6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypersensitivity and Other Administration Reactions [see Warnings and Precautions (5.1)] .
Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Warnings and Precautions (5.2)] .
Neutropenia [see Warnings and Precautions (5.3)] .
Thrombocytopenia [see Warnings and Precautions (5.4)] .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant

In Combination with Bortezomib, Lenalidomide and Dexamethasone

The safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone (n=351) from the start of induction to the end of consolidation compared to bortezomib, lenalidomide and dexamethasone (VRd) (n=347) was evaluated in PERSEUS [see Clinical Studies (14.1)] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8 and once every 2 weeks from weeks 9 to 16 during induction in combination with VRd or VRd alone. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT. Within 12 weeks of ASCT, and when engraftment was complete, patients received DARZALEX FASPRO once every 2 weeks from weeks 1 to 8 during consolidation in combination with VRd or VRd alone.

The median duration of treatment for induction and consolidation was 9.9 months (0.5 to 18.5 months) for DARZALEX FASPRO-VRd.

Serious adverse reactions occurred in 37% of patients who received DARZALEX FASPRO-VRd. The most frequent serious adverse reaction in >5% of patients who received DARZALEX FASPRO-VRd was pneumonia (6%). Fatal adverse reactions occurred in 1.7% of patients who received DARZALEX FASPRO-VRd.

Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-VRd. An adverse reaction which resulted in permanent discontinuation of DARZALEX FASPRO-VRd in more than 1 patient included sepsis.

The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, edema, pyrexia, upper respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia, and rash.

Table 7 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PERSEUS.

Table 7: Adverse Reactions (≥10%) in Patients with Newly Diagnosed Multiple Myeloma Eligible for ASCT Who Received DARZALEX FASPRO-VRd through the End of Consolidation in PERSEUS
Adverse Reaction	DARZALEX FASPRO-VRd (N=351)		VRd (N=347)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Key: VRd=bortezomib-lenalidomide-dexamethasone
* Peripheral neuropathy includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. † Only Grade 3 adverse reactions occurred. ‡ Includes other related terms. § Upper respiratory tract infection includes fungal pharyngitis, h1n1 influenza, influenza, influenza like illness, laryngitis, nasopharyngitis, oral candidiasis, oropharyngeal candidiasis, parainfluenzae virus infection, pharyngitis, respiratory moniliasis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, upper respiratory tract infection, viral tonsillitis, and viral upper respiratory tract infection. ¶ Pneumonia includes bronchopulmonary aspergillosis, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, and pneumonia streptococcal. # Fatal adverse reactions included Pneumonia: n=1 (0.3%) in the VRd arm. Þ Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic cytolysis, hepatic failure, hepatic function abnormal, hepatoxicity, hyperbilirubinemia, hypertransaminasemia, and liver disorder
Nervous system disorders
Peripheral neuropathy *	52	5	54	4
Paraesthesia	11	<1 †	11	<1 †
General disorders and administration site conditions
Fatigue ‡	35	3 †	37	5 †
Edema ‡	22	1	21	1 †
Pyrexia	21	2 †	22	3 †
Infections
Upper respiratory tract infection §	32	1 †	26	2 †
Pneumonia ¶	14	9	10	6 #
Gastrointestinal disorders
Constipation	31	2 †	30	2 †
Diarrhea	23	3 †	25	5 †
Nausea	16	1 †	12	1 †
Abdominal pain ‡	11	0	12	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain ‡	26	1 †	23	1 †
Muscle spasm	12	0	9	<1 †
Psychiatric disorders
Insomnia	26	2 †	16	2 †
Skin and subcutaneous tissue disorders
Rash ‡	25	3 †	31	5
Hepatobiliary disorders
Hepatotoxicity Þ	16	6 †	16	5
Respiratory, thoracic and mediastinal disorders
Cough ‡	12	<1 †	8	0

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, lenalidomide and dexamethasone include:

