (HR=0.39; 95% CI: 0.28, 0.53; p<0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. After a median follow-up of 50 months, the median PFS was 16.7 months (95% CI: 13.1, 19.4) in the DVd arm and was 7.1 months (95% CI: 6.2, 7.7) in the Vd arm.

    *
    PFS median follow-up of 7.4 months
    Figure 6: Kaplan-Meier Curve of PFS in CASTOR*

    Figure 6

    Additional efficacy results from CASTOR are presented in Table 24 below.

    Table 24: Additional Efficacy Results From CASTOR*
    DVd (N=251)Vd (N=247)
    DVd = daratumumab- bortezomib-dexamethasone; Vd = bortezomib-dexamethasone
    *
    Based on Intent-to-treat population
    p-value from Cochran Mantel-Haenszel Chi-Squared test.
    Overall response (sCR+CR+VGPR+PR)199 (79.3%)148 (59.9%)
      P-value<0.0001
      Stringent complete response (sCR)11 (4.4%)5 (2.0%)
      Complete response (CR)35 (13.9%)16 (6.5%)
      Very good partial response (VGPR)96 (38.2%)47 (19.0%)
      Partial response (PR)57 (22.7%)80 (32.4%)

    In responders, the median time to response was 0.8 months (range: 0.7 to 4 months) in the DVd group and 1.5 months (range: 0.7 to 5 months) in the Vd group. The median duration of response had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ to 12+ months) in the Vd group.

    With a median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in the Vd group were observed.

    Combination Treatment with Pomalidomide and Dexamethasone

    EQUULEUS (NCT01998971) was an open-label trial in which 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent, received 16 mg/kg DARZALEX in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication.

    The median patient age was 64 years (range: 35 to 86 years) with 8% of patients ≥75 years of age. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.

    Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see Table 25).

    Table 25: Efficacy Results for EQUULEUS
    N=103
    ORR = sCR+CR+VGPR+PR
    CI = Confidence Interval
    Overall response rate (ORR)
    95% CI (%)
    61 (59.2%)
    (49.1, 68.8)
      Stringent complete response (sCR)8 (7.8%)
      Complete response (CR)6 (5.8%)
      Very good partial response (VGPR)29 (28.2%)
      Partial response (PR)18 (17.5%)

    The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months).

    Monotherapy

    SIRIUS (NCT01985126), was an open-label trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.

    The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were White. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents.

    Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 26).

    Table 26: Efficacy Results for SIRIUS
    N=106
    ORR = sCR+CR+VGPR+PR
    CI = confidence interval
    Overall response rate (ORR)
    95% CI (%)
    31 (29.2%)
    (20.8, 38.9)
      Stringent complete response (sCR)3 (2.8%)
      Complete response (CR)0
      Very good partial response (VGPR)10 (9.4%)
      Partial response (PR)18 (17.0%)

    The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months).

    Study GEN501 (NCT00574288) was an open-label dose escalation trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.

    The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were White. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents.

    Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months).

  • 15 REFERENCES

    1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545–1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    How Supplied

    DARZALEX is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as:

    NDC 57894-502-05 contains one 100 mg/5 mL single-dose vial

    NDC 57894-502-20 contains one 400 mg/20 mL single-dose vial

    Storage and Stability

    Store in a refrigerator at 2°C to 8°C (36°F to 46°F).

    Do not freeze or shake. Protect from light. This product contains no preservative.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Patient Information).

    Infusion-Related Reactions

    Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing [see Warnings and Precautions (5.1)].

    Neutropenia

    Advise patients to contact their healthcare provider if they have a fever [see Warnings and Precautions (5.3)].

    Thrombocytopenia

    Advise patients to contact their healthcare provider if they notice signs of bruising or bleeding [see Warnings and Precautions (5.4)].

    Interference with Laboratory Tests

    Advise patients to inform their healthcare providers, including personnel at blood transfusion centers that they are taking DARZALEX, in the event of a planned transfusion [see Warnings and Precautions (5.2)].

    Advise patients that DARZALEX can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response [see Warnings and Precautions (5.5)].

