Darzalex SC Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ............................................................................................ 2

Table of Contents ............................................................................................................. 2

Part 1: Healthcare Professional Information .................................................................... 5

1. 1.

   Indications ................................................................................................................. 5

   1.1. Pediatrics .......................................................................................................... 6

   1.2. Geriatrics .......................................................................................................... 6

2. 2. Contraindications ........................................................................................................ 6
3. 4.

   Dosage and Administration ........................................................................................ 6

   4.1. Dosing Considerations ...................................................................................... 6

   4.2. Recommended Dose and Dosage Adjustment .................................................. 7

   4.3. Reconstitution ................................................................................................ 11

   4.4. Administration ................................................................................................ 11

   4.5. Missed Dose ................................................................................................... 14

4. 5. Overdose .................................................................................................................. 14
5. 6. Dosage Forms, Strengths, Composition, and Packaging ............................................. 14
6. 7.

   Warnings and Precautions ........................................................................................ 15

   General ........................................................................................................................... 15

   Cardiovascular ................................................................................................................ 15

   Hematologic ................................................................................................................... 15

   Immune .......................................................................................................................... 16

   Monitoring and Laboratory Tests ................................................................................... 17

   7.1. Special Populations ......................................................................................... 18

   7.1.1. Pregnancy .................................................................................................. 18

   7.1.2. Breastfeeding ............................................................................................. 18

   7.1.3. Pediatrics ................................................................................................... 18

   7.1.4. Geriatrics ................................................................................................... 19

7. 8.

   Adverse Reactions .................................................................................................... 19

   8.1. Adverse Reaction Overview ............................................................................ 19

   8.2. Clinical Trial Adverse Reactions ...................................................................... 24

   8.3. Less Common Clinical Trial Adverse Reactions ............................................... 73

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ........................................................................................................... 84

   8.5. Post-Market Adverse Reactions ...................................................................... 91

8. 9.

   Drug Interactions ..................................................................................................... 92

   9.2. Drug Interactions Overview ............................................................................ 92

   9.3. Drug-Behaviour Interactions .......................................................................... 92

   9.4. Drug-Drug Interactions ................................................................................... 92

   9.5. Drug-Food Interactions ................................................................................... 92

   9.6. Drug-Herb Interactions ................................................................................... 92

   9.7. Drug-Laboratory Test Interactions .................................................................. 92

9. 10.

   Clinical Pharmacology .............................................................................................. 93

   10.1. Mechanism of Action ...................................................................................... 93

   10.2. Pharmacodynamics ........................................................................................ 93

   10.3. Pharmacokinetics ........................................................................................... 94

   10.4. Immunogenicity .............................................................................................. 98

10. 11. Storage, Stability, and Disposal ................................................................................ 98
11. 12. Special Handling Instructions ................................................................................... 99

Part 2: Scientific Information .............................................................................................. 100

1. 13. Pharmaceutical Information ................................................................................... 100
2. 14.

   Clinical Trials ........................................................................................................... 100

   14.1. Clinical Trials by Indication ........................................................................... 100

   Newly diagnosed multiple myeloma (NDMM), eligible for autologous stem cell transplant. .............................................................................................................. 100

   Newly diagnosed multiple myeloma, not a candidate for autologous stem cell transplant. .............................................................................................................. 105

   Newly diagnosed multiple myeloma, ineligible for autologous stem cell transplant. ……………………………………………………………………………………………………………………….109

   Multiple myeloma, received at least one prior therapy. .......................................... 117

   Multiple myeloma, received at least one prior therapy, including lenalidomide and a proteasome inhibitor. ............................................................................................. 127

   Multiple myeloma, received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD. ........................................................................ 134

   High-risk smouldering multiple myeloma (SMM) .................................................... 138

   Newly diagnosed light chain (AL) amyloidosis ......................................................... 141

3. 15. Microbiology .......................................................................................................... 144
4. 16. Non-Clinical Toxicology .......................................................................................... 144

Patient Medication Information ......................................................................................... 147

Part 1: Healthcare Professional Information

This Product Monograph for DARZALEX® SC (daratumumab injection) includes information based on DARZALEX® (daratumumab for injection) which is the intravenous formulation.

1. Indications

Darzalex SC (daratumumab injection) is indicated:

• in combination with bortezomib, lenalidomide, and dexamethasone, followed by maintenance treatment in combination with lenalidomide, for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.
• in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplant.
• in combination with lenalidomide and dexamethasone, or with bortezomib, melphalan and prednisone, for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.
• in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor.
• in combination with carfilzomib and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy.

• for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD.

  Marketing authorization was based on the primary efficacy endpoint of overall response rate demonstrated in a single-arm study. Progression-free survival and overall survival benefits cannot be characterized in a single-arm study (see 14. Clinical Trials).

• for the treatment of adult patients with high-risk smouldering multiple myeloma (SMM).

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

  The safety and efficacy of Darzalex SC have not been established in AL amyloidosis patients with advanced cardiac disease (Mayo Stage IIIB or NYHA Class IIIB or IV).

1.1. Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥65 years of age): No overall differences in effectiveness were observed between elderly and younger patients. Some differences in clinical safety have been identified between elderly and younger subjects (see 7.1.4. Geriatrics). No dose adjustments are considered necessary in elderly patients.

2. Contraindications

Darzalex SC is contraindicated for patients with a history of severe hypersensitivity to daratumumab or who are hypersensitive to any ingredient in the formulation or component of the container. For a complete listing, see 6. Dosage Forms, Strengths, Composition, and Packaging.

4. Dosage and Administration

4.1. Dosing Considerations

It is important to check the product labels to ensure that the appropriate formulation (SC or IV) is being given to the patient, as described.

• Darzalex SC should be administered under the supervision of a healthcare professional experienced in the treatment of cancer.
• Do not administer intravenously. Darzalex SC is for subcutaneous use only. Darzalex SC has different dosage and administration instructions than Darzalex intravenous daratumumab. Do not dilute (see 4.4. Administration).
• Use proper technique when withdrawing Darzalex SC from the vial. To reduce the incidence of stopper coring, avoid the use of large diameter or blunt tip transfer needles or multiple stopper punctures.
• Pre- and post-injection medications should be administered to reduce the risk of administration-related reactions (see 4.4. Administration).
• Immunoglobulin levels should be monitored and local-treatment guidelines should be followed to manage hypogammaglobulinemia (see 7. Warnings and Precautions).
• Monitor patients for signs and symptoms of infections prior to and during treatment with Darzalex SC and treat appropriately according to local guidelines. Administer prophylactic antimicrobials according to local guidelines (see 7. Warnings and Precautions).

4.2. Recommended Dose and Dosage Adjustment

Recommended Dose for Multiple Myeloma

The recommended dose of Darzalex SC is 1800 mg administered subcutaneously, over approximately 3-5 minutes. See Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7 for the recommended dosing schedules when Darzalex SC is administered as monotherapy or as part of a combination.

Dosing Schedule:

Combination therapy with bortezomib/lenalidomide/dexamethasone (4-week cycle regimen)

The dosing schedule in Table 1 is for combination therapy with bortezomib, lenalidomide and dexamethasone (4-week cycle regimens) for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14. Clinical Trials, and consult the corresponding Product Monographs.

Combination therapy with bortezomib/lenalidomide/dexamethasone (3-week cycle regimen)

The dosing schedule in Table 2 is for combination therapy with bortezomib, lenalidomide and dexamethasone (3-week cycle regimens) for the treatment of patients with newly diagnosed multiple myeloma who are not candidates for ASCT.

For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14. Clinical Trials, and consult the corresponding Product Monographs.

Combination therapy with lenalidomide/dexamethasone or pomalidomide/dexamethasone, and Monotherapy (4-week cycle regimens)

The dosing schedule in Table 3 is for combination therapy with 4-week cycle regimens (e.g. lenalidomide or pomalidomide) and for monotherapy as follows:

• combination therapy with lenalidomide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).
• combination therapy with lenalidomide and low-dose dexamethasone for patients with multiple myeloma who have received at least one prior therapy.
• combination therapy with pomalidomide and dexamethasone for patients with multiple myeloma who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor.
• monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD.

For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14. Clinical Trials, and consult the corresponding Product Monographs.

Combination therapy with carfilzomib and dexamethasone (4-week cycle regimen)

The Darzalex SC dosing schedule in Table 4 is for combination therapy with carfilzomib and dexamethasone (4-week regimen) for patients with relapsed multiple myeloma who have received one to three prior lines of therapy:

In the CANDOR Study of Darzalex in combination with carfilzomib and dexamethasone, carfilzomib was administered twice-weekly (20/56 mg/m²). For further details and dosing instructions for medicinal products administered with Darzalex SC, see 14. Clinical Trials , and consult the corresponding Product Monographs.

Combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimens)

The dosing schedule in Table 5 is for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma ineligible for ASCT.

Bortezomib is given twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at Weeks 1, 2, 4 and 5 for eight more 6-week cycles. Melphalan (9 mg/m²) and prednisone (60 mg/m²) are given on days 1-4 of each cycle. For more information on the VMP dose and dosing schedule when administered with Darzalex SC, see 14. Clinical Trials .

Combination therapy with bortezomib/dexamethasone (3-week cycle regimens)

The dosing schedule in Table 6 is for combination therapy with bortezomib and dexamethasone (3-week cycle regimen) for patients with multiple myeloma who have received at least one prior therapy.

For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14. Clinical Trials, and consult the corresponding Product Monographs.

Recommended Dose for Smouldering Multiple Myeloma

The Darzalex SC dosing schedule in Table 7 is for monotherapy (4-week cycle regimen) for patients with high-risk smouldering multiple myeloma. The recommended dose is Darzalex SC 1800 mg, as monotherapy, administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

Table 7: Darzalex SC dosing schedule for monotherapy (4-week cycle dosing regimen)

^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

Recommended Dose for AL Amyloidosis

The Darzalex SC dosing schedule in Table 8 is for combination therapy with bortezomib, cyclophosphamide and dexamethasone (4-week cycle regimen) for patients with AL amyloidosis.

The recommended dose is Darzalex SC 1800 mg administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

For dosing instructions of medicinal products administered in combination with Darzalex SC, see 14. Clinical Trials, and consult the corresponding Product Monographs.

Dose modifications:

No dose reductions of Darzalex SC are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity (see 7. Warnings and Precautions). For information concerning medicinal products given in combination with Darzalex SC, consult the corresponding Product Monographs.

4.3. Reconstitution

Not applicable.

4.4. Administration

Recommended Concomitant Medications:

Pre-injection medication:

For all patients, to reduce the risk of administration-related reactions administer the following pre-medications approximately 1-3 hours prior to every dose of Darzalex SC:

Combination therapy:

• Administer 20 mg dexamethasone (or equivalent) prior to every Darzalex SC dose. When dexamethasone is the background-regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-medication on Darzalex SC injection days (see 14. Clinical Trials).
• Dexamethasone is given orally or intravenously prior to Darzalex SC injections.
• Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on Darzalex SC injection days when patients have received dexamethasone as a pre-medication.
• Antipyretics (oral paracetamol/acetaminophen 650 to 1000 mg).
• Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Monotherapy:

• corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate-acting or long-acting corticosteroid) given intravenously or orally
• oral antipyretics (acetaminophen 650 to 1000 mg), plus
• oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent).
• Leukotriene inhibitor (montelukast 10 mg PO, or equivalent) is recommended on Cycle 1 Day 1 for patients with SMM.

Following the second Darzalex SC injection, the dose of corticosteroid may be reduced (e.g., methylprednisolone 60 mg IV).

Post-injection medication:

Administer post-injection medication to reduce the risk of delayed administration-related reactions as follows:

Combination therapy:

• Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent the day after Darzalex SC injection.

  • However, if a background regimen-specific corticosteroid (e.g. dexamethasone or prednisone) is administered the day after Darzalex SC injection, additional post-injection medications may not be needed (see 14. Clinical Trials).