Gastrointestinal disorders:vomiting, hemorrhoids
Musculoskeletal and connective tissue disorders:arthralgia
Infections:bronchitis, sepsis, urinary tract infection, herpes zoster, Covid-19, cytomegalovirus infection
Respiratory, thoracic, and mediastinal disorders:dyspnea, pulmonary edema
Metabolism and nutrition disorders:hypocalcemia, decreased appetite, hyperglycemia, dehydration
Vascular disorders:hypotension, hypertension, orthostatic hypotension
General disorders and administration site conditions:infusion reactions, injection site reaction, chills
Nervous system disorders:dizziness, headache, syncope
Cardiac disorders:thrombosis, atrial fibrillation, tachycardia
Skin and subcutaneous tissue disorders:pruritus

Table 8 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PERSEUS.

Table 8: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline in Patients with Newly Diagnosed Multiple Myeloma Eligible for ASCT Who Received DARZALEX FASPRO-VRd through the End of Consolidation in PERSEUS
Laboratory Abnormality	DARZALEX FASPRO-VRd *		VRd *
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Key: VRd=bortezomib-lenalidomide-dexamethasone
* Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=351 for DARZALEX FASPRO-VRd and N=346 for VRd.
Hematology
Decreased platelets	89	34	78	25
Decreased lymphocytes	87	69	69	43
Decreased leukocytes	78	47	56	22
Decreased neutrophils	67	52	47	34
Decreased hemoglobin	39	7	43	6
Chemistry
Increased alanine aminotransferase (ALT)	52	7	48	5
Decreased sodium	40	5	25	5
Increased alkaline phosphatase	39	0	36	1
Decreased potassium	30	6	24	3

Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant

In Combination with Bortezomib, Melphalan and Prednisone

The safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.1)] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity (N=67) in combination with bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for 6 months or longer and 19% were exposed for greater than one year.

Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.

Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient was neutropenic sepsis.

Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia.

The most common adverse reactions (≥20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.

Table 9 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.

Table 9: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADES
Adverse Reaction	DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (N=67)
Adverse Reaction	All Grades (%)	Grades ≥3 (%)
* Upper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. † Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. ‡ Only Grade 3 adverse reactions occurred. § Abdominal pain includes abdominal pain, and abdominal pain upper. ¶ Fatigue includes asthenia, and fatigue. # Edema peripheral includes edema, edema peripheral, and peripheral swelling. Þ Cough includes cough, and productive cough.
Infections
Upper respiratory tract infection *	39	0
Bronchitis	16	0
Pneumonia †	15	7 ‡
Gastrointestinal disorders
Constipation	37	0
Nausea	36	0
Diarrhea	33	3 ‡
Vomiting	21	0
Abdominal pain §	13	0
General disorders and administration site conditions
Fatigue ¶	36	3
Pyrexia	34	0
Edema peripheral #	13	1 ‡
Nervous system disorders
Peripheral sensory neuropathy	34	1 ‡
Dizziness	10	0
Respiratory, thoracic and mediastinal disorders
Cough Þ	24	0
Psychiatric disorders
Insomnia	22	3 ‡
Musculoskeletal and connective tissue disorders
Back pain	21	3 ‡
Musculoskeletal chest pain	12	0
Metabolism and nutrition disorders
Decreased appetite	15	1 ‡
Skin and subcutaneous tissue disorders
Rash	13	0
Pruritus	12	0
Vascular disorders
Hypertension	13	6 ‡
Hypotension	10	3 ‡

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone included:

General disorders and administration site conditions:infusion reaction, injection site reaction, chills
Infections:herpes zoster, urinary tract infection, influenza, sepsis
Musculoskeletal and connective tissue disorders:arthralgia, muscle spasms
Nervous system disorders:headache, paresthesia
Metabolism and nutrition disorders:hypocalcemia, hyperglycemia
Respiratory, thoracic and mediastinal disorders:dyspnea, pulmonary edema
Cardiac disorders:atrial fibrillation

Table 10 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.

