Darzalex

DARZALEX is indicated for the treatment of adult patients with multiple myeloma:

• in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
• in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.
• in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant.
• in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.
• in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.
• in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
• as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

• Pre-medicate with corticosteroids, antipyretics and antihistamines. (
  
  
  2.3 Recommended Concomitant Medications

  Pre-infusion Medication

  Administer the following pre-infusion medications 1 hour to 3 hours before every DARZALEX infusion:

  • Corticosteroid (long- or intermediate-acting)

  Monotherapy:

  Administer methylprednisolone 100 mg (or equivalent) intravenously. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally or intravenously.
  
  

  In Combination:

  
  
  Administer dexamethasone 20 mg (or equivalent) orally or intravenously.
  
  When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days

  [see Clinical Studies (14)].

  
  
  Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as a pre-medication.

  • Acetaminophen 650 mg to 1,000 mg orally
  • Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously.

  Post-infusion Medication

  Administer the following post-infusion medications:

  • Monotherapy:
    
    
    Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX.
    
    
    In Combination:
    
    
    Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of a DARZALEX infusion.
    
    If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed
    [see Clinical Studies (14)].

  For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major infusion-related reaction.

  Prophylaxis for Herpes Zoster Reactivation

  Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following the end of treatment

  [see Adverse Reactions (6.1)].
  )
  
• Dilute and administer as an intravenous infusion. (
  
  
  2.5 Preparation and Administration

  Preparation

  DARZALEX is for single dose only.

  Prepare the solution for infusion using aseptic technique as follows:

  • Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.
  • DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag
    [see Description (11), How Supplied/Storage and Handling (16)]
    .
  • Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
  • Remove a volume of 0.9% Sodium Chloride Injection from the infusion bag/container that is equal to the required volume of DARZALEX solution.
  • Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection as specified in Table 6
    [see Dosage and Administration (2.2)]
    . Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
  • Gently invert the bag/container to mix the solution. Do not shake.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
  • If not used immediately, store the diluted solution refrigerated for up to 24 hours at 2°C to 8°C (36°F to 46°F) and/or at room temperature up to 15 hours at 15°C to 25°C (59°F to 77°F). The room temperature storage includes infusion time. Protect from light during storage. Do not freeze.

  Administration

  • If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 micrometer or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.
  • Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.
  • Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
  )
  
• Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule. (
  
  
  2.2 Recommended Dosage

  Monotherapy and In Combination with Lenalidomide (D-Rd) or Pomalidomide (D-Pd) and Dexamethasone

  The DARZALEX dosing schedule in Table 1 is for combination therapy (4-week cycle regimens) and monotherapy as follows:

  - combination therapy with lenalidomide and low-dose dexamethasone for newly diagnosed patients ineligible for autologous stem cell transplant (ASCT) and in patients with relapsed/refractory multiple myeloma

  - combination therapy with pomalidomide and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma

  - monotherapy for patients with relapsed/refractory multiple myeloma.

  The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:

  Table 1: DARZALEX Dosing Schedule in Combination With Lenalidomide or Pomalidomide (4-Week Cycle) and Low-Dose Dexamethasone and for Monotherapy

  Weeks	Schedule
  Weeks 1 to 8	weekly (total of 8 doses)
  Weeks 9 to 24First dose of the every-2-week dosing schedule is given at Week 9	every two weeks (total of 8 doses)
  Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25	every four weeks

  For dosing instructions of combination agents administered with DARZALEX,

  see Clinical Studies (14)

  and manufacturer's prescribing information.

  In Combination with Bortezomib, Melphalan and Prednisone (D-VMP)

  The DARZALEX dosing schedule in Table 2 is for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma ineligible for ASCT.

