DARZALEX FASPRO SIDE EFFECTS
- Generic Name: daratumumab and hyaluronidase-fihj injection
- Brand Name: Darzalex Faspro
- Drug Class: Antineoplastics, Anti-CD38 Monoclonal Antibodies
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hypersensitivity and Other Administration Reactions.
- Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis.
- Neutropenia.
- Thrombocytopenia.
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. 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 1 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.
Table 1: 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 (%) |
|
| Infections | ||
| Upper respiratory tract infectiona | 39 | 0 |
| Bronchitis | 16 | 0 |
| Pneumoniab | 15 | 7# |
| Gastrointestinal disorders | ||
| Constipation | 37 | 0 |
| Nausea | 36 | 0 |
| Diarrhea | 33 | 3# |
| Vomiting | 21 | 0 |
| Abdominal painc | 13 | 0 |
| General disorders and administration site conditions | ||
| Fatigued | 36 | 3 |
| Pyrexia | 34 | 0 |
| Edema peripherale | 13 | 1# |
| Nervous system disorders | ||
| Peripheral sensory neuropathy | 34 | 1# |
| Dizziness | 10 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Coughf | 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# |
| a Upper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. b Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. c Abdominal pain includes abdominal pain, and abdominal pain upper. d Fatigue includes asthenia, and fatigue. e Edema peripheral includes edema, edema peripheral, and peripheral swelling. f Cough includes cough, and productive cough. # Only grade 3 adverse reactions occurred. |
||
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 2 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.
Table 2: 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 Prednisonea |
|
| All Grades (%) |
Grades 3-4 (%) |
|
| Decreased leukocytes | 96 | 52 |
| Decreased lymphocytes | 93 | 84 |
| Decreased platelets | 93 | 42 |
| Decreased neutrophils | 88 | 49 |
| Decreased hemoglobin | 48 | 19 |
| a Denominator is based on the safety population treated with DARZALEX FASPRO-VMP (N=67). | ||
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. 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 3 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.
Table 3: 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 (%) | |
| General disorders and administration site conditions | ||
| Fatiguea | 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 infectionb | 43 | 3# |
| Pneumoniac | 23 | 17 |
| Bronchitisd | 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 | ||
| Dyspneae | 22 | 3 |
| Coughf | 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 |
| a Fatigue includes asthenia, and fatigue. b Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. c Pneumonia includes lower respiratory tract infection, lung infection, and pneumonia. d Bronchitis includes bronchitis, and bronchitis viral. e Dyspnea includes dyspnea, and dyspnea exertional. f Cough includes cough, and productive cough. # Only grade 3 adverse reactions occurred. |
||
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 4 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in PLEIADES.
Table 4: 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 Dexamethasonea |
|
| All Grades (%) |
Grades 3-4 (%) |
|
| Decreased leukocytes | 94 | 34 |
| Decreased lymphocytes | 82 | 58 |
| Decreased platelets | 86 | 9 |
| Decreased neutrophils | 89 | 52 |
| Decreased hemoglobin | 45 | 8 |
| a Denominator is based on the safety population treated with DARZALEX FASPRO-Rd (N=65). | ||
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. 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 5 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO.
Table 5: 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 (%) |
|
| General disorders and administration site conditions | ||||
| Fatiguea | 46 | 13 | 39 | 5# |
| Pyrexia | 19 | 0 | 14 | 0 |
| Edema peripheralb | 15 | 0 | 9 | 0 |
| Infections | ||||
| Pneumoniac | 38 | 23@ | 27 | 17@ |
| Upper respiratory infectiond | 36 | 1# | 22 | 2# |
| Gastrointestinal disorders | ||||
| Diarrhea | 22 | 5# | 14 | 1# |
| Respiratory, thoracic and mediastinal disorders | ||||
| Coughe | 13 | 0 | 8 | 0 |
| Key: Pd=pomalidomide-dexamethasone a Fatigue includes asthenia, and fatigue. b Edema peripheral includes edema, edema peripheral and peripheral swelling. c Pneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. d 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. e Cough includes cough, and productive cough. # Only grade 3 adverse reactions occurred. @ Grade 5 adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO-Pd arm and n=2 (1.3%) in the Pd arm. |
||||
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 6 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO in APOLLO.