Monotherapy:

• Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid (intermediate or long-acting) in accordance with local standards) to patients the first and second day after each injection of Darzalex SC (beginning the day after the injection).

If the patient experiences no major systemic administration-related reactions (ARRs) after the first three injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued.

Additionally, for patients with a history of chronic obstructive pulmonary disease, consider the use of post-injection medications including bronchodilators (short and long acting), and inhaled corticosteroids. Following the first four injections, if the patient experiences no major systemic administration-related reactions, these inhaled post-injection medications may be discontinued.

Prophylaxis for herpes zoster virus reactivation:

Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

Instructions for Use, Handling, and Disposal

To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Darzalex SC and not intravenous Darzalex. Darzalex SC is not intended for intravenous administration and should be administered via subcutaneous injection only.

• Darzalex SC is for single use only and is ready to use without dilution.
• Remove the Darzalex SC vial from refrigerated storage [2°C-8°C] and equilibrate to ambient temperature [15°C-30°C]. The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake.
• Darzalex SC should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use if opaque particles, discolouration or other foreign particles are present.
• Prepare the dosing syringe in aseptic conditions. Withdraw 15 mL from the vial into a syringe using an 18G - 22G transfer needle with a regular bevel to minimize the risk of stopper coring. Insert the needle into the vial at a 90°angle within the ring of the stopper and minimize the number of punctures to prevent fragmentation of the stopper. Inspect the content of the syringe to ensure the absence of particulate matter, discoloration or other foreign particles.
• Darzalex SC is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles.
• To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.

Storage of prepared syringe

• If the syringe containing Darzalex SC is not used immediately, store the Darzalex SC solution for up to 24 hours refrigerated followed by up to 12 hours at 15°C-25°C and ambient light.
• Discard if stored more than 24 hours of being refrigerated or more than 12 hours of being at 15°C-25°C.
• If stored in the refrigerator, allow the solution to come to ambient temperature before administration.

Administration

• Inject 15 mL (equivalent to 1800 mg) Darzalex SC into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel over approximately 3-5 minutes. Do not inject Darzalex SC at other sites of the body as no data are available.
• Alternate injection sites for successive injections.
• Darzalex SC should never be injected 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 slowing down the injection, 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 SC, do not administer other medications for subcutaneous use at the same site as Darzalex SC.
• Dispose of any waste material in accordance with local requirements.

4.5. Missed Dose

If a planned dose of Darzalex SC is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.

5. Overdose

There is no information on overdosage with Darzalex SC.

There is no known specific antidote for daratumumab overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment be instituted immediately.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

To ensure the traceability of biologic products, healthcare professionals should record both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 10 – Dosage Forms, Strengths, Composition and Packaging

*Recombinant human hyaluronidase PH20 (rHuPH20): an enzyme used to increase the dispersion and absorption of co-administered daratumumab.

Darzalex SC: supplied as a colourless to yellow, clear to opalescent, preservative-free solution for subcutaneous administration. Each single-dose vial contains 1800 mg daratumumab in 15 mL (120 mg/mL).

7. Warnings and Precautions

General

Darzalex SC (daratumumab injection) should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer. Darzalex SC can be used in combination with other medications; therefore, the warnings and precautions applicable for use with those medications also apply to Darzalex SC combination therapy including the potential risk of fetal harm, the presence and transmission in sperm and blood, and prohibitions against blood and/or sperm donation. The prescribing information for all medications used in combination with Darzalex SC must be consulted before starting therapy. See 7.1.1. Pregnancy and 7.1.2. Breastfeeding.

Cardiovascular

Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis

Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received Darzalex SC in combination with bortezomib, cyclophosphamide, and dexamethasone (see 8. Adverse Reactions). Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with Mayo Stage IIIB, NYHA Class IIIB or IV were not studied.

Monitor patients with cardiac involvement of AL amyloidosis more frequently for cardiac adverse reaction and administer supportive care as appropriate. Due to the potentially increased risk of cardiac toxicity, Darzalex SC is not recommended for use in patients with AL amyloidosis with advanced cardiac disease.

Hematologic

Neutropenia/Thrombocytopenia

Darzalex SC alone or in combination with other medications increases neutropenia. In lower body weight patients receiving Darzalex SC, further increases in the rate of neutropenia and thrombocytopenia, including higher rates of Grade 3-4 events, were observed. When used in combination with background therapy, Darzalex SC increases neutropenia and thrombocytopenia induced by the background therapy (see 8. Adverse Reactions ).

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. Darzalex SC dose delay may be required to allow recovery of blood cell counts (neutrophils or platelets). No dose reduction is recommended. Consider supportive care with transfusions or growth factors as needed.

Immune

Administration-Related Reactions

Darzalex SC can cause severe and/or serious administration-related reactions (ARRs), including anaphylactic reactions.

In clinical trials with Darzalex SC in patients with multiple myeloma (n=1446) or light chain (AL) amyloidosis (n=193), ARRs (defined as administration-related systemic reactions) were reported in approximately 8% of patients. Most ARRs occurred following the first injection and were Grade 1-2. ARRs occurring with subsequent injections were seen in 1% of patients. Severe ARRs occurred in 1% of patients treated with Darzalex SC.

The median time to onset of ARRs following Darzalex SC was approximately 3.3 hours (range 0.08-83 hours). The majority of ARRs occurred on the day of treatment. Delayed ARRs have occurred in 1% of patients.

Signs and symptoms of ARRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, hypotension, and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia and ocular adverse events (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see 8. Adverse Reactions).

Pre medicate patients with antihistamines, antipyretics and corticosteroids to reduce the risk of ARRs prior to treatment with Darzalex SC. For patients with high-risk smouldering multiple myeloma, pre-medication with leukotriene inhibitors on Cycle 1 Day 1 should also be considered. Patients should be monitored and counselled regarding ARRs, especially during and following the first and second injections. If an anaphylactic reaction or life threatening (Grade 4) reactions occur, institute appropriate emergency care and permanently discontinue Darzalex SC.

To reduce the risk of delayed ARRs, administer oral corticosteroids to all patients after each injection of Darzalex SC. Additionally, consider the use of post-injection medications (e.g. inhaled corticosteroids, short and long-acting bronchodilators) for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications should they occur. Pre- and post-injection medications may vary when Darzalex SC is used in combination therapy. If ocular symptoms occur, interrupt Darzalex SC and seek immediate ophthalmologic evaluation prior to restarting Darzalex SC (see 4. Dosage and Administration).

Hypogammaglobulinemia

Hypogammaglobulinemia can occur in patients treated with Darzalex SC. Immunoglobulin levels should be monitored during treatment with Darzalex SC. In patients with low immunoglobulin levels, pre-emptive measures according to local guidelines such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be considered.

Infections

Darzalex SC can cause serious, life-threatening, or fatal infections, with higher incidences reported in patients when Darzalex SC is used in combination with additional therapies including but not limited to proteasome inhibitors and immunomodulatory agents compared to patients treated with these additional therapies without Darzalex SC (see 8. Adverse Reactions). Monitor patients for signs and symptoms of infections prior to and during treatment with Darzalex SC and treat appropriately. Administer prophylactic antimicrobials according to guidelines prior to, during or post-treatment (See 4. Dosage and Administration).

Hepatitis B Virus Reactivation

Hepatitis B Virus (HBV) reactivation, in some cases fatal, has been reported in patients treated with daratumumab. HBV screening should be performed in all patients before initiation of treatment with Darzalex SC.

For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of Darzalex SC treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated.

In patients who develop reactivation of HBV while on Darzalex SC, suspend treatment with Darzalex SC and any concomitant steroids, chemotherapy, and institute appropriate treatment. Resumption of Darzalex SC treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

Monitoring and Laboratory Tests

Interference with indirect antiglobulin test (indirect Coombs test)

Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab dose. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum (see 9. Drug Interactions). The determination of a patient’s ABO and Rhesus (Rh) blood type are not impacted.

Patient’s blood should be typed and screened prior to starting Darzalex SC. In the event of a planned transfusion notify blood transfusion centers of this interference with serological testing.

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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. In patients with persistent very good partial response, consider other methods to evaluate the depth of response (see 9. Drug Interactions).

7.1. Special Populations

7.1.1. Pregnancy

Risks of Darzalex SC use during pregnancy have not been assessed. Animal studies have not been conducted. However, immunoglobulin G1 (IgG1) monoclonal antibodies are known to transfer across the placenta. 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. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect leukocyte populations, infant monkeys had a reversible reduction in leukocytes.

Based on its mechanism of action, daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone density (see 16. Non-Clinical Toxicology ).

Darzalex SC should not be used during pregnancy. If the patient becomes pregnant while taking this drug, the patient should be informed of the potential risk to the fetus. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed.

Patients of childbearing potential should use effective contraception during treatment and for at least 3 months after cessation of Darzalex SC treatment.

Darzalex SC is administered with other agents that can cause fetal harm. For example, lenalidomide and pomalidomide can cause embryo-fetal harm and are contraindicated for use in pregnancy due to the potential for severe outcomes including life-threatening human birth defects. Refer to the Product Monographs for all other agents to be administered with Darzalex SC, depending on the specific combination therapy regimen, for requirements regarding contraception and for additional details.

7.1.2. Breastfeeding

It is not known whether daratumumab is excreted into human or animal milk or affects milk production. There are no studies to assess the effect of daratumumab on an infant who has received breast milk from a patient administered Darzalex SC. Human IgG is excreted in breast milk. Because the risks of daratumumab to the infant are unknown, a decision should be made whether to discontinue feeding an infant breast-milk (by breast-feeding or by other means), or discontinue Darzalex SC therapy, taking into account the benefit for the child of receiving breast-milk and/or breast-feeding versus the benefits of Darzalex SC therapy for the patient.

Darzalex SC may be administered as part of a combination therapy regimen that includes but is not limited to proteasome inhibitors, immunomodulatory agents and cytotoxic chemotherapies. Therefore, serious adverse reactions may occur in infants receiving breast milk from a patient not only due to the presence of daratumumab but also from the additional therapies. This includes lenalidomide and pomalidomide, which are teratogenic, and it is contraindicated to give an infant breast milk from a patient treated with these immunomodulatory agents. Refer to the necessary Product Monographs for any additional therapies used in combination with Darzalex SC for identified and potential risks to infants receiving breast milk from a patient treated as part of a combination therapy regimen.

7.1.3. Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

Geriatrics (≥ 65 years of age): No overall differences in effectiveness were observed between elderly and younger patients. Some differences in clinical safety have been identified between elderly and younger subjects (see 8.2. Clinical Trial Adverse Reactions - Special Population: Geriatrics). No dose adjustments are considered necessary in elderly patients.

In the CANDOR study 308 patients were treated with daratumumab in combination with carfilzomib (twice-weekly) and dexamethasone (DKd). Of these, 146 patients (47%) were ≥ 65 years of age and 28 patients (9%) were ≥ 75 years of age. The incidence of serious adverse events was 52% in patients < 65 years of age, 61% in patients 65 to 74 years of age, and 57% in patients ≥ 75 years of age. Fatal treatment-emergent adverse events (TEAEs) occurred in 6% of patients < 65 years of age and 14% of patients ≥ 65 years of age. In the Kd arm, fatal TEAEs occurred in 8% of patients < 65 years of age and 3% of patients ≥ 65 years of age (see 8.2. Clinical Trial Adverse Reactions -Special Population: Geriatrics). There are increased risks for cardiovascular events in patients ≥ 75 years of age compared with patients < 75 years of age when treated with DKd.