    Hepatitis B Virus (HBV) Reactivation:

    Advise patients to inform healthcare providers if they have ever had or might have a hepatitis B infection and that DARZALEX could cause hepatitis B virus to become active again [see Adverse Reactions (6.1)].

    Embryo-Fetal Toxicity

    Advise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].

    Advise females of reproductive potential to avoid becoming pregnant during treatment with DARZALEX and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

    Advise patients that lenalidomide, pomalidomide, or thalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide, pomalidomide, and thalidomide are only available through a REMS program [see Use in Specific Populations (8.1, 8.3)].

  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    Janssen Biotech, Inc.
    Horsham, PA 19044
    U.S. License Number 1864

    © 2015 Janssen Pharmaceutical Companies

  • PATIENT PACKAGE INSERT

    This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 06/2020
    PATIENT INFORMATION
    DARZALEX® (Dar'-zah-lex)
    (daratumumab)
    injection, for intravenous use
    What is DARZALEX?
    DARZALEX is a prescription medicine used to treat adults with multiple myeloma:
    • in combination with the medicines lenalidomide and dexamethasone in people with newly diagnosed multiple myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant) and in people who have received at least one prior medicine to treat multiple myeloma.
    • in combination with the medicines bortezomib, melphalan and prednisone, in people with newly diagnosed multiple myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant).
    • in combination with the medicines bortezomib, thalidomide, and dexamethasone in newly diagnosed people who are eligible to receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant).
    • in combination with the medicines bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma.
    • in combination with the medicines pomalidomide and dexamethasone in people who have received at least two prior medicines to treat multiple myeloma, including lenalidomide and a proteasome inhibitor.
    • alone in people who have received at least three prior medicines, including a proteasome inhibitor and an immunomodulatory agent, or did not respond to a proteasome inhibitor and an immunomodulatory agent.
    It is not known if DARZALEX is safe and effective in children.
    Do not receive DARZALEX:
    • if you have a history of a severe allergic reaction to daratumumab or any of the ingredients in DARZALEX. See the end of this leaflet for a complete list of ingredients in DARZALEX.
    Before you receive DARZALEX, tell your healthcare provider about all of your medical conditions, including if you:
    • have a history of breathing problems
    • have had shingles (herpes zoster)
    • have ever had or might now have a hepatitis B infection as DARZALEX could cause hepatitis B virus to become active again. Your healthcare provider will check you for signs of this infection before, during and for some time after treatment with DARZALEX. Tell your healthcare provider right away if you get worsening tiredness or yellowing of your skin or white part of your eyes.
    • are pregnant or plan to become pregnant. DARZALEX may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with DARZALEX.
      • Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment and for at least 3 months after your final dose of DARZALEX. Talk to your healthcare provider about birth control methods that you can use during this time.
      • Before starting DARZALEX in combination with lenalidomide, pomalidomide, or thalidomide, females and males must agree to the instructions in the lenalidomide, pomalidomide, or thalidomide REMS program.
        • The lenalidomide, pomalidomide, and thalidomide REMS has more information about effective methods of birth control, pregnancy testing, and blood donation for females who can become pregnant.
        • For males who have female partners who can become pregnant, there is information in the lenalidomide, pomalidomide, and thalidomide REMS about sperm donation and how lenalidomide, pomalidomide, and thalidomide can pass into human semen.
    • are breastfeeding or plan to breastfeed. It is not known if DARZALEX passes into your breast milk.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    How will I receive DARZALEX?
    • DARZALEX may be given alone or together with other medicines used to treat multiple myeloma.
    • DARZALEX will be given to you by your healthcare provider by intravenous (IV) infusion into your vein.
    • Your healthcare provider will decide the time between doses as well as how many treatments you will receive.
    • Your healthcare provider will give you medicines before each dose of DARZALEX and after each dose of DARZALEX to help reduce the risk of infusion-related reactions.
    • If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
    What are the possible side effects of DARZALEX?
    DARZALEX may cause serious reactions, including:
    • Infusion-related reactions. Infusion-related reactions are common with DARZALEX and can be severe or serious. Your healthcare provider may temporarily stop your infusion or completely stop treatment with DARZALEX if you have infusion-related reactions. Get medical help right away if you get any of the following symptoms:
    • shortness of breath or trouble breathing
    • dizziness or lightheadedness (hypotension)
    • cough
    • wheezing
    • throat tightness
    • runny or stuffy nose
    • headache
    • itching
    • nausea
    • vomiting
    • chills
    • fever
    • Changes in blood tests. DARZALEX can affect the results of blood tests to match your blood type. These changes can last for up to 6 months after your final dose of DARZALEX. Your healthcare provider will do blood tests to match your blood type before you start treatment with DARZALEX. Tell all of your healthcare providers that you are being treated with DARZALEX before receiving blood transfusions.
    • Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Your healthcare provider will check your blood cell counts during treatment with DARZALEX. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.
    The most common side effects of DARZALEX include:
    • tiredness
    • nausea
    • diarrhea
    • shortness of breath
    • trouble sleeping
    • feeling weak
    • decreased appetite
    • fever
    • cough
    • muscle spasms
    • back pain
    • joint pain
    • vomiting
    • bronchitis
    • cold-like symptoms (upper respiratory infection)
    • nerve damage causing tingling, numbness or pain
    • swollen hands ankles or feet
    • constipation
    • chills
    • dizziness
    • lung infection (pneumonia)
    Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of DARZALEX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
    General information about the safe and effective use of DARZALEX
    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about DARZALEX that is written for health professionals.
    What are the ingredients in DARZALEX?
    Active ingredient:
    daratumumab
    Inactive ingredients: glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, sodium chloride, and water for injection
    Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044 U.S. License Number 1864
    For more information, call 1-800-526-7736 or go to www.DARZALEX.com.
  • PRINCIPAL DISPLAY PANEL - 100 mg/5 mL Vial Carton