  The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:

  Table 2: DARZALEX Dosing Schedule in Combination With Bortezomib, Melphalan and Prednisone ([VMP], 6-Week Cycle)

  Weeks	Schedule
  Weeks 1 to 6	weekly (total of 6 doses)
  Weeks 7 to 54First dose of the every-3-week dosing schedule is given at Week 7	every three weeks (total of 16 doses)
  Week 55 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 55	every four weeks

  For dosing instructions of combination agents administered with DARZALEX

  see Clinical Studies (14.1).

  In Combination with Bortezomib, Thalidomide and Dexamethasone (D-VTd)

  The DARZALEX dosing schedule in Table 3 is for combination therapy with bortezomib, thalidomide, and dexamethasone (4-week cycle regimen) for patients with newly diagnosed multiple myeloma eligible for ASCT.

  The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:

  Table 3: DARZALEX Dosing Schedule in Combination With Bortezomib, Thalidomide and Dexamethasone ([VTd]; 4-Week Cycle)

  Treatment phase	Weeks	Schedule
  Induction	Weeks 1 to 8	weekly (total of 8 doses)
  	Weeks 9 to 16First dose of the every-2-week dosing schedule is given at Week 9	every two weeks (total of 4 doses)
  Stop for high dose chemotherapy and ASCT
  Consolidation	Weeks 1 to 8First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT	every two weeks (total of 4 doses)

  For dosing instructions of combination agents administered with DARZALEX,

  see Clinical Studies (14.1)

  and the manufacturer's prescribing information.

  In Combination with Bortezomib and Dexamethasone (D-Vd)

  The DARZALEX dosing schedule in Table 4 is for combination therapy with bortezomib and dexamethasone (3-week cycle) for patients with relapsed/refractory multiple myeloma.

  The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:

  Table 4: DARZALEX Dosing Schedule With Bortezomib and Dexamethasone (3-Week Cycle)

  Weeks	Schedule
  Weeks 1 to 9	weekly (total of 9 doses)
  Weeks 10 to 24First dose of the every-3-week dosing schedule is given at Week 10	every three weeks (total of 5 doses)
  Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25	every four weeks

  For dosing instructions of combination agents administered with DARZALEX

  see Clinical Studies (14.2)

  and manufacturer's prescribing information

  .

  In Combination with Carfilzomib and Dexamethasone (DKd)

  The recommended dosage for DARZALEX when administered in combination with carfilzomib and dexamethasone (4-week cycle) for patients with relapsed/refractory multiple myeloma is provided in Table 5.

  Table 5: DARZALEX Dosing Schedule With Carfilzomib and Dexamethasone (4-Week Cycle)

  Weeks	DARZALEX DoseBased on actual body weight	Schedule
  Week 1	8 mg/kg	days 1 and 2 (total 2 doses)
  Weeks 2 to 8	16 mg/kg	weekly (total of 7 doses)
  Weeks 9 to 24First dose of the every-2-week dosing schedule is given at Week 9	16 mg/kg	every two weeks (total of 8 doses)
  Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25	16 mg/kg	every four weeks

  For dosing instructions of combination agents administered with DARZALEX

  see Clinical Studies (14.2)

  and manufacturer's prescribing information

  .

  Infusion Rates

  Administer DARZALEX intravenously at the infusion rate described below in Table 6. Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions.

  The recommended dose of 16 mg/kg to be administered on Day 1 when DARZALEX is administered as monotherapy or in combination may be split over two consecutive days, such that an 8 mg/kg dose is administered on Day 1 and Day 2, respectively.