8. Adverse Reactions

8.1. Adverse Reaction Overview

SUBCUTANEOUS FORMULATION (Darzalex SC):

Monotherapy – Relapsed/Refractory Multiple Myeloma

The safety of Darzalex SC (1800 mg subcutaneously) and Darzalex (16mg/kg intravenously) monotherapy was evaluated in the Phase 3, randomized, open-label, active-controlled study MMY3012, which included 260 and 258 patients, respectively, with multiple myeloma who had received at least three prior lines of therapy including a PI and an IMiD, or who were refractory to both a PI and an IMiD. The only TEAEs occurring at a frequency ≥20% in either the Darzalex SC or Darzalex arm were anemia and upper respiratory tract infections. After a median study follow up of 7.46 months, the overall incidence of serious TEAEs was 26.2% in the SC arm and 29.5% in the IV arm. The only serious TEAE with a frequency ≥2% was pneumonia (SC: 5.0%; IV: 6.0%). Study treatment discontinuation due to a TEAE occurred in 6.9% of subjects in the SC group, and 8.1% in the IV group. Infusion-related reactions were reported in 12.7% of patients receiving Darzalex SC and 34.5% of patients receiving Darzalex. Neutropenia was the only TEAE reported at ≥ 5% higher frequency for Darzalex SC compared to intravenous Darzalex (Grade 3 or 4: 13.1 % vs 7.8%, respectively).

Combination Therapies in Multiple Myeloma

The safety of Darzalex SC was evaluated in combination therapy in the open-label Phase 2 Study MMY2040 including patients receiving bortezomib, melphalan and prednisone (D-VMP in patients with transplant ineligible newly diagnosed multiple myeloma [NDMM], n=67), lenalidomide and dexamethasone (D-Rd in patients with relapsed/refractory MM, n=65), or carfilzomib and dexamethasone (DKd in patients with relapsed/refractory MM, n=66). After a median study follow up of 6.5 and 7 months on the D-VMP and D-Rd cohorts, respectively, the most frequently reported TEAEs (≥20%) for subjects in the D-VMP cohort were thrombocytopenia, neutropenia, anemia, nausea, constipation, peripheral sensory neuropathy, pyrexia, diarrhea, fatigue, vomiting, lymphopenia, and upper respiratory tract infection. The most frequently reported TEAEs (≥20%) for subjects in the DRd cohort were neutropenia, diarrhea, thrombocytopenia, muscle spasms, dyspnea, anemia, upper respiratory tract infection, fatigue, constipation, and pyrexia. Based on an exploratory analysis of the safety profile after a median of 14 months follow-up, additional common TEAEs (≥20%) of insomnia and back pain were reported in the D-VMP cohort. The incidence of serious TEAEs was 37.3% in the D-VMP cohort, and 40.0% in the DRd cohort. The most common serious TEAEs (≥5% in any cohort) were pyrexia (D-VMP: 7.5%; DRd: 3.1%), pneumonia (D-VMP: 4.5%, DRd: 6.2%) and influenza (D-VMP: 1.5%; DRd: 4.6%). Based on an exploratory analysis of the safety profile in the D-Rd cohort after a median of 14 months follow-up, an additional common serious TEAE (≥5%) of diarrhea was reported (D-Rd: 6.2%). Study treatment discontinuation due to a TEAE occurred in 3.0% of subjects in the D-VMP cohort, and 4.6% of subjects in the DRd cohort. Infusion-related reactions were reported in 9.0% of patients in the D-VMP cohort and in 9.0% of patients in the DRd cohort. In the DKd cohort, the median treatment duration was 8.3 months (range: 0 to 17 months). The most frequently reported TEAEs (≥20%) for patients in the DKd cohort were thrombocytopenia, anemia, insomnia, hypertension, diarrhea, nasopharyngitis, headache, neutropenia, asthenia, nausea, and pyrexia. The incidence of serious TEAEs was 27.3%. No serious TEAEs occurred in ≥5% of patients. Study treatment discontinuation due to a TEAE occurred in 6.1% of patients. Infusion-related reactions were reported in 4.5% of patients.

Patients who received Darzalex SC in combination with bortezomib, lenalidomide and dexamethasone

The safety of Darzalex SC in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), followed by maintenance with Darzalex SC and lenalidomide, was evaluated in a Phase 3, randomized, open-label clinical study for the treatment of patients with newly diagnosed multiple myeloma patients who are eligible for ASCT (n=709). The most frequently reported TEAEs (≥20%) in the D-VRd arm were COVID-19, upper respiratory tract infection, neutropenia, thrombocytopenia, anemia, diarrhea, constipation, nausea, pyrexia, asthenia, fatigue, peripheral edema, peripheral sensory neuropathy, back pain, rash, cough, and insomnia. The overall incidence of serious TEAEs was 57.0% in the D-VRd arm and 49.3% in the VRd arm. Serious adverse events with a 2% higher incidence in the D-VRd arm compared to the VRd arm were pneumonia (D-VRd 20.3%; VRd: 10%), COVID-19 (D-VRd 8.2%; VRd: 3.7%), and atrial fibrillation (D-VRd 3.2; VRd: 0.7%). Study treatment discontinuation due to an AE occurred in 8.8% of subjects in the D-VRd group, and 21.3% in the VRd group.

The safety of Darzalex SC in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) was also evaluated in a Phase 3, randomized, open-label clinical study for the treatment of adult patients with newly diagnosed multiple myeloma who are not candidates for ASCT (n=197). The most frequently reported TEAEs (≥20%) in the D-VRd arm were upper respiratory tract infection, peripheral sensory neuropathy, diarrhea, neutropenia, fatigue, musculoskeletal pain, edema peripheral, thrombocytopenia, COVID-19, constipation, anemia, insomnia, cough, hypokalemia, pneumonia, cataract, rash, nausea, pyrexia, abdominal pain, arthralgia, decreased appetite, urinary tract infection, dyspnea, and dizziness. The overall incidence of serious TEAEs was 72.1% in the D-VRd arm and 67.2% in the VRd arm. Serious adverse reactions with a 2% greater incidence in the D-VRd arm compared to the VRd arm were COVID-19 (D-VRd: 15% vs. VRd: 10%), sepsis (D-VRd: 7% vs. VRd: 4%), diarrhea (D-VRd: 5% vs. VRd: 3%), urinary tract infection (D-VRd: 4% vs. VRd: 2%), fatigue (D-VRd: 3% vs. VRd: 1%), and hyperglycemia (D-VRd: 2% vs. VRd: 0%). Study treatment discontinuation due to an AE occurred in 7.6% of subjects in the D-VRd group, and 15.9% in the VRd group.

Patients who received Darzalex SC in combination with pomalidomide and dexamethasone

The safety of Darzalex SC in combination with pomalidomide and dexamethasone (DPd) was evaluated in a Phase 3, randomized, open-label clinical study in multiple myeloma patients (n=299) who had received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor. The most frequently reported TEAEs (≥20%) in the DPd arm were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, pneumonia, lower respiratory tract infection, fatigue, asthenia, pyrexia, and diarrhea. The overall incidence of serious TEAEs was 50.3% in the DPd arm and 39.3% in the Pd arm. Serious TEAEs with a 2% higher incidence in the DPd arm compared to the Pd arm were pneumonia (D-Pd 26.2% vs Pd 17.3%), neutropenia (DPd 4.7% vs Pd 2.7%), thrombocytopenia (DPD 2.7% vs PD 0.7%) and syncope (DPd 2.0% vs Pd 0%). Study treatment discontinuation due to an AE occurred in 2.0% of subjects in the DPd group, and 2.7% in the Pd group.

Monotherapy – High-Risk Smouldering Multiple Myeloma (SMM)

The safety of Darzalex SC was investigated in patients with high-risk SMM in a Phase 3 randomized, open-label trial (Study SMM3001) in which patients received Darzalex SC as monotherapy (n=193). The most frequently reported TEAEs (≥20%) in the Darzalex SC arm were upper respiratory tract infections, fatigue, musculoskeletal pain, diarrhoea, injection site reaction, arthralgia, insomnia. The overall incidence of serious TEAEs was 29.0% in the Darzalex SC arm and 19.4% in the active monitoring (ACTM) arm. Serious adverse events with a 2% or higher incidence in the Darzalex SC arm compared to the ACTM arm were pneumonia (Darzalex SC 5.7% vs ACTM 1.5%) and upper respiratory tract infection (Darzalex SC 1.6% vs ACTM 0%). Study treatment discontinuation due to an AE occurred in 5.7% of subjects in the Darzalex SC arm and no subjects in the ACTM arm.

Combination Treatment for AL Amyloidosis

The safety of Darzalex SC (subcutaneous formulation, 1800 mg) with bortezomib, cyclophosphamide and dexamethasone (D-VCd; n=193) compared to bortezomib, cyclophosphamide and dexamethasone (VCd; n=188) in patients with newly diagnosed AL amyloidosis was evaluated in an open-label, randomized, Phase 3 study, AMY3001. The median follow-up was 11.4 months.

The most common TEAEs occurring at a frequency ≥20% in the D-VCd arm were peripheral edema, fatigue, diarrhea, constipation, nausea, upper respiratory tract infection, peripheral sensory neuropathy, dyspnea, cough, insomnia, and anemia. The incidence of serious TEAEs was 43.0% in the D-VCd arm, and 36.2% in the VC-d arm. The most common serious TEAEs (≥5% in any cohort) were pneumonia (D-VCd 7.3%; VCd 4.8%) and cardiac failure/cardiac failure congestive (D-VCd 6.7%; VCd 5.3%). Serious adverse reactions that occurred in at least 2% more D-VCd than VCd patients included pneumonia, sepsis, and cardiac arrest. Fatal adverse reactions occurred in 11% of D-VCd patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (3%), sudden death (3%), cardiac failure (3%), and sepsis (1%). Study treatment discontinuation due to a TEAE occurred in 4.1% of the D-VCd arm, and 4.3% of the VCd arm.

INTRAVENOUS FORMULATION (Darzalex):

The following sections present safety information from a separate Product Monograph for Darzalex intravenous formulation studies:

• Patients with newly diagnosed multiple myeloma who are ineligible for ASCT
• Patients with multiple myeloma who have received at least one prior therapy
• Patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD

Patients with newly diagnosed multiple myeloma who are ineligible for ASCT:

The data described below reflect exposure to Darzalex intravenous formulation in two Phase 3 active-controlled trials that included 710 patients with multiple myeloma treated with Darzalex at 16 mg/kg in combination with either lenalidomide and dexamethasone (DRd) [Study MMY3008; n=364] or bortezomib, melphalan, and dexamethasone (D-VMP) [Study MMY3007; n=346].

Patients who received Darzalex in combination with lenalidomide and dexamethasone

The safety of Darzalex intravenous formulation in combination with lenalidomide and dexamethasone (DRd) was evaluated in a Phase 3, randomized, open-label study in patients with newly diagnosed multiple myeloma (MMY3008; n=729). The most frequently reported TEAEs (≥20%) in the DRd arm were infusion-related reactions, diarrhea, neutropenia, constipation, fatigue, peripheral edema, anemia, back pain, asthenia, nausea, insomnia, muscle spasms, bronchitis, dyspnea, weight decreased, cough, peripheral sensory neuropathy, pyrexia, upper respiratory tract infection, pneumonia, decreased appetite, and hypokalemia. The overall incidence of serious TEAEs was 62.9% in the DRd arm and 62.7% in the Rd arm. Serious TEAEs with a 2% higher incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15.4% vs Rd 7.7%) and bronchitis (DRd 3.6% vs Rd 1.9%). Study treatment discontinuation due to an AE occurred in 7.4% of subjects in the DRd group, and 16.2% in the Rd group.

Patients who received Darzalex in combination with bortezomib, melphalan, and prednisone

The safety of Darzalex intravenous formulation in combination with bortezomib, melphalan, and prednisone (D-VMP) was evaluated in a Phase 3, randomized, open-label study in patients with newly diagnosed multiple myeloma (MMY3007; n=700). The most frequently reported TEAEs (≥20%) in the D-VMP arm were infusion-related reactions, neutropenia, thrombocytopenia, anemia, upper respiratory tract infection, pyrexia, diarrhea, nausea, and peripheral sensory neuropathy. The overall incidence of serious TEAEs was 41.6% in the D-VMP arm and 32.5% in the VMP arm. Serious TEAEs (≥2%) with at least a 2% higher incidence in the D-VMP arm compared to the VMP arm included infections (23.1% vs 11.9%), including pneumonia (D-VMP 10.1% vs VMP 3.1%). Study treatment discontinuation due to a TEAE occurred in 4.9% of subjects in the D-VMP group, and 9.0% in the VMP group.