    NDC 57894-502-05
    Rx only

    DARZALEX®
    (daratumumab)
    Injection
    100 mg/5 mL
    (20 mg/mL)

    For Intravenous Infusion Only
    Dilute Before Use
    Single-Dose Only. Discard Unused
    Portion

    janssen

    PRINCIPAL DISPLAY PANEL - 100 mg/5 mL Vial Carton
  • INGREDIENTS AND APPEARANCE
    DARZALEX 
    daratumumab injection, solution, concentrate
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:57894-502
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    Daratumumab (UNII: 4Z63YK6E0E) (Daratumumab - UNII:4Z63YK6E0E) Daratumumab100 mg  in 5 mL
    Inactive Ingredients
    Ingredient NameStrength
    sodium acetate (UNII: 4550K0SC9B)  
    sodium chloride (UNII: 451W47IQ8X)  
    mannitol (UNII: 3OWL53L36A)  
    polysorbate 20 (UNII: 7T1F30V5YH)  
    water (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:57894-502-051 in 1 CARTON11/16/2015
    15 mL in 1 VIAL; Type 0: Not a Combination Product
    2NDC:57894-502-201 in 1 CARTON11/16/2015
    220 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA76103611/16/2015
    Labeler - Janssen Biotech, Inc. (099091753)
    Establishment
    NameAddressID/FEIBusiness Operations
    Cilag AG483237103MANUFACTURE(57894-502) , ANALYSIS(57894-502) , PACK(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Vetter Pharma Fertigung GmbH & Co. KG312670654MANUFACTURE(57894-502) , ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Janssen Biologics B.V.409612918ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Janssen Biotech, Inc.038978363ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    PharmAssist, Inc.883068306ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Vetter Pharma Fertigung GmbH & Co. KG344217323ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Vetter Pharma Fertigung GmbH & Co. KG316126754ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Vetter Pharma Fertigung GmbH & Co. KG341629292ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Janssen Sciences Ireland UC986030167ANALYSIS(57894-502) , API MANUFACTURE(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    PPD Development Ireland Ltd.985036175ANALYSIS(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    AndersonBrecon, Inc.053217022PACK(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Biogen, MA Inc.841087823API MANUFACTURE(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Samsung Biologics Co, LTD557810567API MANUFACTURE(57894-502)
    Establishment
    NameAddressID/FEIBusiness Operations
    Baxter Pharmaceutical Solutions, LLC604719430MANUFACTURE(57894-502)