DARZALEX

Daratumumab is an immunoglobulin

G1 kappa monoclonal antibody developed by Janssen and Genmab.

It was first described in the literature in as a monoclonal antibody that targets CD38+ multiple myeloma cells; the first of its kind.

Daratumumab was granted

FDA approval on 16 November 2015.

It is approved for the treatment of multiple myeloma as monotherapy or combination therapy and light chain (AL) amyloidosis in combination with other drugs. 6, 7 A subcutaneous formulation of daratumumab co-formulated with hyaluronidase-fihj is also approved for the treatment of adults with multiple myeloma.

In July 2024, it was further approved in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) for induction and consolidation therapy in newly diagnosed, transplant-eligible patients.

This approval was based on results from the Phase 3 PERSEUS study, which demonstrated significant improvement in progression-free survival and higher rates of minimal residual disease (MRD) negativity compared to standard VRd therapy. 8.

Most recently, in November 2025, the subcutaneous formulation received approval as a monotherapy for the treatment of adult patients with high-risk smoldering multiple myeloma.

Daratumumab is indicated as an intravenous injection, alone or in combination with other medications, for the treatment of multiple myeloma.

Daratumumab is also approved for subcutaneous administration in combination with hyaluronidase (human recombinant) for the treatment of adults with multiple myeloma (as monotherapy or in combination), light chain (AL) amyloidosis (in combination), and high-risk smoldering multiple myeloma (as monotherapy). 7, 8, 9 "

Daratumumab is a monoclonal antibody that targets and induces apoptosis in cells that highly express CD38, including multiple myeloma cells. 6, 7 It has a long duration of action as it is given every 1-4 weeks. 6, 7 Patients should be counselled regarding the risk of hypersensitivity, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interferences with cross-matching and red blood cell antibody screening. 6, 7.

Subcutaneous daratumumab reaches a

C max of 592 µg/mL compared to intravenous daratumumab, which reaches a C max of 688 µg/mL.

AUC of subcutaneous daratumumab is 4017 µg/mLday compared to intravenous daratumumab, which has an AUC of 4019 µg/mLday.

Daratumumab intravenous monotherapy has a volume of distribution of 4.7 ± 1.3 L and the combination therapy has a volume of distribution of 4.4 ± 1.5 L.

Subcutaneous daratumumab has a volume of distribution of the central compartment of 5.2 L and a volume of distribution of the peripheral compartment of 3.8 L.

Monoclonal antibodies are expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes.

Monoclonal antibodies are metabolized to amino acids used for synthesis of new proteins or are eliminated by the kidneys.

Intravenous daratumumab has a terminal half life of 18 ± 9 days.

Subcutaneous daratumumab has a half life of 20 days.

Intravenous daratumumab has a clearance of 171.4 ± 95.3 mL/day.

Subcutaneous daratumumab has a clearance of 119 mL/day.

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Data regarding overdoses of daratumumab are not readily available. 6, 7 Patients should be treated with symptomatic and supportive measures. 6, 7.

is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

Patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

For subcutaneous use only.

Pre-medicate with a corticosteroid, acetaminophen and a histamine-1 receptor antagonist.

The recommended dosage of DARZALEX

FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately to 5 minutes according to recommended schedule.

Administer post-medications as recommended. 2.1 Important Dosing Information DARZALEX FASPRO is for subcutaneous use only.

Administer medications before and after administration of DARZALEX FASPRO to minimize administration-related reactions.

Type and screen patients prior to starting DARZALEX FASPRO. 2.2 Recommended Dosage for Multiple Myeloma The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately to 5 minutes.

Tables 1, 2, 3, 4, 5, and 6 provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of a combination therapy.

Monotherapy and In Combination with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd), Pomalidomide and Dexamethasone (DARZALEX FASPRO-Pd) or Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) Use the dosing schedule provided in Table 1 when DARZALEX FASPRO is administered: in combination with lenalidomide and dexamethasone (4-week cycle) OR in combination with pomalidomide and dexamethasone (4-week cycle) OR in combination with carfilzomib and dexamethasone (4-week cycle) OR as monotherapy.