Patients with multiple myeloma who have received at least one prior therapy:

The data described below reflect exposure to Darzalex intravenous formulation in two Phase 3 active-controlled trials that included 423 patients with multiple myeloma treated with Darzalex at 16 mg/kg in combination with either lenalidomide and dexamethasone (DRd) [Study MMY3003] or bortezomib and dexamethasone (DVd) [Study MMY3004].

Patients who received Darzalex in combination with lenalidomide/dexamethasone

The safety of Darzalex intravenous formulation in combination with lenalidomide and dexamethasone was evaluated in a Phase 3, randomized, open-label study in patients with relapsed/refractory multiple myeloma after at least one prior therapy (n=569). In MMY3003, the most frequently reported TEAEs (≥20%) in the DRd arm were infusion-related reactions, neutropenia, thrombocytopenia, anemia, diarrhea, constipation, upper respiratory tract infection, pneumonia, cough, dyspnea, nausea, fatigue, muscle spasms, insomnia, and pyrexia. The overall incidence of serious TEAEs was 54.1% in the DRd arm and 44.8% in the Rd arm. Serious TEAEs (≥2%) with at least a 2% higher incidence in the DRd arm compared to the Rd arm included infections (33.6% vs 23.8%) such as influenza (DRd 3.9% vs Rd 1.4%) and febrile neutropenia (DRd 4.2% vs Rd 1.4%). Study treatment discontinuation due to a TEAE occurred in 16.3% of subjects in the DRd group, and 13.9% in the Rd group. The most common TEAEs leading to study treatment discontinuation were pneumonia, septic shock and fatigue (each 1.4%), and general physical health deterioration (1.1%) in the DRd group, and pulmonary embolism (1.1%) in the Rd group.

Patients who received Darzalex in combination with bortezomib/dexamethasone

The safety of Darzalex intravenous formulation in combination with bortezomib and dexamethasone was evaluated in a Phase 3, randomized, open-label clinical study in multiple myeloma patients (n=498) who had received at least one prior therapy. In Study MMY3004, the most frequently reported TEAEs (≥20%) for the DVd group were infusion-related reactions, thrombocytopenia, anemia, peripheral sensory neuropathy, diarrhea, constipation, upper respiratory tract infection, cough, and fatigue. The overall incidence of serious TEAEs was 49% of patients in the DVd group and 34% in the Vd group. Serious TEAEs with at least a 2% higher incidence in the DVd arm compared to the Vd arm included anemia (DVd 3.3% vs Vd 0.4%), bronchitis (DVd 2.9% vs Vd 0.8%), thrombocytopenia (DVd 2.5% vs Vd 0.4%), atrial fibrillation (DVd 2.5% vs Vd 0%) and second primary malignancy (3.7% vs 0.4%). TEAEs resulting in treatment discontinuation occurred in 9.3% (n=22) of subjects in the DVd group, and 9.1% (n=22) in the Vd group.

Patients who received Darzalex in combination with carfilzomib/dexamethasone

The safety of Darzalex in combination with twice-weekly carfilzomib and dexamethasone (DKd) was evaluated in a Phase 3, randomized, open-label clinical study in multiple myeloma patients (n=461) who had received 1 to 3 prior lines of therapy (CANDOR study). The median duration of treatment for the DKd arm was 68.14 weeks (range: 0.1 to 100.3 weeks). In the CANDOR study, which included 153 patients in the Kd twice weekly dosing arm and 308 patients in the DKd dosing arm, the most common adverse reactions (> 20%) in either treatment arm included: thrombocytopenia, anemia, diarrhea, fatigue, respiratory tract infection, cough, and hypertension. Serious adverse events were reported in 56% of the patients in the DKd arm and 46% of the patients in the Kd arm. The most common serious adverse reactions that occurred with ≥ 2% incidences in either treatment arm were pneumonia, urinary tract infection, influenza, sepsis, pyrexia, pulmonary embolism, dyspnea, cardiac failure, acute kidney injury, anemia, and plasma cell myeloma. Grade ≥ 3 adverse events occurred in 82% of patients in the DKd arm as compared with 74% in the Kd arm. Discontinuation of any study treatment due to any adverse event occurred in 22% of patients in the DKd arm versus 25% in the Kd arm. The most common adverse reactions leading to discontinuation of any study drug were cardiac failure (n = 6, 2%) and fatigue (n = 6, 2%) in the DKd arm and cardiac failure (n = 3, 2%), hypertension (n = 3, 2%) and acute kidney injury (n = 3, 2%) in the Kd arm. The most common reaction leading to discontinuation of daratumumab was pneumonia (n = 4, 1%). The most common reactions leading to discontinuation of carfilzomib were cardiac failure (n = 6, 2%) and fatigue (n = 6, 2%) in the DKd arm and cardiac failure (n = 3, 2%), hypertension (n = 3, 2%) and acute kidney injury (n = 3, 2%) in the Kd arm. Additionally, deaths due to adverse events within 30 days of the last dose of any study treatment occurred in 30/308 (10%) patients in the DKd arm compared with 8/153 (5%) patients in the Kd arm. The most common causes of death occurring in patients (%) in the two arms (DKd vs. Kd) was infections 14 (5%) vs. 4 (3%). The risk of fatal treatment-emergent adverse events was higher among patients ≥ 65 years of age.

Patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD:

The data described below reflect exposure to Darzalex intravenous formulation in three pooled open label clinical studies that included 156 patients with relapsed and refractory multiple myeloma treated with Darzalex at 16 mg/kg. The median duration of Darzalex treatment was 3.3 months (range: 0.03 to 41.5 months).

Infusion-related reactions were the most frequently observed treatment-emergent adverse events [TEAEs] and occurred in 48% of patients treated at 16 mg/kg.

Other frequently reported (≥20%) adverse events included fatigue, pyrexia, upper respiratory tract infection, nausea, back pain, cough, anemia, neutropenia and thrombocytopenia.

Grade 3 or 4 TEAEs were reported for 57.1% of patients. The most commonly reported Grade 3 or 4 TEAEs (≥10%) were anemia (17%, all Grade 3), thrombocytopenia (8.3% Grade 3, 5.8% Grade 4), and neutropenia (9.6% Grade 3, 2.6% Grade 4).

The most common (≥ 2%) serious TEAEs were pneumonia (6%), general physical health deterioration, hypercalcemia and pyrexia (each at 3%), cross-match incompatible and herpes zoster (each at 2%). Four percent of patients discontinued Darzalex treatment due to an adverse event. The adverse events leading to discontinuation were general physical health deterioration, H1N1 influenza, hypercalcemia, pneumonia, and spinal cord compression. The median time to discontinuation was 21.5 days (1.0, 106.0). Adverse events leading to treatment delay were observed in 25 (16.0%) of patients, and the most frequent adverse event was infections, reported in 14 (9.0%) patients.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

SUBCUTANEOUS FORMULATION (Darzalex SC)

Monotherapy

Study MMY3012

TEAEs in Table 11 reflect exposure to Darzalex SC (1800 mg SC injection) for a median treatment duration of 4.7 months (range: 0.03 to 12.91 months) or Darzalex (16 mg/kg IV infusion) for a median treatment duration of 5.4 months (range: 0.03; 12.16).

Combination Therapies in Multiple Myeloma

Study MMY2040

TEAEs in Table 12 reflect exposure to Darzalex SC (1800 mg SC injection) in combination with bortezomib, melphalan and prednisone (D-VMP) in patients with newly diagnosed MM who are ineligible for transplant, and in combination with lenalidomide and dexamethasone (D-Rd) in subjects with relapsed or refractory MM (Table 13). The median treatment duration was 6.5 months (0.36 to 9.26 months) for D-VMP; and 7 months (0.49 to 8.97 months) for D-Rd. TEAEs in Table 14 reflect exposure to Darzalex SC (1800 mg SC injection) in combination with carfilzomib and dexamethasone (DKd) in patients with MM who have received one to three prior lines of therapy. The median treatment duration was 8.3 months (0 to 17.0 months).

Study MMY3014: Darzalex SC in combination with bortezomib/lenalidomide/dexamethasone (adult patients with newly diagnosed multiple myeloma who are eligible for ASCT)

TEAEs in Table 15 reflect exposure to Darzalex SC in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), followed by maintenance with DARZALEX SC and lenalidomide for a median duration of treatment of 45.7 months (range 0.49 to 54.3 months) and a median treatment duration of 42.2 months (range 0.07 to 53.9 months) for the bortezomib, lenalidomide and dexamethasone (VRd) followed by lenalidomide maintenance group.

Study MMY3019: Darzalex SC in combination with bortezomib/lenalidomide/dexamethasone (adult patients with newly diagnosed multiple myeloma who are not candidates for ASCT)

TEAEs in Table 16 reflect exposure to Darzalex SC in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) for a median duration of treatment of 56.3 months (range 0.1 to 64.6 months) and 34.3 months (range 0.5 to 63.8 months) for the bortezomib, lenalidomide and dexamethasone (VRd) group.

Study MMY3013: Darzalex SC in combination with pomalidomide/dexamethasone

TEAEs in Table 17 reflect exposure to Darzalex SC in combination with pomalidomide and dexamethasone (DPd) for a median treatment duration of 11.5 months (range: 0 to 36.0 months) and a median treatment duration of 6.6 months (range: 0 to 27.0 months) for the

pomalidomide/dexamethasone (Pd) group. Among patients receiving DPd, 71% were exposed for 6 months or longer and 50% were exposed for greater than one year.

Monotherapy in Smouldering Multiple Myeloma (SMM)

Study SMM3001

TEAEs in Table 18 reflect exposure to Darzalex SC (1800 mg) for a median treatment duration of 35 months (range: 0 to 36 months) and 26 months (range 0.1 to 36 months) for ACTM.

Table 18 below summarizes the TEAEs in SMM3001.

Combination Treatment for AL Amyloidosis

Study AMY3001: Darzalex SC in combination with bortezomib, cyclophosphamide and dexamethasone

TEAEs in Table 19 reflect exposure to Darzalex SC (1800 mg) in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd) or bortezomib, cyclophosphamide and dexamethasone (VCd) for cycles 1-6 of treatment.

INTRAVENOUS FORMULATION (Darzalex)

The following sections present data from a separate Product Monograph for Darzalex intravenous formulation studies:

• Patients with newly diagnosed multiple myeloma who are ineligible for ASCT
• Patients with multiple myeloma who have received at least one prior therapy
• Patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD

Patients with newly diagnosed multiple myeloma who are ineligible for ASCT

Study MMY3008: Darzalex in combination with lenalidomide and dexamethasone

TEAEs described in Table 20 reflect exposure to Darzalex intravenous formulation in combination with lenalidomide and dexamethasone (DRd) for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) and a median treatment duration of 21.3 months (range: 0.03 to 40.64 months) for the lenalidomide-dexamethasone group (Rd).

Infusion-related reactions (including terms determined by investigators to be related to infusion; see Infusion-Related Reactions (IRRs) from Pooled Clinical Studies) were reported in 40.9% of patients in the DRd group.

Study MMY3007: Darzalex in combination with bortezomib, melphalan, and prednisone

TEAEs described in Table 21 reflect exposure to Darzalex intravenous formulation in combination with bortezomib, melphalan, and prednisone (D-VMP) for a median treatment duration of 14.7 months (range: 0 to 25.8 months) and a median treatment duration of 12 months (range: 0.1 to 14.8 months) for the bortezomib, melphalan, and prednisone (VMP) group.

