New TALVEY® (talquetamab-tgvs) plus DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) data demonstrate the strength of a bispecific combination in earlier-line relapsed or refractory multiple myeloma

Because of the risk of CRS and neurologic toxicity, including ICANS, TALVEY is available only through a restricted program called the TECVAYLI and TALVEY Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE

TALVEY is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing Information

Administer TALVEY subcutaneously according to the step-up dosing schedule in Tables 1 and 2 to reduce the incidence and severity of cytokine release syndrome (CRS) [see Dosage and Administration (2.2)].

Administer pretreatment medications prior to each dose of TALVEY in the step-up dosing schedule as recommended [see Dosage and Administration (2.2, 2.3)].

TALVEY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Warnings and Precautions (5.1, 5.2)].

Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of all doses within the TALVEY step-up dosing schedule [see Dosage and Administration (2.5) and Warnings and Precautions (5.1, 5.2)].

2.2 Recommended Dosage

For subcutaneous injection.

Administer pretreatment medications prior to each dose of TALVEY in the step-up dosing schedule [see Dosage and Administration (2.3)].

Administer TALVEY subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2. Continue treatment until disease progression or unacceptable toxicity.

Table 1: TALVEY Weekly Dosing Schedule

^a Based on actual body weight.

^b Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions.

^c Maintain a minimum of 6 days between weekly doses.

Table 2: TALVEY Biweekly (Every 2 Weeks) Dosing Schedule

^a Based on actual body weight.

^b Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions.

^c Dose may be administered between 2 to 7 days after step-up dose 3.

^d Maintain a minimum of 12 days between biweekly (every 2 weeks) doses.

2.3 Recommended Pretreatment Medications

Administer the following pretreatment medications 1 to 3 hours before each dose of TALVEY in the step-up dosing schedule to reduce the risk of CRS [see Warnings and Precautions (5.1)].

• Corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent)

• Antihistamines (oral or intravenous diphenhydramine, 50 mg or equivalent)

• Antipyretics (oral or intravenous acetaminophen, 650 mg to 1,000 mg or equivalent)

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Administration of pretreatment medications may be required for subsequent doses for patients who repeat doses within the TALVEY step-up dosing schedule due to dose delays (see Table 3 or Table 4) or for patients who experienced CRS (see Table 5).

2.4 Dosage Delays

If a dose of TALVEY is delayed, restart therapy based on the recommendations in Table 3 and Table 4 and resume weekly or biweekly (every 2 weeks) dosing schedule accordingly [see Dosage and Administration (2.1)]; if a dose is delayed by more than 28 days for an adverse reaction, evaluate the benefit-risk of restarting TALVEY. Administer pretreatment medications prior to restarting TALVEY and monitor patients following administration of TALVEY [see Dosage and Administration (2.2)].

Table 3: Recommendations for Restarting TALVEY after Dose Delay – Weekly Dosing Schedule

1 (0.01 mg/kg). * Administer pretreatment medications prior to restarting TALVEY. After restarting TALVEY, resume weekly dosing schedule accordingly [see Dosage and Administration (2.2)].

Table 4: Recommendations for Restarting TALVEY after Dose Delay – Biweekly (Every 2 Weeks) Dosing Schedule

^* Administer pretreatment medications prior to restarting TALVEY. After 1 (0.01 mg/kg). restarting TALVEY, resume biweekly (every 2 weeks) dosing schedule accordingly [see Dosage and Administration (2.2)].

2.5 Dosage Modifications for Adverse Reactions

Dose delays may be required to manage toxicities related to TALVEY [see Warnings and Precautions (5)].

See Table 5, Table 6, and Table 7 for recommended actions for the management of CRS, ICANS, and neurologic toxicity. See Table 8 for recommended dose modifications for other adverse reactions.

Cytokine Release Syndrome (CRS)

Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold TALVEY until CRS resolves or permanently discontinue based on severity, manage according to the recommendations in Table 5, consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.

Table 5: Recommendations for Management of CRS

^a Based on American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS (Lee et al 2019).

^b Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anticytokine therapy (e.g., corticosteroids).