Table 1: DARZALEX FASPRO dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) and for monotherapy Weeks Schedule Weeks to 8 weekly (total of 8 doses) Weeks to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies 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 to 6 weekly (total of 6 doses) Weeks to 54 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 16 doses) Week 55 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 55 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies and the prescribing information for dosage recommendations for the other drugs.

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 to 8 weekly (total of 8 doses) Weeks to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs.

Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Eligible for Autologous Stem Cell Transplant (ASCT) Use the dosing schedule in Table 4 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT.

Table 4: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle) Treatment phase Weeks Schedule Induction Weeks to 8 weekly (total of 8 doses) Weeks to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies and the prescribing information for dosage recommendations for the other drugs.

Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Who Are Ineligible for ASCT Use the dosing schedule in Table 5 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (3-week cycle) for treatment of newly diagnosed multiple myeloma patients who are ineligible for ASCT.

Table 5: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (3-week cycle) Weeks Schedule Weeks to 6 weekly (total of 6 doses) Weeks to 24 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 6 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies and the prescribing information for dosage recommendations for the other drugs.

In Combination with Bortezomib and

Dexamethasone (DARZALEX FASPRO-Vd) Use the dosing schedule in Table 6 when DARZALEX FASPRO is administered in combination with bortezomib and dexamethasone (3-week cycle).

Table 6: DARZALEX FASPRO dosing schedule in combination with bortezomib and dexamethasone (3-week cycle) Weeks Schedule Weeks to 9 weekly (total of 9 doses) Weeks to 24 First dose of the every-3-week dosing schedule is given at Week 10 every three weeks (total of 5 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. 2.3 Recommended Dosage for High-Risk Smoldering Multiple Myeloma The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately to 5 minutes.

Use the dosing schedule provided in

Table 7 when DARZALEX FASPRO is administered as monotherapy in high-risk smoldering multiple myeloma patients (4-week cycle).

Table 7: DARZALEX FASPRO dosing schedule for monotherapy (4-week cycle) Weeks Schedule Weeks to 8 weekly (total of 8 doses) Weeks 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 to 5 minutes.

Table 8 when DARZALEX FASPRO is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).

Table 8: DARZALEX FASPRO dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle) Weeks Schedule Weeks to 8 weekly (total of 8 doses) Weeks to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progression or a maximum of 2 years First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies and the prescribing information for dosage recommendations for the other drugs. 2.5 Missed DARZALEX FASPRO Doses If a dose of DARZALEX FASPRO is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval. 2.6 Recommended Concomitant Medications Pre-medication Administer the following pre-medications to 3 hours before each dose of DARZALEX FASPRO: Acetaminophen 650 mg to 1,000 mg orally Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously Corticosteroid (long - or intermediate-acting) Monotherapy Administer methylprednisolone 100 mg (or equivalent) orally or intravenously.

Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO.

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.

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.

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.

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.

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. 2.7 Dosage Modifications for Adverse Reactions No dose reductions of DARZALEX FASPRO are recommended.

Consider withholding DARZALEX

FASPRO to allow recovery of blood cell counts in the event of myelosuppression. 2.8 Preparation and Administration DARZALEX FASPRO should be administered by a healthcare provider.

To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DA.

® (daratumumab and hyaluronidase-fihj) injection is a sterile, preservative-free, colorless to yellow, and clear to opalescent solution for subcutaneous use supplied as individually packaged single-dose vials providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase per 15 mL (NDC 57894-503-01).

FASPRO vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light.

Do not freeze or shake.

FASPRO vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light.

Do not freeze or shake.

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.

There are no available data on the use of DARZALEX FASPRO in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Animal reproduction studies have not been conducted.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The combination of DARZALEX

FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child.

Lenalidomide, thalidomide and pomalidomide are only available through a REMS program.

Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.

Fetal/Neonatal Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta.

Based on its mechanism of action, DARZALEX FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density.

Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed.

FASPRO for subcutaneous injection contains daratumumab and hyaluronidase.

Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age.

Data from studies using

CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).

No systemic exposure of hyaluronidase was detected in monkeys given 220,000 U/kg subcutaneously (440 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 360,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 720 times higher than the human dose.

There were no effects on pre.

• and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 1,100,000 U/kg hyaluronidase subcutaneously, which is 2,200 times higher than the human doses.