Infusion-related reactions (including terms determined by investigators to be related to infusion; see Infusion-Related Reactions (IRRs) from Pooled Clinical Studies) were reported in 27.7% of patients in the D-VMP group.

Patients with multiple myeloma who have received at least one prior therapy

Study MMY3003: Darzalex in combination with lenalidomide/dexamethasone

TEAEs described in Table 22 reflect exposure to Darzalex intravenous formulation in combination with lenalidomide and dexamethasone (DRd) for a median treatment duration of 16.6 months (range: 0 to 24.4 months) and to lenalidomide and dexamethasone (Rd) for a median treatment duration of 14.8 months (range: 0.2 to 24.0 months).

Infusion-related reactions (including terms determined by investigators to be related to infusion; see Infusion-Related Reactions (IRRs) from Pooled Clinical Studies) were reported in 48% of patients in the DRd group.

Study MMY3004: Darzalex in combination with bortezomib/dexamethasone

TEAEs described in Table 23 reflect exposure to Darzalex intravenous formulation in combination with bortezomib and dexamethasone (DVd) for a median treatment duration of 11.1 months (range: 0 to 21.2 months) and to bortezomib and dexamethasone (Vd) for a median treatment duration of 5.2 months (range: 0.2 to 8.0 months).

Infusion-related reactions (including terms determined by investigators to be related to infusion; see Infusion-Related Reactions (IRRs) from Pooled Clinical Studies) were reported in 45% of patients in the DVd group.

CANDOR Study: Darzalex in combination with carfilzomib and dexamethasone

Patients received treatment with any study drug for a median duration of 70 weeks in the DKd arm and 40 weeks in the Kd arm. Patients received a median of 68 weeks of treatment with daratumumab and a median of 58 weeks of carfilzomib treatment in the DKd arm; patients in the Kd arm received a median of 40 weeks of carfilzomib. Adverse events that occurred in ≥5% of patients are presented in Table 24.

Patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD

Studies MMY2002 and GEN501: Darzalex monotherapy

The information below reflect exposure to Darzalex intravenous formulation. TEAEs occurring at a rate of ≥2% are presented in Table 25.

There were 4 deaths due to TEAEs (cardio-respiratory arrest [n=1], pneumonia [n=2] and general physical health deterioration [n=1]).

Bleeding events occurred in 20 patients (18.9%) in Study MMY2002 and 2 patients (4.4%) in Study GEN501. These were mainly Grade 1/2, with two Grade 3 events. Of these patients, 9 patients also had thrombocytopenia.

Adverse Events from Clinical Trials

Cardiac Disorders

Multiple myeloma

In Darzalex SC monotherapy Study MMY3012, the incidence of all grade cardiac disorder TEAEs was comparable between the Darzalex SC (7.3%) and Darzalex IV (6.6%) groups. Grade 3 and 4 cardiac disorder TEAEs were generally balanced between the 2 treatment groups (Darzalex SC: 1.2%; Darzalex IV 1.9%)

In Darzalex SC combination therapy Study MMY2040, for patients with newly diagnosed multiple myeloma treated with D-VMP the incidence of all grade cardiac disorder TEAEs was 7.5%, and the incidence of Grade 3 and 4 cardiac disorder TEAEs was 3.0%. For patients with relapsed or refractory multiple myeloma treated with D-Rd the incidence of all grade cardiac disorder TEAEs was 16.9%, and the incidence of Grade 3 and 4 cardiac disorder TEAEs was 6.2%. For patients with relapsed or refractory multiple myeloma treated with DKd the incidence of all Grade cardiac disorder TEAEs was 7.6%, and the incidence of Grade 3 and 4 cardiac disorder TEAEs was 3.0%.

In Darzalex SC Study MMY3013, the incidence of all grade cardiac disorder TEAEs was 12.7% in the DPd arm and 9.3% in the Pd arm. The incidence of Grade 3 and 4 cardiac disorder TEAEs was 4.2% and 4.0% in the DPd and Pd arms, respectively. The most commonly reported cardiac disorder TEAEs in the DPd arm were atrial fibrillation (DPd: 4.7%, Pd: 2.0%) and sinus tachycardia (DPd: 2.0%, Pd: 0%).

In Darzalex SC Study MMY3014, the incidence of all grade cardiac disorder TEAEs was 17.1% in the D-VRd arm and 10.1% in the VRd arm. The incidence of Grade 3 and 4 cardiac disorder TEAEs was 6.6% and 2.6% in the D-VRd and VRd arms, respectively. The most commonly reported cardiac disorder TEAEs in the D-VRd arm were atrial fibrillation (D-VRd: 5.1%, VRd: 2.3%) and sinus tachycardia (D-VRd: 2.8%, VRd: 0.6%).

In Darzalex SC Study MMY3019, the incidence of all grade cardiac disorder TEAEs was 28.4% in the D-VRd arm and 25.1% in the VRd arm. The incidence of Grade 3 or 4 cardiac disorder TEAEs was 8.1% and 7.7% in the D-VRd and VRd arms, respectively. The most commonly reported cardiac disorder TEAEs in the D-VRd arm were atrial fibrillation (D-VRd: 8.6%, VRd: 10.3%) and cardiac failure (D-VRd: 4.1%, VRd: 2.6%).

In Darzalex intravenous formulation combination therapy studies, a higher incidence of all grade cardiac disorder TEAEs occurred in the Darzalex arm compared with the control arm: in Study MMY3008 (DRd: 27.5 vs Rd: 26.3%); in Study MMY3007 (D-VMP: 14.7% vs VMP: 11.3%); in Study MMY3003 (DRd: 16.3% vs Rd: 10.0%); and in Study MMY3004 (DVd: 14.0% vs Vd: 6.3%). Grade 3 and 4 cardiac disorder TEAEs were generally balanced between the 2 arms in the studies (MMY3008, DRd: 8.2 % vs Rd: 8.2%; MMY3007, D-VMP: 3.8% vs VMP: 3.1%; MMY3003, DRd: 3.9% vs Rd: 3.2%; MMY3004, DVd: 4.5% vs Vd: 3.0%).

In Study MMY3008, the most commonly reported cardiac disorder TEAEs in the DRd arm were atrial fibrillation (DRd: 6.3%, Rd: 10.1%), palpitations (DRd: 3.3%, Rd: 2.2%), and cardiac failure (DRd: 3.0%, Rd: 3.6%).

In Study MMY3007, the most commonly reported cardiac disorder TEAE (≥2% incidence vs VMP arm) was atrial fibrillation (D-VMP: 4.9%; VMP: 2.0%).

In Study MMY3003, the most commonly reported cardiac disorder TEAEs in the DRd arm were atrial fibrillation (DRd 3.5%; Rd 2.8%), tachycardia (DRd 3.5%; Rd 0.7%), and angina pectoris (DRd 2.8%; Rd 0.4%).

In Study MMY3004, the most commonly reported cardiac disorder TEAEs in the DVd arm were atrial fibrillation (DVd 4.5%; Vd 1.7%), sinus tachycardia (DVd 2.5%; Vd 0.4%), and palpitations (DVd 2.1%; Vd 0.8%). Deaths due to cardiac disorders occurred in 1.2% of patients in the DVd arm and 0.4% of patients in the Vd arm.

In the CANDOR study, the most commonly reported cardiac disorder TEAEs in the DKd arm was cardiac failure (DKd 7.5%; Kd 10.5%). Deaths due to cardiac disorders occurred in 1.3% of patients in the DKd arm and none in the Kd arm.

In Darzalex SC Study SMM3001, the incidence of all grades cardiac disorder TEAEs was 14.5% in the Darzalex SC arm and 6.1% in the ACTM arm. The incidence of Grade 3 or 4 cardiac disorder TEAEs was 1.0% in the Darzalex SC and 2.0% in the ACTM arm. The most commonly reported cardiac disorder TEAEs in the Darzalex SC arm were palpitations (Darzalex SC 6.7%; ACTM 0.5%), tachycardia (Darzalex SC 4.1%; ACTM 0.5%), atrial fibrillation (Darzalex SC 2.1%; ACTM 0.5%), and sinus tachycardia (Darzalex SC 2.1%; ACTM 0.5%).

AL Amyloidosis

Among patients who received Darzalex SC in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3%), Stage II (46%), and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage I and II and 28% of patients with Stage III). Serious cardiac disorders that occurred in >2% of patients included cardiac failure (8%), cardiac arrest (4%), and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage I and II and 19% of patients with Stage III) who received Darzalex SC in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the D-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).

Herpes Zoster Virus Reactivation

Multiple myeloma

In the Darzalex SC monotherapy study MMY3012, systemic anti-viral medications were used in 77% of patients. Herpes zoster was reported in 1.2% of patients. In the Darzalex SC combination study, systemic anti-viral medications were used in 94%, 83%, and 94% of patients in the D-VMP, D-Rd, and

DKd cohorts, respectively. Herpes zoster was reported in 7.5%, 1.5%, and 1.5% of patients in the D-VMP, D-Rd, and DKd cohorts, respectively.

In Darzalex SC Study MMY3013, prophylactic anti-viral medication for herpes infection was used in 91.3% of patients in the DPd arm and 78.0% of patients in the Pd arm. Herpes zoster infection was reported in one patient in the DPd arm.

In Darzalex SC Study MMY3014, systemic anti-viral medications were used in 97.2% of patients in the D-VRd arm and 96.3% of patients in the VRd arm. Herpes zoster infection was reported in 5.1% and 6.6% of subjects in the D-VRd and VRd arms, respectively.

In Darzalex SC Study MMY3019, systemic anti-viral medications were used in 82.7% of patients in the D-VRd arm and 78.8% of patients in the VRd arm. Herpes zoster infection was reported in 5.1% of subjects in each the D-VRd and the VRd arm.

In Darzalex SC Study SMM3001, systemic anti-viral medications were used in 65.8% of participants in the Darzalex SC arm and 7.1% of patients in the ACTM arm. Herpes zoster TEAEs were reported in 4.7% and 1% of subjects in the Darzalex SC and ACTM arms, respectively.

In Darzalex intravenous formulation 16 mg/kg monotherapy studies, systemic anti-viral medications were used in 75% of patients. Herpes zoster was reported in 3% of patients.

In Darzalex intravenous formulation combination studies for patients with relapsed or refractory multiple myeloma, systemic anti-viral medications were used in 61.4% of patients. Herpes zoster was reported in 2.8% of patients. In Darzalex intravenous formulation combination studies for patients with newly diagnosed multiple myeloma, systemic anti-viral medications were used in 75% of patients. Herpes zoster was reported in 3.0% of patients.

AL Amyloidosis

In the Darzalex SC study AMY3001 in patients with newly diagnosed AL amyloidosis, systemic anti-viral medication was used in 76.1% of patients and prophylactic antivirals were administered in 82.4% of patients. Herpes zoster was reported in 5.2% and 6.4% of patients in the D-VCd and VCd cohorts, respectively.

Infections

Multiple myeloma

In patients receiving Darzalex SC monotherapy in Study MMY3012, the incidence of infections was similar between Darzalex SC (45.8%) and intravenous Darzalex groups (45.3%). Additionally, Grade 3 or 4 infections also occurred at similar frequencies between Darzalex SC (10.4%) and intravenous Darzalex (11.2%). Most infections were manageable and rarely led to treatment discontinuation (SC: 1.2%; IV:3.5%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection (SC: 2.7%; IV: 3.9%).

In the Darzalex SC combination therapy Study MMY2040 for patients with newly diagnosed multiple myeloma treated with D-VMP, the incidence of infections was 68.7%. Grade 3 or 4 infections were reported in 11.9% of patients. Pneumonia was the most commonly reported severe (Grade 3 or 4) infection (4.5%). Discontinuations from treatment due to infection were reported in 1.5% of patients. For patients with relapsed or refractory myeloma treated with D-Rd, infections were reported in 72.3%, and Grade 3 or 4 infections were reported in 23.1% of treated patients. Pneumonia was the most commonly reported severe (grade 3 or 4) infection (6.2%). Discontinuations from treatment due to infection were reported in 3.1% of patients. For patients with relapsed or refractory myeloma treated with DKd, infections were reported in 74.2%, and Grade 3 or 4 infections were reported in 10.6% of treated patients. Pneumonia was the most commonly reported severe (Grade 3 or 4) infection (3.0%).