Table 6: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Pd or Pd in APOLLO
| Laboratory Abnormality | DARZALEX FASPRO-Pda | Pda | ||
| All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
| 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 |
| Key: Pd=pomalidomide-dexamethasone a 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. |
||||
In Combination with Carfilzomib and Dexamethasone
The safety of DARZALEX FASPRO with carfilzomib and dexamethasone was evaluated in a single-arm cohort of PLEIADES. 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 6 summarizes the adverse reactions in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone (DARZALEX FASPRO-Kd) in PLEIADES.
Table 6: 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 (%) |
|
| Infections and infestations | ||
| Upper respiratory tract infectiona | 52 | 0 |
| Bronchitisb | 12 | 2# |
| General disorders and administration site conditions | ||
| Fatiguec | 39 | 2# |
| Pyrexia | 21 | 2# |
| Edema peripherald | 20 | 0 |
| Psychiatric disorders | ||
| Insomnia | 33 | 6# |
| Vascular disorders | ||
| Hypertensione | 32 | 21# |
| Gastrointestinal disorders | ||
| Diarrhea | 29 | 0 |
| Nausea | 21 | 0 |
| Vomiting | 15 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Coughf | 24 | 0 |
| Dyspneag | 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 |
| a 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. b Bronchitis includes bronchitis, and bronchitis viral. c Fatigue includes asthenia, and fatigue. d Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling. e Hypertension includes blood pressure increased, and hypertension. f Cough includes cough, and productive cough. g Dyspnea includes dyspnea, and dyspnea exertional. # Only Grade 3 adverse reactions occurred. |
||
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 7 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with carfilzomib and dexamethasone in PLEIADES.
Table 7: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADES
| Laboratory Abnormality | DARZALEX FASPRO-Kda | |
| All Grades (%) | Grades 3-4 (%) | |
| 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 |
| a Denominator is based on the safety population treated with DARZALEX FASPRO-Kd (N=66). | ||
Monotherapy
The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA. 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 8 summarizes the adverse reactions in COLUMBA.
Table 8: 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 (%) |
|
| Infections | ||||
| Upper respiratory tract infectiona | 24 | 1# | 22 | 1# |
| Pneumoniab | 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 | ||||
| Fatiguec | 15 | 1# | 16 | 2# |
| Infusion reactionsd | 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 | ||||
| Coughe | 9 | 1# | 14 | 0 |
| Dyspneaf | 6 | 1# | 11 | 1# |
| a 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. b Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. c Fatigue includes asthenia, and fatigue. d Infusion reactions includes terms determined by investigators to be related to infusion e Cough includes cough, and productive cough. f Dyspnea includes dyspnea, and dyspnea exertional. # Only grade 3 adverse reactions occurred. @ Grade 5 adverse reactions occurred. |
||||
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 9 summarizes the laboratory abnormalities in COLUMBA.
Table 9: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or Intravenous Daratumumab in COLUMBA
| Laboratory Abnormality | DARZALEX FASPROa | Intravenous Daratumumaba | ||
| All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
| 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 |
| a Denominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258). | ||||
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. 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 10 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA.
Table 10: 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 (%) |
|
| Infections | ||||
| Upper respiratory tract infectiona | 40 | 1# | 21 | 1# |
| Pneumoniab | 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 | ||||
| Dyspneac | 26 | 4 | 20 | 4# |
| Coughd | 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 | ||||
| Arrhythmiae | 11 | 4 | 5 | 2 |
| General disorders and administration site conditions | ||||
| Injection site reactionsf | 11 | 0 | 0 | 0 |
| # Only grade 3 adverse reactions occurred. a 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. b Pneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. c Dyspnea includes dyspnea, and dyspnea exertional. d Cough includes cough, and productive cough. e Arrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia f Injection site reactions includes terms determined by investigators to be related to daratumumab injection. |
||||
Clinically relevant adverse reactions not included in Table 10 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 failurea, 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 11: 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 (%) |
|
| 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 |
| 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. | ||||
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%).
Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products or other hyaluronidase products may be misleading.
In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, less than 1% of 819 patients developed treatment-emergent anti-daratumumab antibodies.
In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of 812 patients developed treatment-emergent anti-rHuPH20 antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.
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
SRC: NLM .