Table 10: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADES
Laboratory Abnormality	DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone *
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)
* Denominator is based on the safety population treated with DARZALEX FASPRO-VMP (N=67).
Decreased leukocytes	96	52
Decreased lymphocytes	93	84
Decreased platelets	93	42
Decreased neutrophils	88	49
Decreased hemoglobin	48	19

Relapsed/Refractory Multiple Myeloma

In Combination with Lenalidomide and Dexamethasone

The safety of DARZALEX FASPRO with lenalidomide and dexamethasone was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for 6 months or longer and 20% were exposed for greater than one year.

Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients.

Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient were pneumonia and anemia.

Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased.

The most common adverse reactions (≥20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.

Table 11 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.

Table 11: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADES
Adverse Reaction	DARZALEX FASPRO with Lenalidomide and Dexamethasone (N=65)
Adverse Reaction	All Grades (%)	Grades ≥3 (%)
* Fatigue includes asthenia, and fatigue. † Only Grade 3 adverse reactions occurred. ‡ Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. § Pneumonia includes lower respiratory tract infection, lung infection, and pneumonia. ¶ Bronchitis includes bronchitis, and bronchitis viral. # Dyspnea includes dyspnea, and dyspnea exertional. Þ Cough includes cough, and productive cough.
General disorders and administration site conditions
Fatigue *	52	5 †
Pyrexia	23	2 †
Edema peripheral	18	3 †
Gastrointestinal disorders
Diarrhea	45	5 †
Constipation	26	2 †
Nausea	12	0
Vomiting	11	0
Infections
Upper respiratory tract infection ‡	43	3 †
Pneumonia §	23	17
Bronchitis ¶	14	2 †
Urinary tract infection	11	0
Musculoskeletal and connective tissue disorders
Muscle spasms	31	2 †
Back pain	14	0
Respiratory, thoracic and mediastinal disorders
Dyspnea #	22	3
Cough Þ	14	0
Nervous system disorders
Peripheral sensory neuropathy	17	2 †
Psychiatric disorders
Insomnia	17	5 †
Metabolism and nutrition disorders
Hyperglycemia	12	9 †
Hypocalcemia	11	0

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with lenalidomide and dexamethasone included:

Musculoskeletal and connective tissue disorders:arthralgia, musculoskeletal chest pain
Nervous system disorders:dizziness, headache, paresthesia
Skin and subcutaneous tissue disorders:rash, pruritus
Gastrointestinal disorders:abdominal pain
Infections:influenza, sepsis, herpes zoster
Metabolism and nutrition disorders:decreased appetite
Cardiac disorders:atrial fibrillation
General disorders and administration site conditions:chills, infusion reaction, injection site reaction
Vascular disorders:hypotension, hypertension

Table 12 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.

Table 12: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADES
Laboratory Abnormality	DARZALEX FASPRO with Lenalidomide and Dexamethasone *
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)
* Denominator is based on the safety population treated with DARZALEX FASPRO-Rd (N=65).
Decreased leukocytes	94	34
Decreased lymphocytes	82	58
Decreased platelets	86	9
Decreased neutrophils	89	52
Decreased hemoglobin	45	8

In Combination with Pomalidomide and Dexamethasone

The safety of DARZALEX FASPRO with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone (Pd) in patients who had received at least one prior line of therapy with lenalidomide and a proteasome inhibitor (PI) was evaluated in APOLLO [see Clinical Studies (14.2)] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity in combination with pomalidomide and dexamethasone (n=149) or pomalidomide and dexamethasone (n=150). Among patients receiving DARZALEX FASPRO-Pd, 71% were exposed for 6 months or longer and 50% were exposed for greater than one year.

Serious adverse reactions occurred in 50% of patients who received DARZALEX FASPRO-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO-Pd were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients who received DARZALEX FASPRO-Pd.

Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-Pd.