In the Darzalex SC combination therapy Study MMY3013 for patients with relapsed or refractory multiple myeloma treated with DPd, the incidence of infections was 70.5% compared to 55.3% for patients treated with Pd. Grade 3 or 4 infections were reported in 28.2% of DPd treated patients compared to 22.7% of Pd treated patients. The most commonly reported severe (Grade 3 or 4) infection were pneumonia (13.4%) and lower respiratory tract infection (11.4%). Grade 5 (fatal) infections were reported for 5% of DPd patients (pneumonia, 3 patients; COVID-19, lower respiratory tract infection, sepsis, septic shock, 1 patient each; campylobacter infection and systemic candida in 1 patient) and for 3% of Pd treated patients (pneumonia, 2 patients; septic shock, 2 patients; lower respiratory tract infection, 1 patient). Discontinuations from treatment due to infection was reported for one patient.

In the Darzalex SC combination therapy Study MMY3014 of D-VRd for the treatment of patients with newly diagnosed multiple myeloma who are eligible for ASCT, the incidence of infections was 86.9% compared to 76.7% for patients treated with VRd. Grade 3 or 4 infections were reported in 35.3% of D-VRd treated patients compared to 27.4% of VRd treated patients. The most commonly (≥5%) reported severe (Grade 3 or 4) infection was pneumonia (10.5% D-VRd and 6.1% VRd). Grade 5 (fatal) infections were reported for 2.3% of D-VRd patients (COVID-19, COVID-19 pneumonia, and sepsis: 2 patients each; post-procedural sepsis, and septic shock: 1 patient each) and for 2.6% of VRd treated patients (sepsis, and septic shock: 3 patients each; COVID-19, pneumonia, and pneumonia influenzal: 1 patient each). The rate of infections leading to discontinuation 2.3% in D-VRd patients and 2.0% in VRd patients. Opportunistic infections occurred in 5.7% and 4.6% of patients treated with D-VRd and VRd, respectively.

In the Darzalex SC combination therapy Study MMY3019 for patients with newly diagnosed multiple myeloma who are not undergoing ASCT as initial therapy treated with D-VRd, the incidence of infections was 91.9% compared to 85.6% for patients treated with VRd. Grade 3 or 4 infections were reported in 40.1% of D-VRd treated patients compared to 31.8% of VRd treated patients. The most commonly (≥5%) reported severe (Grade 3 or 4) infection was pneumonia (14.2% D-VRd and 12.8% VRd). Grade 5 (fatal) infections were reported for 8.1% of D-VRd patients (COVID-19: 7 patients; COVID-19 pneumonia: 5 patients; pneumonia: 3 patients; septic shock: 1 patient) and for 6.2% of VRd treated patients (COVID-19: 5 patients; pneumonia: 4 patients; COVID-19 pneumonia, septic shock, and sepsis: 1 patient each). The rate of infections leading to discontinuation of all study treatment was 2.0% in D-VRd patients and 1.0% in VRd patients. Opportunistic infections occurred in 2.5% and 3.1% of patients treated with D-VRd and VRd, respectively.

In the Darzalex intravenous formulation combination therapy studies for patients with newly diagnosed multiple myeloma, infections were reported with Darzalex combinations and background therapies (DRd: 86%, Rd: 73%, D-VMP: 67%, VMP: 48%). Grade 3 or 4 infections were reported (DRd: 32%, Rd:

23%, D-VMP: 23%, VMP: 15%). Discontinuations from treatment due to infection were reported (DRd: 0.5%, Rd: 1.4%, D-VMP: 0.9%, VMP: 1.4%). Fatal infections were reported in 1.4% to 2.2% of patients across studies primarily due to pneumonia, sepsis, peritonitis, or upper respiratory tract infection.

In Darzalex intravenous formulation combination therapy studies for patients with relapsed or refractory multiple myeloma, infections were reported in 87% and 73% of patients in the DRd and DVd groups, respectively. Grade 1 or 2 infections were reported with Darzalex combinations and background therapies (Grade 1 - DVd: 7.8%, Vd: 10%, DRd: 14.1%, Rd: 10.7%; Grade 2 – DVd: 39.1%, Vd: 24.9%, DRd: 41.0%, Rd: 39.5%). Grade 3 or 4 infections were reported with Darzalex combinations and background therapies (DVd: 26%, Vd: 19%, DRd: 31%, Rd: 24%). Grade 5 infections were also reported (DVd: 1.2%, Vd: 1.7%, DRd: 2.8%, Rd: 1.4%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment due to infection were reported (DVd: 4.1%, Vd: 2.5%, DRd: 4.6%, Rd: 2.5%). Fatal infections were reported in 1.2% to 2.8% of patients across studies primarily due to pneumonia and sepsis. Higher rates of fatal infections (5%) have been observed when daratumumab is combined with carfilzomib/dexamethasone. In Darzalex intravenous formulation 16 mg/kg monotherapy studies, infections were reported in 59% of patients, the majority were respiratory tract infections (including upper respiratory tract infections and pneumonia) (48.1%). Most infections were Grade 1/2 in severity and Grade 3/4 infections were reported in 10% of patients. Pneumonia was the most common Grade 3/4 infection (5.8%).

In the CANDOR study for patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior therapies, infections were reported in 81.2% of patients in the DKd group. Grade ≥3 infections were reported for 37.3% of patients in the DKd group and 29.4% in the Kd group. Grade 5 infections were reported in 4.5% of patients in the DKd group and 2.6% in the Kd group. Pneumonia was the most commonly reported Grade ≥3 infection (DKd: 13.3%; Kd: 8.5%). Discontinuations from treatment due to infection were occurred in 4.5% of patients in the DKd group and 2.0% in the Kd group.

Opportunistic infections occurred at a higher incidence in patients receiving DVd (14%) compared to Vd alone (9%). Grade 3 and 4 TEAEs of opportunistic infection occurred in 5% of patients in the DVd arm and 0.4% of patients in the Vd arm. The incidence of opportunistic infections (any grade) was 13.1% in the DRd arm compared with 11.4% in the Rd arm. Serious opportunistic infection occurred in 2.5% of patients in the DRd arm and in 1.4% of patients in the Rd arm. In the CANDOR study, the incidence of opportunistic infections was 9.1% in the DKd arm and 3.9% in the Kd arm. Opportunistic infections were observed in 10.9% of the patients in Darzalex 16 mg/kg monotherapy studies.

Cytomegalovirus (CMV) infection was reported in 0.7% of patients treated with daratumumab in randomized clinical trials, with 0.5% of patients reporting serious events. These included cytomegalovirus infection, cytomegaloviral pneumonia, cytomegalovirus chorioretinitis, cytomegalovirus gastroenteritis and cytomegalovirus esophagitis.

In patients with high-risk SMM receiving Darzalex SC monotherapy in Study MMY3001, the incidence of Grade 3 or 4 infections was 16% in the Darzalex SC arm compared with 5% in the ACTM arm. The incidence of Grade 5 (fatal) infections was 1% in the Darzalex SC arm and 0% in the ACTM arm.

AL amyloidosis

In patients with AL amyloidosis receiving Darzalex SC combination therapy with VCd, the incidence of Grade 3 or 4 infections was 16.6% in the D-VCd arm, and 10.1% in the VCd arm. The incidence of Grade

5 (fatal) infections was 1% in both the D-VCd and VCd arms. The most commonly reported Grade 3 or 4 infection was pneumonia (D-VCd: 7.8%; VCd: 4.3%). The incidence of discontinuation due to infection was 1.6% in the D-VCd arm and 0.5% in the VCd arm.

Infusion-related Reactions (IRRs) from Pooled Clinical Studies

In clinical trials with Darzalex SC (monotherapy and combination treatments; N=1639), the incidence of any grade infusion related reactions was approximately 7.2% with the first (Week 1) injection, 0.5% with the Week 2 injection, and 1.3% with subsequent injections. Grades 3 and 4 IRRs were seen in 0.7% and 0.1% of patients, respectively.

In clinical trials with intravenous Darzalex (monotherapy and combination treatments, n=2356), the majority of IRRs were Grades 1 and 2. Grade 3 and Grade 4 IRRs were reported in approximately 4% and 0.2% of patients, respectively. The incidence of any grade infusion-related reactions was approximately 33% with the first (16 mg/kg, Week 1) infusion of Darzalex, 2% with the Week 2 infusion, and 6% with subsequent infusions. Less than 1% of patients had a Grade ≥3 infusion reaction with Week 2 or subsequent infusions. The median time to onset of a reaction was 1.5 hours (range: 0.0 to 72.8 hours). The incidence of infusion modifications due to reactions was approximately 32%. Median durations of 16 mg/kg infusions for the 1st, 2nd and subsequent infusions were 6.9, 4.3 and 3.5 hours respectively. Discontinuation of daratumumab treatment due to an IRR occurred in <1% of patients.

Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension and tachycardia.

Injection site reactions (ISRs)

In clinical trials with Darzalex SC, the incidence of any grade injection site reaction was 9.8%. There were no Grade 3 or 4 ISRs. The most common (≥ 1%) ISRs were erythema and rash.

Special Population

Geriatrics: The incidence of serious adverse reactions was higher in older than in younger patients.

Among patients with relapsed and refractory multiple myeloma (n=1213), the most common serious adverse reactions that occurred more frequently in elderly patients (≥65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the most common serious adverse reactions that occurred more frequently in elderly patients (≥75 years of age) was pneumonia. Among patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (n=351) the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia. Among patients with newly diagnosed multiple myeloma who are not undergoing autologous stem cell transplant as initial therapy (n=197), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia.

Of the 149 patients who received Darzalex SC as combination therapy with pomalidomide and dexamethasone for relapsed and refractory multiple myeloma, 42% were 65 to <75 years of age, and 16% were 75 years of age or older. No overall differences in effectiveness were observed based on age. Adverse reactions occurring at a higher frequency (≥5% difference) in patients ≥65 years of age included fatigue, pyrexia, peripheral edema, diarrhea, and cough. Serious adverse reactions occurring at a higher frequency (≥2% difference) in patients ≥65 years of age included pneumonia and thrombocytopenia.

Among patients with high-risk SMM (n=193), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia.

Among patients with newly diagnosed AL amyloidosis (n=193, including 87 aged ≥65 years), the most common serious adverse reaction that occurred more frequently in elderly patients (≥65 years of age) was pneumonia.

Other Adverse Reactions

Other adverse reactions (any grade) reported in patients treated with daratumumab in pooled clinical studies are listed in Table 26.

Table 26: Other adverse reactions reported in patients treated with daratumumab in clinical trials

8.3. Less Common Clinical Trial Adverse Reactions

SUBCUTANEOUS FORMULATION (Darzalex SC)

Monotherapy

Study MMY3012

Other TEAEs (<5% in the Darzalex SC arm) of clinical relevance include:

Infections and infestations: bronchitis, urinary tract infection, influenza, oral herpes, viral infection, herpes zoster, rhinitis, sepsis, septic shock, abscess limb, cellulitis, fungal infection, hepatitis B virus reactivation, salmonellosis.

Blood and lymphatic system disorders: febrile neutropenia.

General disorders and administration site conditions: chest pain, pain.

Gastrointestinal disorders: abdominal pain, gastrooesophageal reflux disease, stomatitis.

Metabolism and nutrition disorders: hypokalaemia, hyponatraemia, hyperkalaemia, diabetes mellitus.

Respiratory, thoracic and mediastinal disorders: hypoxia, respiratory failure.

