Darzalex Faspro

DARZALEX FASPRO is a combination of daratumumab, a CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with:

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

• DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials (
  1.3 Light Chain Amyloidosis

  DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis.

  Limitations of Use

  DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials

  [see Warnings and Precautions (5.2)]

  .
  )

• Pre-medicate with a corticosteroid, acetaminophen and a histamine-1 receptor antagonist. (
  2.6 Recommended Concomitant Medications

  Pre-medication

  Administer the following pre-medications 1–3 hours before each dose of DARZALEX FASPRO:

  • Acetaminophen 650 mg to 1,000 mg orally
  • Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously
  • Corticosteroid (long- or intermediate-acting)
    • Monotherapy
    • Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO.
    • In Combination
    • Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO administration.
    • When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX FASPRO administration days
      [see Clinical Studies (14)]
      .
    • Do not administer background regimen-specific corticosteroids (e.g., prednisone) on DARZALEX FASPRO administration days when patients have received dexamethasone (or equivalent) as a pre-medication.

  Post-medication

  Administer the following post-medications:

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

  If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).

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

  Prophylaxis for Herpes Zoster Reactivation

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

  [see Adverse Reactions (6.1)].
  )
• The recommended dosage of DARZALEX FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to recommended schedule. (
  2.2 Recommended Dosage for Multiple Myeloma

  The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Tables 1, 2, 3, 4, and 5 provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of a combination therapy.

  Monotherapy and In Combination with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd), Pomalidomide and Dexamethasone (DARZALEX FASPRO-Pd) or Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd)

  Use the dosing schedule provided in Table 1 when DARZALEX FASPRO is administered:

  • in combination with lenalidomide and dexamethasone (4-week cycle) OR
  • in combination with pomalidomide and dexamethasone (4-week cycle) OR
  • in combination with carfilzomib and dexamethasone (4-week cycle) OR
  • as monotherapy.

  Table 1: DARZALEX FASPRO dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) and for monotherapy

  Weeks	Schedule
  Weeks 1 to 8	weekly (total of 8 doses)
  Weeks 9 to 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

  When DARZALEX FASPRO is administered as part of a combination therapy,

  see Clinical Studies (14.2)

  and the prescribing information for dosage recommendations for the other drugs.

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

  Use the dosing schedule provided in Table 2 when DARZALEX FASPRO is administered in combination with bortezomib, melphalan and prednisone (6-week cycle).

  Table 2: DARZALEX FASPRO dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle)

  Weeks	Schedule
  Weeks 1 to 6	weekly (total of 6 doses)
  Weeks 7 to 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

  When DARZALEX FASPRO is administered as part of a combination therapy,

  see Clinical Studies (14.1)

  and the prescribing information for dosage recommendations for the other drugs.

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

  Use the dosing schedule in Table 3 when DARZALEX FASPRO is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle).

  Table 3: DARZALEX FASPRO dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle)

  Treatment phase	Weeks	Schedule
  Induction	Weeks 1 to 8	weekly (total of 8 doses)
  	Weeks 9 to 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)

  When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs.

  In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd)

  Use the dosing schedule in Table 4 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for autologous stem cell transplant (ASCT).

  Table 4: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle)

  Treatment phase	Weeks	Schedule
  Induction	Weeks 1 to 8	weekly (total of 8 doses)
  	Weeks 9 to 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)

  When DARZALEX FASPRO is administered as part of a combination therapy,

  see Clinical Studies (14.1)

  and the prescribing information for dosage recommendations for the other drugs.

  In Combination with Bortezomib and Dexamethasone (DARZALEX FASPRO-Vd)

  Use the dosing schedule in Table 5 when DARZALEX FASPRO is administered in combination with bortezomib and dexamethasone (3-week cycle).

  Table 5: DARZALEX FASPRO dosing schedule in combination with bortezomib and dexamethasone (3-week cycle)

  Weeks	Schedule
  Weeks 1 to 9	weekly (total of 9 doses)
  Weeks 10 to 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

  When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs.
  ,
  2.3 Recommended Dosage for High-Risk Smoldering Multiple Myeloma

  The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes.

  Use the dosing schedule provided in Table 6 when DARZALEX FASPRO is administered as monotherapy in high-risk smoldering multiple myeloma patients (4-week cycle).

  Table 6: DARZALEX FASPRO dosing schedule for monotherapy (4-week cycle)

  Weeks	Schedule
  Weeks 1 to 8	weekly (total of 8 doses)
  Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9	every two weeks (total of 8 doses)
  Week 25 onwards until diagnosis of multiple myeloma or a maximum of 3 years First dose of the every-4-week dosing schedule is given at Week 25	every four weeks
  ,
  2.4 Recommended Dosage for Light Chain Amyloidosis

  In Combination with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd)

  The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes.

  Use the dosing schedule provided in Table 7 when DARZALEX FASPRO is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).

  Table 7: DARZALEX FASPRO dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle)

  Weeks	Schedule
  Weeks 1 to 8	weekly (total of 8 doses)
  Weeks 9 to 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 progression or a maximum of 2 yearsFirst dose of the every-4-week dosing schedule is given at Week 25	every four weeks

  When DARZALEX FASPRO is administered as part of a combination therapy,

  see Clinical Studies (14.4)

  and the prescribing information for dosage recommendations for the other drugs.
  )
• Administer post-medications as recommended. (
  2.6 Recommended Concomitant Medications

  Pre-medication

  Administer the following pre-medications 1–3 hours before each dose of DARZALEX FASPRO:

  • Acetaminophen 650 mg to 1,000 mg orally
  • Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously
  • Corticosteroid (long- or intermediate-acting)
    • Monotherapy
    • Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO.
    • In Combination
    • Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO administration.
    • When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX FASPRO administration days
      [see Clinical Studies (14)]
      .
    • Do not administer background regimen-specific corticosteroids (e.g., prednisone) on DARZALEX FASPRO administration days when patients have received dexamethasone (or equivalent) as a pre-medication.

  Post-medication

  Administer the following post-medications:

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

  If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).

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

  Prophylaxis for Herpes Zoster Reactivation

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

  [see Adverse Reactions (6.1)].
  )

Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units/mL) colorless to yellow and clear to opalescent solution in a single-dose vial.

DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models

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 FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available through a REMS program. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.

Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab

DARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase

No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose.

There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.