The most common adverse reactions (≥20%) were fatigue, pneumonia, upper respiratory tract infection, and diarrhea.

Table 13 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO.

Table 13: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DARZALEX FASPRO-Pd Arm in APOLLO
Adverse Reaction	DARZALEX FASPRO-Pd (N=149)		Pd (N=150)
Adverse Reaction	All Grades (%)	Grades ≥3 (%)	All Grades (%)	Grades ≥3 (%)
Key: Pd=pomalidomide-dexamethasone
* Fatigue includes asthenia, and fatigue. † Only Grade 3 adverse reactions occurred. ‡ Edema peripheral includes edema, edema peripheral and peripheral swelling. § Pneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. ¶ Grade 5 adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO-Pd arm and n=2 (1.3%) in the Pd arm. # Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection. Þ Cough includes cough, and productive cough.
General disorders and administration site conditions
Fatigue *	46	13	39	5 †
Pyrexia	19	0	14	0
Edema peripheral ‡	15	0	9	0
Infections
Pneumonia §	38	23 ¶	27	17 ¶
Upper respiratory infection #	36	1 †	22	2 †
Gastrointestinal disorders
Diarrhea	22	5 †	14	1 †
Respiratory, thoracic and mediastinal disorders
Cough Þ	13	0	8	0

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with pomalidomide and dexamethasone include:

Metabolism and nutrition disorders:hypocalcemia, hypokalemia, decreased appetite, dehydration
Nervous system disorders:peripheral sensory neuropathy, syncope, headache, paresthesia, dizziness
Musculoskeletal and connective tissue disorders:muscle spasms, musculoskeletal chest pain, arthralgia
Psychiatric disorders:insomnia
Gastrointestinal disorders:nausea, abdominal pain, vomiting
Skin and subcutaneous tissue disorders:rash, pruritus
Cardiac disorders:atrial fibrillation
General disorders and administration site conditions:infusion reactions, chills, injection site reaction
Infections:urinary tract infection, influenza, hepatitis B reactivation, herpes zoster, sepsis
Vascular disorders:hypertension, hypotension

Table 14 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in APOLLO.

Table 14: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Pd or Pd in APOLLO
Laboratory Abnormality	DARZALEX FASPRO-Pd *		Pd *
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Key: Pd=pomalidomide-dexamethasone
* Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=148 for DARZALEX FASPRO-Pd and N=149 for Pd.
Decreased neutrophils	97	84	84	63
Decreased leukocytes	95	64	82	40
Decreased lymphocytes	93	59	79	33
Decreased platelets	75	19	60	19
Decreased hemoglobin	51	16	57	15

In Combination with Carfilzomib and Dexamethasone

The safety of DARZALEX FASPRO with carfilzomib and dexamethasone was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity (N=66) in combination with carfilzomib and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year.

Serious adverse reactions occurred in 27% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone.

Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO.

Dosage interruptions due to an adverse reaction occurred in 46% of patients who received DARZALEX FASPRO.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

Table 15 summarizes the adverse reactions in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES.

Table 15: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO with Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES
Adverse Reaction	DARZALEX FASPRO-Kd (N=66)
Adverse Reaction	All Grades (%)	Grade ≥3 (%)
* Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. † Bronchitis includes bronchitis, and bronchitis viral. ‡ Only Grade 3 adverse reactions occurred. § Fatigue includes asthenia, and fatigue. ¶ Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling. # Hypertension includes blood pressure increased, and hypertension. Þ Cough includes cough, and productive cough. ß Dyspnea includes dyspnea, and dyspnea exertional.
Infections and infestations
Upper respiratory tract infection *	52	0
Bronchitis †	12	2 ‡
General disorders and administration site conditions
Fatigue §	39	2 ‡
Pyrexia	21	2 ‡
Edema peripheral ¶	20	0
Psychiatric disorders
Insomnia	33	6 ‡
Vascular disorders
Hypertension #	32	21 ‡
Gastrointestinal disorders
Diarrhea	29	0
Nausea	21	0
Vomiting	15	0
Respiratory, thoracic and mediastinal disorders
Cough Þ	24	0
Dyspnea ß	23	2 ‡
Nervous system disorders
Headache	23	0
Peripheral sensory neuropathy	11	0
Musculoskeletal and connective tissue disorders
Back pain	17	2 ‡
Musculoskeletal chest pain	11	0