Nervous system disorders: dizziness, peripheral sensory neuropathy, paraesthesia, tremor, aphasia, cognitive disorder, dysgeusia, hypoaesthesia.

Skin and subcutaneous tissue disorders: erythema, rash, urticaria.

Renal and urinary disorders: acute kidney injury.

Investigations: alanine aminotransferase increased, blood creatine increased, aspartate aminotransferase increased.

Vascular disorders: hypotension, hypertensive crisis.

Psychiatric disorders: anxiety.

Cardiac disorders: tachycardia, cardiac failure, atrial fibrillation, angina pectoris.

Eye disorders: cataract.

Hepatobiliary disorders: hepatitis toxic.

Combination Therapies in Multiple Myeloma

Study MMY2040 (D-VMP and D-Rd cohorts)

Other TEAEs (<5% across all cohorts) of clinical relevance include:

General disorders and administration site conditions: chest pain, influenza like illness.

Gastrointestinal disorders: odynophagia, stomatitis.

Blood and lymphatic system disorders: febrile neutropenia.

Nervous system disorders: peripheral motor neuropathy, syncope.

Infection and infestations: cellulitis, gastroenteritis, influenza, cytomegalovirus infection, neutropenic sepsis, oral candidiasis, sepsis.

Psychiatric disorders: anxiety, depression.

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased.

Metabolism and nutrition disorders: hyperkalaemia, diabetic metabolic decompensation.

Vascular disorders: deep vein thrombosis, orthostatic hypotension.

Cardiac disorders: atrial fibrillation, cardiac failure, tachycardia.

Renal and urinary disorders: renal failure.

Study MMY2040 (DKd cohort)

Other TEAEs (<5% in the DKd cohort) of clinical relevance include:

Gastrointestinal disorders: pancreatitis.

Infection and infestations: urinary tract infection, herpes zoster, sepsis.

Metabolism and nutrition disorders: decreased appetite, hypocalcemia.

Nervous system disorders: dizziness, syncope.

General disorders and administration site conditions: infusion reactions, chills.

Vascular disorders: hypotension.

Study MMY3014: Darzalex SC in combination with bortezomib/lenalidomide/dexamethasone (adult patients with newly diagnosed multiple myeloma who are eligible for ASCT)

Other TEAEs (<5% in the D-VRd arm) of clinical relevance include:

Cardiac disorders: sinus tachycardia, palpitations.

Ear and labyrinth disorder: tinnitus, vertigo.

Eye disorders: cataract, dry eye.

Gastrointestinal disorders: hemorrhoids, dry mouth, gastroesophageal reflux disease, toothache, inguinal hernia rectal hemorrhage, abdominal distension, mouth ulceration.

General disorders and administration site conditions: injection site erythema, malaise, chills, chest pain, pain, peripheral swelling, edema.

Hepatobiliary disorders: hepatic cytolysis, hyperbilirubinemia, cholestasis.

Infection and infestations: rhinitis, sinusitis, COVID-19 pneumonia, conjunctivitis, respiratory syncytial infection, tooth infection, cystitis, ear infection, oral candidiasis, pharyngitis, parainfluenza virus infection, sepsis, Escherichia urinary tract infection, respiratory tract infection, viral upper respiratory tract infection.

Injury, poisoning and procedural complications: fall, tooth fracture.

Investigations: weight decreased, blood creatinine increased.

Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, iron deficiency, hyponatremia.

Musculoskeletal and connective tissue disorders: neck pain, muscular weakness, musculoskeletal pain, spinal pain, flank pain.

Neoplasms benign, malignant and unspecified (incl cysts and polyps): basal cell carcinoma, squamous cell carcinoma.

Nervous system disorders: peripheral motor neuropathy, peripheral sensorimotor neuropathy, syncope, presyncope, dysesthesia, somnolence, ageusia.

Psychiatric disorders: agitation, depression.

Renal and urinary disorders: renal impairment, dysuria, renal failure.

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, rhinorrhea, pulmonary embolism, dysphonia, hiccups, productive cough, dyspnea exertional, epistaxis.

Skin and subcutaneous tissue disorders: hyperhidrosis, urticaria, eczema.

Vascular disorders: deep vein thrombosis, superficial vein thrombosis, orthostatic hypotension.

Study MMY3019: Darzalex SC in combination with bortezomib/lenalidomide/dexamethasone (adult patients with newly diagnosed multiple myeloma who are not candidates for ASCT)

Other TEAEs (<5% in the D-VRd arm) of clinical relevance include:

Blood and lymphatic system disorders: febrile neutropenia, iron deficiency anaemia, leukocytosis.

Cardiac disorders: cardiac failure, angina pectoris, sinus tachycardia, arrhythmia.

Ear and labyrinth disorder: hypoacusis, deafness.

Eye disorders: ocular hyperaemia, lacrimation increased, visual acuity reduced, visual impairment.

Gastrointestinal disorders: inguinal hernia, gingival pain, rectal haemorrhage, abdominal pain.

General disorders and administration site conditions: non-cardiac chest pain, chest pain, gait disturbance, injection site bruising, injection site pain.

Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatocellular injury.

Immune system disorders: hypersensitivity.

Infection and infestations: COVID-19 pneumonia, skin infection, fungal skin infection, gingivitis, oral herpes, septic shock, erysipelas, oral candidiasis, candida infection, viral infection.

Injury, poisoning and procedural complications: limb injury, joint dislocation, skin abrasion.

Investigations: C-reactive protein increased, blood lactate dehydrogenase increased, fibrin D dimer increased.

Metabolism and nutrition disorders: hyperkalaemia, hypoalbuminaemia, hyperuricaemia, vitamin D deficiency, diabetes mellitus, hypoglycaemia.

Musculoskeletal and connective tissue disorders: arthritis, osteoporosis, pain in jaw, pathological fracture.

Nervous system disorders: presyncope, memory impairment, neuropathy peripheral, cerebrovascular accident, dysaesthesia, somnolence, taste disorder, ageusia, amnesia, sciatica.

Renal and urinary disorders: haematuria, acute kidney injury, chronic kidney disease, pollakiuria, urinary incontinence.

Reproductive system and breast disorders: pelvic pain.

Respiratory, thoracic and mediastinal disorders: dyspnoea exertional, rhinitis allergic, respiratory failure, upper-airway cough syndrome.

Skin and subcutaneous tissue disorders: alopecia, hyperhidrosis, dermatitis allergic, rash pruritic, urticaria, ecchymosis.

Vascular disorders: hot flush.

Study MMY3013: Darzalex SC in combination with pomalidomide/dexamethasone

Other TEAEs (<5% in the DPd arm) of clinical relevance include:

General disorders and administration site conditions: non-cardiac chest pain, influenza like illness, chills, malaise, general physical health deterioration, pain.

Gastrointestinal disorders: dyspepsia, abdominal distension, abdominal pain, odynophagia, colitis ischemic, stomatitis.

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, spinal pain, myalgia, myopathy.

Nervous system disorders: headache, paraesthesia, dizziness, neuropathy peripheral, amnesia, balance disorder, dysgeusia, hypoesthesia.

Infection and infestations: influenza, cellulitis, fungal infection, gastroenteritis, COVID-19, conjunctivitis, otitis media, viral infection.

Psychiatric disorders: anxiety, depression, agitation, confusional state, mood altered, nervousness, affective disorder.

Investigations: ECOG performance status worsened, blood creatinine increased, alanine aminotransferase increased, aspartate aminotransferase increased, c-reactive protein increased, weight decreased, blood bicarbonate decreased, fibrin D dimer increased.

Metabolism and nutrition disorders: decreased appetite, hypophosphatemia, hypomagnesemia, hyperuricemia, type-2 diabetes mellitus, hyperlipidemia, hyponatremia.

Respiratory, thoracic and mediastinal disorders: rhinorrhea, productive cough, catarrh, hiccups, oropharyngeal pain, pulmonary embolism, respiratory failure, rhinitis allergic.

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritis, erythema, alopecia, dry skin, ecchymosis.

Vascular disorders: hypertension, flushing, orthostatic hypotension, thrombosis.

Cardiac disorders: atrial fibrillation, sinus tachycardia, angina pectoris, tachycardia.

Renal and urinary disorders: renal impairment, acute kidney injury.

Injury, poisoning and procedural complications: lumbar vertebral fracture, rib fracture

Eye disorder: cataract

Endocrine disorders: cushingoid

Hepatobiliary disorders: hyperbilirubinaemia

Immune system disorders: hypogammaglobulinemia

Smouldering Multiple Myeloma

Study SMM3001: Darzalex SC for Monotherapy

Other TEAEs (<5% in the Darzalex SC arm) of clinical relevance include:

General disorders and administration site conditions: malaise, injection site haematoma, pain

Blood and lymphatic system disorders: leukopenia, thrombocytopenia

Gastrointestinal disorders: toothache, gastritis, dry mouth

Infection and infestations: bronchitis, herpes zoster, conjunctivitis, gastroenteritis, diverticulitis, ear infection, folliculitis, sepsis

Nervous system disorders: burning sensation, dizziness postural, dysgeusia, sciatica, syncope

Respiratory, thoracic and mediastinal disorders: dysphonia, rhinitis allergic, hiccups, wheezing

Metabolism and nutrition disorders: hypokalaemia, decreased appetite, hypercholesterolaemia, hyperglycaemia, hypomagnesaemia, iron deficiency

Musculoskeletal and connective tissue disorders: bone pain, osteoarthritis, arthritis, muscular weakness

Skin and subcutaneous tissue disorders: rash maculo-papular, hyperhidrosis, urticaria, night sweats, rash erythematous, rash pruritic

Cardiac disorders: tachycardia, atrial fibrillation, sinus tachycardia

Vascular disorders: deep vein thrombosis

Renal and urinary disorders: haematuria

Eye disorders: cataract, dry eye, vision blurred

Ear and labyrinth disorder: vertigo, tinnitus, vertigo positional

Psychiatric disorders: depression, insomnia

Neoplasms benign, malignant and unspecified (incl cysts and polyps): basal cell carcinoma

Injury, poisoning and procedural complications: hot flush

Hepatobiliary disorders: alanine aminotransferase increased, aspartate aminotransferase increased

Investigations: alanine aminotransferase increased

Combination Treatment for AL Amyloidosis

Study AMY3001: Darzalex SC in combination with bortezomib, cyclophosphamide and dexamethasone

Other TEAEs (<5% in the D-VCd arm) of clinical relevance include:

General disorders and administration site conditions: chest pain, influenza-like illness, malaise, localized edema, sudden death, face edema, injection site discolouration, injection site hematoma.

Blood and lymphatic system disorders: febrile neutropenia.

Gastrointestinal disorders: dysphagia, flatulence, gastroesophageal reflux disease, hemorrhoids, stomatitis, mouth hemorrhage, hematochezia, ascites, aphthous ulcer, gastric ulcer, odynophagia.

Infection and infestations: candidiasis, urinary tract infection, gastroenteritis, otitis media, tooth infection, tooth abscess.

Nervous system disorders: neuralgia, presyncope, hypoesthesia, neuropathy peripheral, somnolence, cerebral infarction, dizziness postural, lethargy, post-herpetic neuralgia.

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, nasal congestion, dysphonia, rales, hiccups, rhinorrhea.

Metabolism and nutrition disorders: hyperkalemia, hyperuricemia, fluid retention, hypertriglyceridemia, hypoglycemia, hypercholesterolemia, hypomagnesemia.

Musculoskeletal and connective tissue disorder: musculoskeletal chest pain.

Skin and subcutaneous tissue disorders: maculo-papular rash, alopecia, dry skin, pruritis, decubitis ulcer, hyperhidrosis, dermatitis allergic, petechia, rash pruritic, urticaria.

Investigations: weight decreased, weight increased, alpha hydroxybutyrate dehydrogenase increased, blood lactate dehydrogenase increased, blood creatinine phosphokinase increased, troponin I increased.

Cardiac disorders: cardiac arrest, angina pectoris, palpitations, pericardial effusion, tachycardia.