  Table 6: Infusion Rates for DARZALEX (16 mg/kg) Administration

  	Dilution volume	Initial rate (first hour)	Rate incrementConsider incremental escalation of the infusion rate only in the absence of infusion-related reactions.	Maximum rate
  Week 1 Infusion
  Option 1 (Single dose infusion)
  Week 1 Day 1 (16 mg/kg)	1,000 mL	50 mL/hour	50 mL/hour every hour	200 mL/hour
  Option 2 (Split dose infusion)
  Week 1 Day 1 (8 mg/kg)	500 mL	50 mL/hour	50 mL/hour every hour	200 mL/hour
  Week 1 Day 2 (8 mg/kg)	500 mL	50 mL/hour	50 mL/hour every hour	200 mL/hour
  Week 2 (16 mg/kg) Use a dilution volume of 500 mL for the 16 mg/kg dose only if there were no infusion-related reactions the previous week. Otherwise, use a dilution volume of 1,000 mL.	500 mL	50 mL/hour	50 mL/hour every hour	200 mL/hour
  Week 3 onwards (16 mg/kg) Use a modified initial rate (100 mL/hour) for subsequent infusions (i.e. Week 3 onwards) only if there were no infusion-related reactions during the previous infusion. Otherwise, continue to use instructions indicated in the table for the Week 2 infusion rate.	500 mL	100 mL/hour	50 mL/hour every hour	200 mL/hour

  Missed DARZALEX Doses

  If a dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.
  )
  
• Administer post-infusion medications. (
  
  
  2.3 Recommended Concomitant Medications

  Pre-infusion Medication

  Administer the following pre-infusion medications 1 hour to 3 hours before every DARZALEX infusion:

  • Corticosteroid (long- or intermediate-acting)

  Monotherapy:

  Administer methylprednisolone 100 mg (or equivalent) intravenously. Following the second infusion, consider reducing the dose to 60 mg (or equivalent) administered either orally or intravenously.
  
  

  In Combination:

  
  
  Administer dexamethasone 20 mg (or equivalent) orally or intravenously.
  
  When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days

  [see Clinical Studies (14)].

  
  
  Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as a pre-medication.

  • Acetaminophen 650 mg to 1,000 mg orally
  • Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously.

  Post-infusion Medication

  Administer the following post-infusion medications:

  • Monotherapy:
    
    
    Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX.
    
    
    In Combination:
    
    
    Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of a DARZALEX infusion.
    
    If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed
    [see Clinical Studies (14)].

  For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major infusion-related reaction.

  Prophylaxis for Herpes Zoster Reactivation

  Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following the end of treatment

  [see Adverse Reactions (6.1)].
  )
  

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.

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

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.

• 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 Dosage Modifications for Adverse Reactions

  No dose reductions of DARZALEX are recommended. Consider withholding DARZALEX to allow recovery of blood cell counts in the event of myelosuppression

  [see Warnings and Precautions (5.3, 5.4)]

  .

  For information concerning drugs given in combination with DARZALEX, see manufacturer's prescribing information.

  Infusion-Related Reactions

  For infusion-related reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion-related reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below

  [see Warnings and Precautions (5.1)]

  .

  • Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6).
  • Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion-related reaction.
  • Grade 4 (life-threatening): Permanently discontinue DARZALEX.
  ,
  
  
  5.1 Infusion-Related Reactions

  DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported

  [see Adverse Reactions (6.2)]

  .

  In clinical trials (monotherapy and combination: N=2,066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). The incidence of infusion modification due to reactions was 36%. Median durations of 16 mg/kg infusions for the Week 1, Week 2, and subsequent infusions were approximately 7, 4, and 3 hours respectively. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion-related reactions occurred up to 48 hours after infusion.

  Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision

  [see Adverse Reactions (6.1)]

  .

  When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption for ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions.

  In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 hours for Week 1-Day 1, 4.2 hours for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

  Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion

  [see Dosage and Administration (2.3)]

  . Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion

  [see Dosage and Administration (2.4)]

  .

  To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions

  [see Dosage and Administration (2.3)]

  . Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease

  [see Dosage and Administration (2.3)]

  .

  Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.
  )
  
• 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 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)]

  .
  ,
  
  
  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.
  )
  
• 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 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.
  )
  
• Thrombocytopenia
  : Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets. (
  
  
  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.
  )
  
• 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 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.
  ,
  
  
  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).
  ,
  
  
  8.3 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.
  )