^c See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)].

^d Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.

Neurologic Toxicity, including ICANS

At the first sign of neurologic toxicity, including ICANS, withhold TALVEY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS [see Warnings and Precautions (5.2)]. Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and Table 7 and consider further management per current practice guidelines.

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Table 6: Recommendations for Management of ICANS

Table 6: Recommendations for Management of ICANS (continued) Grade Presenting Symptoms Actions

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Table 6: Recommendations for Management of ICANS (continued)

^a Based on ASTCT 2019 grading for ICANS.

^b Management is determined by the most severe event, not attributable to any other cause.

^c If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

^d Attributable to no other cause.

^e See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)].

^f All references to dexamethasone administration are dexamethasone or equivalent.

Table 7: Recommendations for Management of Neurologic Toxicity (excluding ICANS)

^a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

^b See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)].

^c For ataxia/balance disorder, perform benefit risk assessment prior to resuming treatment with TALVEY.

Other Adverse Reactions

The recommended dose modifications for other adverse reactions are provided in Table 8.

Table 8: Recommended Dose Modifications for Other Adverse Reactions Adverse Severity Dose Modification

^a See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)].

^b For Grade 3 or 4 infection, if TALVEY is withheld for more than 28 days, restart

^c step-up dosing when infection improves to Grade 1 or better. Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.

2.6 Preparation and Administration

Administer TALVEY via subcutaneous injection by a healthcare provider.

TALVEY should be administered by a healthcare provider with adequate medical personnel and appropriate medical equipment to manage severe reactions, including CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1, 5.2)].

TALVEY 3 mg/1.5 mL (2 mg/mL) vial and TALVEY 40 mg/mL vial are supplied as ready-to-use solution for injection that do not need dilution prior to administration. Do not combine TALVEY vials of different concentrations to achieve treatment dose. Use aseptic technique to prepare and administer TALVEY.

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Preparation

Refer to the following reference tables for the preparation of TALVEY.

° Use Table 9 to determine total dose, injection volume, and number of vials required based on patient’s actual body weight for the 0.01 mg/kg dose using TALVEY 3 mg/1.5 mL (2 mg/mL) vial.

Table 9: 0.01 mg/kg Dose: Injection Volumes using TALVEY 3 mg/1.5 mL (2 mg/mL)

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: 2/2026

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FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

1.2 High-Risk Smoldering Multiple Myeloma

1.3 Light Chain Amyloidosis

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing Information

2.2 Recommended Dosage for Multiple Myeloma

2.3 Recommended Dosage for High-Risk Smoldering Multiple Myeloma

2.4 Recommended Dosage for Light Chain Amyloidosis

2.5 Missed DARZALEX FASPRO Doses

2.6 Recommended Concomitant Medications

2.7 Dosage Modifications for Adverse Reactions 2.8 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity and Other Administration Reactions

5.2 Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis

5.3 Infections

5.4 Neutropenia

5.5 Thrombocytopenia

5.6 Embryo-Fetal Toxicity

5.7 Interference with Serological Testing

5.8 Interference with Determination of Complete Response

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Effects of Daratumumab on Laboratory Tests

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.6 Immunogenicity

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES 14.1 Newly Diagnosed Multiple Myeloma

14.2 Relapsed/Refractory Multiple Myeloma 14.3 High-Risk Smoldering Multiple Myeloma 14.4 Light Chain Amyloidosis

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

DARZALEX FASPRO is indicated for the treatment of adult patients with [see Clinical Studies (14)]:

• 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, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible 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.

1.2 High-Risk Smoldering Multiple Myeloma

DARZALEX FASPRO as monotherapy is indicated for the treatment of adult patients with high-risk smoldering multiple myeloma.

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

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing Information

• DARZALEX FASPRO is for subcutaneous use only.

Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials

• Administer medications before and after administration of DARZALEX  FASPRO to minimize administration-related reactions [see Dosage and Administration (2.6)].