Vascular disorders: hypertension.

Renal and urinary disorders: acute kidney injury, hematuria.

Ear and labyrinth disorder: vertigo, deafness, hypoacusis, tinnitus.

Eye disorder: blepharitis, vision blurred, conjunctival hemorrhage, eye irritation, visual impairment, vitreous floaters.

Psychiatric disorders: Confusional state, depressive symptom.

INTRAVENOUS FORMULATION (Darzalex)

The following sections present data from a separate Product Monograph for Darzalex intravenous formulation studies:

• Patients with newly diagnosed multiple myeloma who are ineligible for ASCT
• Patients with multiple myeloma who have received at least one prior therapy
• Patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD

Patients with newly diagnosed multiple myeloma who are ineligible for ASCT

Study MMY3008: Darzalex in combination with lenalidomide and dexamethasone

Other TEAEs (<5% and ≥2% in the DRd arm) of clinical relevance include:

Cardiac disorders: palpitations, cardiac failure, bradycardia, sinus tachycardia.

Ear and labyrinth disorders: vertigo, tinnitus, hypoacusis.

Gastrointestinal disorders: abdominal distension, hemorrhoids, gastritis, flatulence, inguinal hernia.

General disorders and administration site conditions: influenza-like illness, pain, malaise, chest discomfort, peripheral swelling, chest pain, edema.

Hepatobiliary disorders: hyperbilirubinemia.

Infections and infestations: cystitis, pharyngitis, cellulitis, lung infection, sepsis, tooth abscess, conjunctivitis, diverticulitis, tooth infection.

Injury, poisoning and procedural complications: rib fracture, spinal compression fracture.

Investigations: alanine aminotransferase increased, blood alkaline phosphatase increased.

Metabolism and nutritional disorders: gout, hyperkalemia, vitamin D deficiency, hypoalbuminemia, hypoglycemia, vitamin B12 deficiency.

Musculoskeletal and connective tissue disorders: pain in jaw, joint swelling, arthritis.

Neoplasms benign, malignant and unspecified (incl cysts and polyps): basal cell carcinoma, squamous cell carcinoma of skin.

Nervous system disorders: syncope, memory impairment, ageusia, cognitive disorder, neuropathy peripheral.

Psychiatric disorders: agitation, mood altered.

Renal and urinary disorders: dysuria, urinary retention, hematuria, nocturia.

Reproductive system and breast disorders: pelvic pain.

Respiratory, thoracic and mediastinal disorders: productive cough, nasal congestion, throat irritation, rhinitis allergic, wheezing, bronchospasm, hypoxia.

Skin and subcutaneous tissue disorders: skin ulcer.

Vascular disorders: hematoma, flushing, orthostatic hypotension.

Study MMY3007: Darzalex in combination with bortezomib, melphalan, and prednisone

Other TEAEs (<5% and ≥2% in the D-VMP arm) of clinical relevance include:

Infections and infestations: herpes zoster, lower respiratory tract infection, viral upper respiratory tract infection, pharyngitis, sinusitis, influenza, oral herpes, respiratory tract infection.

Gastrointestinal disorders: abdominal distension, abdominal pain or discomfort, stomatitis.

General disorders and administration site conditions: influenza-like illness, injection site erythema, malaise, non-cardiac chest pain, peripheral swelling.

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, bronchospasm, catarrh, epistaxis, nasal congestion, pleural effusion, pulmonary edema.

Musculoskeletal and connective tissue disorders: myalgia, musculoskeletal pain, musculoskeletal chest pain.

Nervous system disorders: paraesthesia, dysgeusia, peripheral sensorimotor neuropathy, syncope, tremor.

Metabolism and nutritional disorders: hyperuricemia, hyperkalemia, hyponatremia, dehydration, hypoalbuminemia.

Psychiatric disorders: depression, confusional state.

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased, gamma-glutamyltransferase increased, blood alkaline phosphatase increased, blood creatinine increased, oxygen saturation decreased.

Renal and urinary disorders: dysuria, acute kidney injury.

Injury, poisoning and procedural complications: fall, spinal compression fracture, contusion.

Cardiac disorders: atrial fibrillation.

Patients with multiple myeloma who have received at least one prior therapy

Study MMY3003: Darzalex in combination with lenalidomide/dexamethasone

Other TEAEs (<5% in the DRd arm) of clinical relevance include:

Infections and infestations: conjunctivitis, gastroenteritis, herpes zoster, oral candidiasis, oral herpes.

Gastrointestinal disorders: toothache, abdominal distension, dry mouth, mouth ulceration, abdominal discomfort, dysphagia, hemorrhoids.

General disorders and administration site conditions: non-cardiac chest pain, malaise, chest discomfort.

Respiratory, thoracic and mediastinal disorders: dysphonia, nasal congestion, bronchospasm, rhinitis allergic, oropharyngeal pain, rhinorrhea, throat irritation, epistaxis, wheezing, hiccups, pulmonary embolism, hypoxia, laryngeal edema.

Musculoskeletal and connective tissue disorders: neck pain, pain in jaw, spinal pain.

Nervous system disorders: paraesthesia, hypoesthesia neuropathy peripheral, syncope, lethargy.

Metabolism and nutritional disorders: dehydration, hypomagnesemia, hyponatremia, hyperuricemia.

Skin and subcutaneous tissue disorders: dry skin, urticaria, erythema.

Psychiatric disorders: restlessness, agitation, irritability, mood altered.

Vascular disorders: flushing.

Investigations: aspartate aminotransferase increased, blood creatinine increased, gamma-glutamyltransferase increased, blood alkaline phosphatase increased.

Eye disorders: eye irritation, lacrimation increased.

Renal and urinary disorders: pollakiuria.

Injury, poisoning and procedural complications: fall, contusion.

Cardiac disorders: atrial fibrillation, tachycardia, angina pectoris.

Ear and labyrinth disorders: tinnitus.

Study MMY3004: Darzalex in combination with bortezomib/dexamethasone

Other TEAEs (<5% in the DVd arm) of clinical relevance include:

Infections and infestations: urinary tract infection, influenza, oral herpes, gastroenteritis.

Nervous system disorders: paraesthesia, dysgeusia, peripheral motor neuropathy, lethargy.

Gastrointestinal disorders: abdominal distension, abdominal pain, abdominal discomfort, gastroesophageal reflux disease, dyspepsia.

General disorders and administration site conditions: chills, pain, chest pain, influenza-like illness, injection site erythema, malaise.

Respiratory, thoracic and mediastinal disorders: epistaxis, nasal congestion, oropharyngeal pain, rhinorrhea, wheezing.

Musculoskeletal and connective tissue disorders: musculoskeletal pain, myalgia, myopathy, spinal pain, neck pain.

Metabolism and nutritional disorders: hypocalcemia, hyponatremia, hypoalbuminemia diabetes mellitus, hypercalcemia.

Psychiatric disorders: depression, restlessness.

Vascular disorders: hypotension, flushing, hematoma.

Investigations: aspartate aminotransferase increased, glutamyltransferase increased, weight increased, blood creatinine increased.

Skin and subcutaneous tissue disorders: hyperhidrosis, erythema, pruritis.

Eye disorders: eye irritation, lacrimation increased, dry eye, vision blurred.

Cardiac disorders: atrial fibrillation, sinus tachycardia, palpitations.

Injury, poisoning and procedural complications: fall.

Ear and labyrinth disorders: vertigo, tinnitus.

Renal and urinary disorders: renal impairment.

Endocrine disorders: cushingoid.

CANDOR Study: Darzalex in combination with carfilzomib and dexamethasone*

* All adverse reactions < 5% based on the DKd arm:

Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpura)

Cardiac disorders: cardiac failure, tachycardia, atrial fibrillation, palpitations, cardiac arrest, myocardial infarction, myocardial ischemia, pericardial effusion

Ear and labyrinth disorders: tinnitus

Eye disorders: vision blurred

Gastrointestinal disorders: dyspepsia, toothache, gastrointestinal hemorrhage

General disorders and administration site conditions: chest pain, pain, influenza like illness, malaise, infusion site reactions

Hepatobiliary disorders: hyperbilirubinemia, cholestasis

Infections and infestations: sepsis, viral infection, gastroenteritis, lung infection, rhinitis, clostridium difficile colitis

Investigations: alanine aminotransferase increased, blood creatinine increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, C-reactive protein increased, ejection fraction decreased, creatinine renal clearance decreased

Metabolism and nutrition disorders: hypocalcemia, hypomagnesaemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, hypophosphatemia, dehydration, tumour lysis syndrome, hypercalcemia

Musculoskeletal and connective tissue disorders: myalgia, musculoskeletal chest pain, muscular weakness, bone pain, musculoskeletal pain

Nervous system disorders: hypoesthesia, cerebrovascular accident, posterior reversible encephalopathy syndrome, intracranial hemorrhage, paresthesia

Psychiatric disorders: anxiety

Renal and urinary disorders: acute kidney injury, renal impairment, renal failure

Respiratory, thoracic and mediastinal disorders: dysphonia, oropharyngeal pain, epistaxis, pulmonary embolism, pulmonary hypertension, pulmonary edema, interstitial lung disease, wheezing, pneumonitis, pulmonary hemorrhage, acute respiratory failure

Skin and subcutaneous tissue disorders: pruritus, erythema, hyperhidrosis

Vascular disorder: hypotension, deep vein thrombosis, flushing, hypertensive crisis

Of the 307 patients in the DKd arm with baseline CrCL data, 174 had CrCL ≥ 80 mL/min (normal renal function), 96 had CrCL ≥ 50 to < 80 mL/min (mild renal impairment), 32 had CrCL ≥ 30 to < 50 mL/min (moderate renal impairment), and 5 had CrCL ≥ 15 to < 30 mL/min (severe renal impairment). Serious adverse events were reported in 58.0%, 56.3%, 87.5% and 80.0% of patients with normal renal function, mild renal impairment, moderate renal impairment and severe renal impairment, respectively; fatal adverse events were reported in 9.2%, 7.3%, 18.8% and 20.0% of patients, respectively. Of the 293 patients in the DKd arm with baseline hepatic status (based on bilirubin and transaminase levels), 269 had normal hepatic function and 24 had mild hepatic impairment. Patients with moderate or severe hepatic impairment were excluded from the study. Serious adverse events were reported in 58.7% and 70.8% of patients with normal hepatic function and mild hepatic impairment, respectively; fatal adverse events were reported in 8.9% and 12.5% of patients, respectively.

Patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD

Studies MMY2002 and GEN501: Darzalex monotherapy

Other TEAEs (<2%) of clinical relevance include:

Blood and lymphatic system disorders: red blood cell agglutination, crossmatch incompatible.

Respiratory, thoracic and mediastinal disorders: hypoxia, throat tightness, upper-airway cough syndrome, respiratory failure, dysphonia, laryngeal edema, laryngitis allergic, pulmonary edema, rhinorrhea.

Gastrointestinal disorders: abdominal distension, gastroesophageal reflux disease, colitis, dysphagia, gastritis, pancreatitis.

Infections and infestations: conjunctivitis, candida infection, varicella, cellulitis, cystitis, ear infection, gastroenteritis, oral fungal infection, pyelonephritis, parainfluenza virus infection, pharyngitis, sepsis.

Metabolism and nutrition disorders: hypocalcemia; diabetes mellitus, hypernatremia, hyperphosphatemia, hypoglycemia.

Nervous system disorders: syncope, depressed level of consciousness, encephalopathy.

Skin and subcutaneous tissue disorders: eczema, erythema, petechia, rash maculo-papular, urticaria.

Vascular disorders: flushing.

Renal and urinary disorders: hematuria, pollakiuria, proteinuria, renal failure, urinary retention.

Investigations: electrocardiogram QT prolonged.

Cardiac disorders: tachycardia, angina pectoris, atrial flutter, bradycardia, cardiac failure congestive, transient ischemic attack.