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with carfilzomib and dexamethasone include:

Gastrointestinal disorders:abdominal pain, constipation, pancreatitis
Infection and infestations:pneumonia, influenza, urinary tract infection, herpes zoster, sepsis
Metabolism and nutrition disorders:hyperglycemia, decreased appetite, hypocalcemia
Musculoskeletal and connective tissue disorders:muscle spasms, arthralgia
Nervous system disorders:paresthesia, dizziness, syncope
General disorders and administration site conditions:injection site reaction, infusion reactions, chills
Skin and subcutaneous tissue disorders:rash, pruritus
Cardiac disorders:cardiac failure
Vascular disorders:hypotension

Table 16 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone in PLEIADES.

Table 16: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADES
Laboratory Abnormality	DARZALEX FASPRO-Kd *
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)
* Denominator is based on the safety population treated with DARZALEX FASPRO-Kd (N=66).
Decreased platelets	88	18
Decreased lymphocytes	83	50
Decreased leukocytes	68	18
Decreased neutrophils	55	15
Decreased hemoglobin	47	6
Decreased corrected calcium	45	2
Increased alanine aminotransferase (ALT)	35	5

Monotherapy

The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see Clinical Trials (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO, 37% were exposed for 6 months or longer and 1% were exposed for greater than one year.

Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than 1 patient were general physical health deterioration, septic shock, and respiratory failure.

Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 2 patients were thrombocytopenia and hypercalcemia.

Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia.

The most common adverse reaction (≥20%) was upper respiratory tract infection.

Table 17 summarizes the adverse reactions in COLUMBA.

Table 17: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA
Adverse Reaction	DARZALEX FASPRO (N=260)		Intravenous Daratumumab (N=258)
Adverse Reaction	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
* Upper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection. † Only Grade 3 adverse reactions occurred. ‡ Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. § Grade 5 adverse reactions occurred. ¶ Fatigue includes asthenia, and fatigue. # Infusion reactions includes terms determined by investigators to be related to infusion. Þ Cough includes cough, and productive cough. ß Dyspnea includes dyspnea, and dyspnea exertional.
Infections
Upper respiratory tract infection *	24	1 †	22	1 †
Pneumonia ‡	8	5	10	6 §
Gastrointestinal disorders
Diarrhea	15	1 †	11	0.4 †
Nausea	8	0.4 †	11	0.4 †
General disorders and administration site conditions
Fatigue ¶	15	1 †	16	2 †
Infusion reactions #	13	2 †	34	5 †
Pyrexia	13	0	13	1 †
Chills	6	0.4 †	12	1 †
Musculoskeletal and connective tissue disorders
Back pain	10	2 †	12	3 †
Respiratory, thoracic and mediastinal disorders
Cough Þ	9	1 †	14	0
Dyspnea ß	6	1 †	11	1 †

Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included:

General disorders and administration site conditions:injection site reaction, peripheral edema
Musculoskeletal and connective tissue disorders:arthralgia, musculoskeletal chest pain, muscle spasms
Gastrointestinal disorders:constipation, vomiting, abdominal pain
Metabolism and nutrition disorders:decreased appetite, hyperglycemia, hypocalcemia, dehydration
Psychiatric disorders:insomnia
Vascular disorders:hypertension, hypotension
Nervous system disorders:dizziness, peripheral sensory neuropathy, paresthesia
Infections:bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis B virus reactivation
Skin and subcutaneous tissue disorders:pruritus, rash
Cardiac disorders:atrial fibrillation
Respiratory, thoracic and mediastinal disorders:pulmonary edema

Table 18 summarizes the laboratory abnormalities in COLUMBA.

Table 18: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA
Laboratory Abnormality	DARZALEX FASPRO *		Intravenous Daratumumab *
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
* Denominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258).
Decreased leukocytes	65	19	57	14
Decreased lymphocytes	59	36	56	36
Decreased neutrophils	55	19	43	11
Decreased platelets	43	16	45	14
Decreased hemoglobin	42	14	39	16

Light Chain Amyloidosis

In Combination with Bortezomib, Cyclophosphamide and Dexamethasone

The safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (DARZALEX FASPRO-VCd) was evaluated in ANDROMEDA [see Clinical Studies (14.3)] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received DARZALEX FASPRO-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year.

Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX FASPRO-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).

Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure.

Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required a dosage interruption in ≥3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

Table 19 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA.

Table 19: Adverse Reactions (≥10%) in Patients with AL Amyloidosis Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) with a Difference Between Arms of >5% Compared to VCd in ANDROMEDA
Adverse Reaction	DARZALEX FASPRO-VCd (N=193)		VCd (N=188)
Adverse Reaction	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
* Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. † Only Grade 3 adverse reactions occurred. ‡ Pneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. § Dyspnea includes dyspnea, and dyspnea exertional. ¶ Cough includes cough, and productive cough. # Arrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia Þ Injection site reactions includes terms determined by investigators to be related to daratumumab injection.
Infections
Upper respiratory tract infection *	40	1 †	21	1 †
Pneumonia ‡	15	10	9	5
Gastrointestinal disorders
Diarrhea	36	6 †	30	4
Constipation	34	2 †	29	0
Nervous system disorders
Peripheral sensory neuropathy	31	3 †	20	2 †
Respiratory, thoracic and mediastinal disorders
Dyspnea §	26	4	20	4 †
Cough ¶	20	1 †	11	0
Musculoskeletal and connective tissue disorders
Back pain	12	2 †	6	0
Arthralgia	10	0	5	0
Muscle spasms	10	1 †	5	0
Cardiac disorders
Arrhythmia #	11	4	5	2
General disorders and administration site conditions
Injection site reactions Þ	11	0	0	0

Clinically relevant adverse reactions not included in Table 19 and occurred in patients who received DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone included:

Skin and subcutaneous tissue disorders:rash, pruritus
Nervous system disorders:paresthesia
General disorders and administration site conditions:infusion reaction, chills
Cardiac disorders:cardiac failure 1, cardiac arrest
Metabolism and nutrition disorders:hyperglycemia, hypocalcemia, dehydration
Infections:bronchitis, herpes zoster, sepsis, urinary tract infection, influenza
Vascular disorders:hypertension
Musculoskeletal and connective tissue disorders:musculoskeletal chest pain
Gastrointestinal disorders:pancreatitis
Respiratory, thoracic and mediastinal disorders:pulmonary edema

Table 20 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in ANDROMEDA.

Table 20: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) in ANDROMEDA
Laboratory Abnormality	DARZALEX FASPRO-VCd		VCd
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Denominator is based on the number of patients with a baseline and post-baseline laboratory value for each laboratory test, N=188 for DARZALEX FASPRO-VCd and N=186 for VCd.
Decreased lymphocytes	81	54	71	46
Decreased hemoglobin	66	6	70	6
Decreased leukocytes	60	7	46	4
Decreased platelets	46	3	40	4
Decreased neutrophils	30	6	18	4

1: Cardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11% of patients.

Cardiac Adverse Reactions in Light Chain (AL) Amyloidosis

Among patients who received DARZALEX FASPRO 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 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 FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the DARZALEX FASPRO-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).

6.2 Postmarketing Experience

The following adverse reactions have been identified with post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System: Anaphylactic reaction, Systemic administration reactions (including death)

Gastrointestinal:Pancreatitis

Infections:Cytomegalovirus, Listeriosis