Darzalex Faspro (Page 3 of 8)

4 CONTRAINDICATIONS

DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity and Other Administration Reactions

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO [see Adverse Reactions (6.3)].

Systemic Reactions

In a pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 9% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

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

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.5)]. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.5)].

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

Local Reactions

In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

5.2 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 FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions (6.1)]. 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 NYHA Class IIIB or IV disease were not studied.

Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

5.3 Neutropenia

Daratumumab may increase neutropenia induced by background therapy [see Adverse Reactions (6.1)].

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3–4 neutropenia were observed.

5.4 Thrombocytopenia

Daratumumab may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1)].

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets.

5.5 Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.

5.6 Interference with Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum [see References (15)]. The determination of a patient’s ABO and Rh blood type are not impacted [see Drug Interactions (7.1)].

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

5.7 Interference with Determination of Complete Response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.1)]. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.

6 ADVERSE REACTIONS

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

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

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

Table 6: 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)
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 7 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.

Table 7: 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 *
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 8 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.

Table 8: 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)
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 9 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.

Table 9: 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 *
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 10 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO.

Table 10: 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)
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 11 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in APOLLO.

Table 11: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Pd or Pd in APOLLO
Laboratory Abnormality DARZALEX FASPRO-Pd * Pd *
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 12 summarizes the adverse reactions in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES.

Table 12: 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)
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 13 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone in PLEIADES.

Table 13: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADES
Laboratory Abnormality DARZALEX FASPRO-Kd *
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 14 summarizes the adverse reactions in COLUMBA.

Table 14: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA
Adverse Reaction DARZALEX FASPRO(N=260) Intravenous Daratumumab(N=258)
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 15 summarizes the laboratory abnormalities in COLUMBA.

Table 15: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA
Laboratory Abnormality DARZALEX FASPRO * Intravenous Daratumumab *
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 16 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA.

Table 16: 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)
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 16 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 17 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in ANDROMEDA.

Table 17: 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
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

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