Darzalex SC Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the monograph: Hypersensitivity and Other Administration Reactions [see Hypersensitivity and Other Administration Reactions under Precautions]; Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis under Precautions]; Neutropenia [see Neutropenia under Precautions]; Thrombocytopenia [see Thrombocytopenia under Precautions].
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 SC 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 Pharmacology: Pharmacodynamics: Clinical Studies: Newly Diagnosed Multiple Myeloma under Actions]. Patients received DARZALEX SC 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 SC 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 SC-VRd.
Serious adverse reactions occurred in 37% of patients who received DARZALEX SC-VRd. The most frequent serious adverse reaction in >5% of patients who received DARZALEX SC-VRd was pneumonia (6%). Fatal adverse reactions occurred in 1.7% of patients who received DARZALEX SC-VRd.
Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX SC-VRd. An adverse reaction which resulted in permanent discontinuation of DARZALEX SC-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 15 summarizes the adverse reactions in patients who received DARZALEX SC in PERSEUS. (See Table 15.)

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Clinically relevant adverse reactions in <10% of patients who received DARZALEX SC 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 16 summarizes the laboratory abnormalities in patients who received DARZALEX SC in PERSEUS. (See Table 16.)

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Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant: In Combination with Bortezomib, Melphalan and Prednisone: The safety of DARZALEX SC with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES [see Pharmacology: Pharmacodynamics: Clinical Studies: Newly Diagnosed Multiple Myeloma under Actions]. Patients received DARZALEX SC 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 SC. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.
Permanent discontinuation of DARZALEX SC due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX SC 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 SC. 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 17 summarizes the adverse reactions in patients who received DARZALEX SC in PLEIADES. (See Table 17.)

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Clinically relevant adverse reactions in <10% of patients who received DARZALEX SC 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 18 summarizes the laboratory abnormalities in patients who received DARZALEX SC in PLEIADES. (See Table 18.)

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Relapsed/Refractory Multiple Myeloma: In Combination with Lenalidomide and Dexamethasone: The safety of DARZALEX SC with lenalidomide and dexamethasone was evaluated in a single-arm cohort of PLEIADES [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Patients received DARZALEX SC 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 SC. 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 SC due to an adverse reaction occurred in 11% of patients who received DARZALEX SC. Adverse reactions resulting in permanent discontinuation of DARZALEX SC in more than 1 patient were pneumonia and anemia.
Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX SC. 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 19 summarizes the adverse reactions in patients who received DARZALEX SC in PLEIADES. (See Table 19.)

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Clinically relevant adverse reactions in <10% of patients who received DARZALEX SC 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 20 summarizes the laboratory abnormalities in patients who received DARZALEX SC in PLEIADES. (See Table 20.)

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In Combination with Pomalidomide and Dexamethasone: The safety of DARZALEX SC 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 Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Patients received DARZALEX SC 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 SC-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 SC-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX SC-Pd were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients who received DARZALEX SC-Pd.
Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX SC-Pd.
The most common adverse reactions (≥20%) were fatigue, pneumonia, upper respiratory tract infection, and diarrhea.
Table 21 summarizes the adverse reactions in patients who received DARZALEX SC in APOLLO. (See Table 21.)

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Clinically relevant adverse reactions in <10% of patients who received DARZALEX SC 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 22 summarizes the laboratory abnormalities in patients who received DARZALEX SC in APOLLO. (See Table 22.)

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In Combination with Carfilzomib and Dexamethasone: The safety of DARZALEX SC with carfilzomib and dexamethasone was evaluated in a single-arm cohort of PLEIADES [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Patients received DARZALEX SC 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 SC in combination with carfilzomib and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received DARZALEX SC in combination with carfilzomib and dexamethasone.
Permanent discontinuation of DARZALEX SC due to an adverse reaction occurred in 6% of patients who received DARZALEX SC.
Dosage interruptions due to an adverse reaction occurred in 46% of patients who received DARZALEX SC.
The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.
Table 23 summarizes the adverse reactions in patients who received DARZALEX SC with carfilzomib and dexamethasone (DARZALEX SC-Kd) in PLEIADES. (See Table 23.)

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Clinically relevant adverse reactions in <10% of patients who received DARZALEX SC 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 24 summarizes the laboratory abnormalities in patients who received DARZALEX SC with carfilzomib and dexamethasone in PLEIADES. (See Table 24.)

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Monotherapy: The safety of DARZALEX SC as monotherapy was evaluated in COLUMBA [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed/Refractory Multiple Myeloma under Actions]. Patients received DARZALEX SC 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 SC, 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 SC. 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 SC. Adverse reactions resulting in permanent discontinuation of DARZALEX SC in more than 2 patients were thrombocytopenia and hypercalcemia.
Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX SC. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia.
The most common adverse reaction (≥20%) was upper respiratory tract infection.
Table 25 summarizes the adverse reactions in COLUMBA. (See Table 25.)

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Clinically relevant adverse reactions in <10% of patients who received DARZALEX SC 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 26 summarizes the laboratory abnormalities in COLUMBA. (See Table 26.)

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Light Chain Amyloidosis: In Combination with Bortezomib, Cyclophosphamide and Dexamethasone: The safety of DARZALEX SC with bortezomib, cyclophosphamide and dexamethasone (DARZALEX SC-VCd) was evaluated in ANDROMEDA [see Pharmacology: Pharmacodynamics: Clinical Studies: Light Chain Amyloidosis under Actions]. Patients received DARZALEX SC 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 SC-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 SC in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX SC-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 SC due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX SC 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 SC. 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 27 as follows summarizes the adverse reactions in patients who received DARZALEX SC in ANDROMEDA. (See Table 27.)

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Clinically relevant adverse reactions not included in Table 27 and occurred in patients who received DARZALEX SC 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^a, 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.
^a 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.
Table 28 summarizes the laboratory abnormalities in patients who received DARZALEX SC in ANDROMEDA. (See Table 28.)

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Cardiac Adverse Reactions in Light Chain (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 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 DARZALEX SC-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).
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.