• 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 3 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

^aFirst dose of the every-2-week dosing schedule is given at Week 9 ^bFirst dose of the every-4-week dosing schedule is given at Week 25

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

^aFirst dose of the every-3-week dosing schedule is given at Week 7

^bFirst dose of the every-4-week dosing schedule is given at Week 55

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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)

^aFirst dose of the every-2-week dosing schedule is given at Week 9

^b First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT

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) 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)

ª First dose of the every-2-week dosing schedule is given at Week 9

^b First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT

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, 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.

^aFirst dose of the every-3-week dosing schedule is given at Week 7 ^bFirst dose of the every-4-week dosing schedule is given at Week 25

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)

Table 6: DARZALEX FASPRO dosing schedule in combination with bortezomib and dexamethasone (3-week cycle) Weeks Schedule

^aFirst dose of the every-3-week dosing schedule is given at Week 10 ^bFirst dose of the every-4-week dosing schedule is given at Week 25

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 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

^aFirst dose of the every-2-week dosing schedule is given at Week 9 ^bFirst dose of the every-4-week dosing schedule is given at Week 25

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 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

^aFirst dose of the every-2-week dosing schedule is given at Week 9 ^bFirst dose of the every-4-week dosing schedule is given at Week 25

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.

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 1 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.

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)].

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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 regimenspecific 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)].

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 [see Warnings and Precautions (5.4, 5.5)].

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 DARZALEX FASPRO for subcutaneous use. Do not administer DARZALEX FASPRO intravenously.

DARZALEX FASPRO is ready to use.

Preparation

• Remove the DARZALEX FASPRO vial from refrigerated storage [2°C to 8°C (36°F to 46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)]. Store the unpunctured vial at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake.

• Withdraw 15 mL from the vial into a syringe using an 18G to 22G transfer needle with a regular bevel. Insert the needle into the vial at a 90° angle within the ring of the stopper.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present.

• DARZALEX  FASPRO is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately.

• After the solution of DARZALEX FASPRO is withdrawn into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe appropriately to include the route of administration per institutional standards. Label the syringe with the peel-off label.

• To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.

Storage

• If the syringe containing DARZALEX FASPRO is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours and/or at room temperature at 15°C to 25°C (59°F to 77°F) for up to 12 hours under ambient light.

• Discard if storage time exceeds these limits.

• If stored in the refrigerator, allow the solution to come to room temperature before administration.

Administration

• Inject 15 mL of DARZALEX FASPRO into the subcutaneous tissue of the abdomen approximately 3 inches [7.5 cm] to the right or left of the navel over approximately 3 to 5 minutes. No data are available on performing the injection at other sites of the body.

• Rotate injection sites for successive injections.

• Never inject DARZALEX FASPRO into areas where the skin is red, bruised, tender, hard or areas where there are scars.

• Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

• During treatment with DARZALEX  FASPRO, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO.

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

DARZALEX  FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity and Other Administration Reactions

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX  FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX  FASPRO [see Adverse Reactions (6.2)].

Systemic Reactions

In a pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3%, Grade 3: 0.8%, Grade 4: 0.1%). In patients with high-risk smoldering multiple myeloma (N=193), systemic administration-related reactions occurred in 17% of patients in AQUILA (Grade 2: 7%, Grade 3: 1%).

In all patients (N=1639), systemic administration-related reactions occurred in 7% of patients with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 283 systemic administrationrelated reactions that occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administrationrelated reactions have occurred in 1% of the patients.

Severe reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.6)]. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX  FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.6)].

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 daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX  FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO.

Local Reactions

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

^a First dose of the every-2-week dosing schedule is given at Week 9 ^b First dose of the every-4-week dosing schedule is given at Week 25 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)

^a First dose of the every-3-week dosing schedule is given at Week 7

^b First dose of the every-4-week dosing schedule is given at Week 55

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)

a First dose of the every-2-week dosing schedule is given at Week 9

^b First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT

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)

a First dose of the every-3-week dosing schedule is given at Week 10

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)

a First dose of the every-2-week dosing schedule is given at Week 9

b First dose of the every-4-week dosing schedule is given at Week 25

c Based on actual body weight

For dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.2) and manufacturer's prescribing information.

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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

^a Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions.

b 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.

^c 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.

Missed DARZALEX Doses

If a dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.

2.3 Recommended Concomitant Medications

Pre-infusion Medication

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

- Corticosteroid (long- or intermediate-acting)

Monotherapy:

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

In Combination:

Administer dexamethasone 20 mg (or equivalent) orally or intravenously. When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX infusion days [see Clinical Studies (14)]. Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX infusion days when patients have received dexamethasone (or equivalent) as a pre-medication.

DARZALEX $ ^{\circ} $ (daratumumab) injection

- Acetaminophen 650 mg to 1,000 mg orally

- Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously.

Post-infusion Medication

Administer the following post-infusion medications:

Monotherapy:

Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX.

In Combination:

Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of a DARZALEX infusion.

If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion,

additional corticosteroids may not be needed [see Clinical Studies (14)].

For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids.

Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major infusion-related reaction.

Prophylaxis for Herpes Zoster Reactivation

Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following the end of treatment [see Adverse Reactions (6.1)].

2.4 Dosage Modifications for Adverse Reactions

No dose reductions of DARZALEX are recommended. Consider withholding DARZALEX to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.4, 5.5)].

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

Infusion-Related Reactions

For infusion-related reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion-related reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below [see Warnings and Precautions (5.1)].

- Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6).

- Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion-related reaction.

- Grade 4 (life-threatening): Permanently discontinue DARZALEX.

2.5 Preparation and Administration

Preparation

DARZALEX is for single dose only.

Prepare the solution for infusion using aseptic technique as follows:

- Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.

- DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag [see Description (11), How Supplied/Storage and Handling (16)].

- Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.

- Remove a volume of 0.9% Sodium Chloride Injection from the infusion bag/container that is equal to the required volume of DARZALEX solution.

- Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing $0.9%$ Sodium Chloride Injection as specified in Table 6 [see Dosage and Administration (2.2)]. Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.

- Gently invert the bag/container to mix the solution. Do not shake.

- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.

- If not used immediately, store the diluted solution refrigerated for up to 24 hours at $ 2^{\circ} \mathrm{C} $ to $ 8^{\circ} \mathrm{C} $ （ $ 36^{\circ} \mathrm{F} $ to $ 46^{\circ} \mathrm{F} $ ）and/or at room temperature up to 15 hours at $ 15^{\circ} \mathrm{C} $ to $ 25^{\circ} \mathrm{C} $ （ $ 59^{\circ} \mathrm{F} $ to $ 77^{\circ} \mathrm{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.

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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. These reactions can be life-threatening and fatal outcomes have been reported [see Adverse Reactions (6.2)].

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

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision [see Adverse Reactions (6.1)].

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

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

Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion [see Dosage and Administration (2.3)] . Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.4)].

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions [see Dosage and Administration (2.3)]. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease [see Dosage and Administration (2.3)].

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

5.2 Interference with Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the

last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum [see References (15)]. The determination of a patient's ABO and Rh blood type are not impacted [see Drug Interactions (7.1)].

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX [see Dosage and Administration (2.1)].

5.3 Infections

DARZALEX can cause serious, life-threatening, or fatal infections. In patients who received DARZALEX in a pooled safety population (N=2066), serious infections, including opportunistic infections, occurred in 22.6% of patients Grade 3 or 4 infections occurred in 24.3%, and fatal infections occurred in 1.2%. The most common $ (\geq 2%) $ types of serious infection reported were pneumonia （11%），upper respiratory tract infection（4%），sepsis（3%），and bronchitis（2%）。 Monitor patients for signs and symptoms of infection prior to and during treatment with DARZALEX and treat appropriately. Administer prophylactic antimicrobials according to guidelines [see Dosage and Administration (2.3)].

5.4 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.

5.5 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.

5.6 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.

5.7 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:

- Infusion-related reactions [see Warnings and Precautions (5.1)].

- Infections [see Warnings and Precautions (5.3)] .

- Neutropenia [see Warnings and Precautions (5.4)].

- Thrombocytopenia [see Warnings and Precautions (5.5)].

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.