Safety and effectiveness of DARZALEX

FASPRO in pediatric patients have not been established.

Of the 291 patients who received DARZALEX FASPRO as monotherapy for relapsed and refractory multiple myeloma, 37% were to <75 years of age, and 19% were 75 years of age and older.

No overall differences in effectiveness of DARZALEX FASPRO have been observed between patients ≥65 years of age and younger patients.

Adverse reactions that occurred at a higher frequency (≥5% difference) in patients ≥65 years of age included upper respiratory tract infection, urinary tract infection, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema.

Serious adverse reactions that occurred at a higher frequency (≥2% difference) in patients ≥65 years of age included pneumonia.

Of the 214 patients who received DARZALEX FASPRO as combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO as combination therapy with lenalidomide and low-dose dexamethasone for relapsed and refractory multiple myeloma, 43% were to <75 years of age, and 18% were 75 years of age and older.

No overall differences in effectiveness were observed between patients ≥65 years (n=131) and <65 years (n=85).

Adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥65 years of age included fatigue, pyrexia, peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia.

Serious adverse reactions occurring at a higher frequency (≥2% difference) in patients ≥65 years of age included neutropenia, thrombocytopenia, diarrhea, anemia, COVID-19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary tract infection.

Of the 355 patients who were newly diagnosed with multiple myeloma and eligible for ASCT who received DARZALEX FASPRO as combination therapy with bortezomib, lenalidomide and dexamethasone during induction and consolidation in the clinical trial, 74% were <65 years of age, and 26% were to 70 years of age.

The clinical trial did not enroll patients older than 70 years of age.

No overall differences in effectiveness of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone were observed between patients <65 years of age compared to patients to 70 years of age.

Adverse reactions that occurred at a higher frequency (≥5% difference) in patients to 70 years of age included constipation, hemorrhoids, nausea, injection site erythema, bronchitis, nasopharyngitis, back pain, myalgia, pain in extremity, dysgeusia, peripheral motor neuropathy, and insomnia.

Serious adverse reactions that occurred at a higher frequency (≥2% difference) in patients to 70 years of age included febrile bone marrow aplasia, atrial fibrillation, pyrexia, and orthostatic hypotension.

Of the 197 patients with newly diagnosed multiple myeloma in CEPHEUS who received DARZALEX FASPRO as combination therapy with bortezomib, lenalidomide and dexamethasone, 61% were to <75 years of age, and 21% were 75 years of age and older.

The clinical trial did not enroll patients over age 80.

No overall differences in effectiveness of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone were observed between younger patients and patients ≥75 years.

Adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥75 years of age included sensory neuropathy, diarrhea, fatigue, constipation, renal impairment, dizziness, pyrexia, rash, dyspnea, fracture, arrhythmia, decreased appetite, urinary tract infection, injection site reaction, encephalopathy, vomiting, taste disorder, and herpes.

Serious adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥75 years of age included urinary tract infection, upper respiratory tract infection, diarrhea, and encephalopathy.

Of the 193 patients who received DARZALEX FASPRO as monotherapy for high-risk smoldering multiple myeloma, 35% (n=67) were to <75 years of age, and 11% (n=21) were 75 years of age and older.

No overall difference in effectiveness were observed between patients to 75 years (n=67) and <65 years (n=105); there were too few patients 75 years of age and older to assess for a difference in effectiveness.

Adverse reactions that occurred at a higher frequency (≥5% difference) in patients ≥65 years of age were pneumonia, dizziness, arrhythmia, hemorrhage, arthritis, and cataract.

Serious adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥65 years of age included pneumonia and fracture.

Of the 193 patients who received DARZALEX FASPRO as part of a combination therapy for light chain (AL) amyloidosis, 35% were to <75 years of age, and 10% were 75 years of age and older.

Clinical studies of DARZALEX

FASPRO as part of a combination therapy for patients with light chain (AL) amyloidosis did not include sufficient numbers of patients aged and older to determine whether effectiveness differs from that of younger patients.

Adverse reactions that occurred at a higher frequency in patients ≥65 years of age were peripheral edema, asthenia, pneumonia and hypotension.

No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients.