DARZALEX (Page 3 of 8)

5.2 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 infusion. 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. Type and screen patients prior to starting DARZALEX [see Dosage and Administration (2.1)].

5.3 Neutropenia

DARZALEX 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 until recovery of neutrophils.

5.4 Thrombocytopenia

DARZALEX 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 until recovery of platelets.

5.5 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 patients with IgG kappa myeloma protein.

5.6 Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX 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 and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

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

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.

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.

Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant

Combination Treatment with Lenalidomide and Dexamethasone (DRd)

The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies (14.1)]. Adverse reactions described in Table 7 reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).

Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).

Table 7: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in MAIA
Body System Adverse Reaction DRd (N=364) Rd (N=365)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
*
Acute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection
Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis
Atypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis
§
Infusion-related reaction includes terms determined by investigators to be related to infusion
Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling
#
Dyspnea, Dyspnea exertional
Þ
Cough, Productive cough
ß
Blood pressure increased, Hypertension
Gastrointestinal disorders
Diarrhea 57 7 0 46 4 0
Constipation 41 1 <1 36 <1 0
Nausea 32 1 0 23 1 0
Vomiting 17 1 0 12 <1 0
Infections
Upper respiratory tract infection * 52 2 <1 36 2 <1
Bronchitis 29 3 0 21 1 0
Pneumonia 26 14 1 14 7 1
Urinary tract infection 18 2 0 10 2 0
General disorders and administration site conditions
Infusion-related reactions § 41 2 <1 0 0 0
Peripheral edema 41 2 0 33 1 0
Fatigue 40 8 0 28 4 0
Asthenia 32 4 0 25 3 <1
Pyrexia 23 2 0 18 2 0
Chills 13 0 0 2 0 0
Musculoskeletal and connective tissue disorders
Back pain 34 3 <1 26 3 <1
Muscle spasms 29 1 0 22 1 0
Respiratory, thoracic and mediastinal disorders
Dyspnea # 32 3 <1 20 1 0
Cough Þ 30 <1 0 18 0 0
Nervous system disorders
Peripheral sensory neuropathy 24 1 0 15 0 0
Headache 19 1 0 11 0 0
Paresthesia 16 0 0 8 0 0
Metabolism and nutrition disorders
Decreased appetite 22 1 0 15 <1 <1
Hyperglycemia 14 6 1 8 3 1
Hypocalcemia 14 1 <1 9 1 1
Vascular disorders
Hypertension ß 13 6 <1 7 4 0

Laboratory abnormalities worsening during treatment from baseline listed in Table 8.

Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA
DRd (N=364) Rd (N=365)
All Grades(%) Grade 3(%) Grade 4(%) All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
Leukopenia 90 30 5 82 20 4
Neutropenia 91 39 17 77 28 11
Lymphopenia 84 41 11 75 36 6
Thrombocytopenia 67 6 3 58 7 4
Anemia 47 13 0 57 24 0

Combination Treatment with Bortezomib, Melphalan and Prednisone

The safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies (14.1)]. Adverse reactions described in Table 9 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.

Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).

Table 9: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the D-VMP Arm in ALCYONE
Body SystemAdverse Reaction D-VMP (N=346) VMP (N=354)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone
*
upper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection
pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis
Infusion-related reaction includes terms determined by investigators to be related to infusion
§
edema peripheral, generalized edema, peripheral swelling
cough, productive cough
#
dyspnea, dyspnea exertional
Þ
hypertension, blood pressure increased
Infections
Upper respiratory tract infection * 48 5 0 28 3 0
Pneumonia 16 12 < 1 6 5 < 1
General disorders and administration site conditions
Infusion-related reactions 28 4 1 0 0 0
Peripheral edema § 21 1 < 1 14 1 0
Respiratory, thoracic and mediastinal disorders
Cough 16 < 1 0 8 < 1 0
Dyspnea # 13 2 1 5 1 0
Vascular disorders
Hypertension Þ 10 4 < 1 3 2 0

Laboratory abnormalities worsening during treatment from baseline listed in Table 10.

Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE
D-VMP (N=346) VMP (N=354)
All Grades(%) Grade 3(%) Grade 4(%) All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone
Thrombocytopenia 88 27 11 88 26 16
Neutropenia 86 34 10 87 32 11
Lymphopenia 85 46 12 83 44 9
Anemia 47 18 0 50 21 0

Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant

Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)

The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies (14.1)]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.

Serious adverse reactions with a 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%).

Table 11: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DVTd Arm in CASSIOPEIA
Body System Adverse Reaction DVTd (N=536) VTd (N=538)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.Note: Hematology laboratory related toxicities were excluded and reported separately in the table below
*
Infusion-related reaction includes terms determined by investigators to be related to infusion
Laryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection
Bronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis
§
Cough, Productive cough
General disorders and administration site conditions
Infusion-related reactions * 35 3 <1 0 0 0
Pyrexia 26 2 <1 21 2 0
Gastrointestinal disorders
Nausea 30 4 0 24 2 <1
Vomiting 16 2 0 10 2 0
Infections
Upper respiratory tract infection 27 1 0 17 1 0
Bronchitis 20 1 0 13 1 0
Respiratory, thoracic and mediastinal disorders
Cough § 17 0 0 9 0 0
Vascular disorders
Hypertension 10 4 0 5 2 0
Table 12: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA
DVTd (N=536) VTd (N=538)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.
Lymphopenia 95 44 15 91 37 10
Leukopenia 82 14 10 57 6 9
Thrombocytopenia 81 9 5 58 8 3
Neutropenia 63 19 14 41 10 9
Anemia 36 4 0 35 5 0

Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Clinical Studies (14.2)]. Adverse reactions described in Table 13 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd).

Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each).

Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.

Table 13: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in POLLUX
Adverse Reaction DRd (N=283) Rd (N=281)
All Grades(%) Grade 3(%) Grade 4(%) All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
*
upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection
Infusion-related reaction includes terms determined by investigators to be related to infusion
cough, productive cough, allergic cough
§
dyspnea, dyspnea exertional
Infections
Upper respiratory tract infection * 65 6 < 1 51 4 0
General disorders and administration site conditions
Infusion-related reactions 48 5 0 0 0 0
Fatigue 35 6 < 1 28 2 0
Pyrexia 20 2 0 11 1 0
Gastrointestinal disorders
Diarrhea 43 5 0 25 3 0
Nausea 24 1 0 14 0 0
Vomiting 17 1 0 5 1 0
Respiratory, thoracic and mediastinal disorders
Cough 30 0 0 15 0 0
Dyspnea § 21 3 < 1 12 1 0
Musculoskeletal and connective tissue disorders
Muscle spasms 26 1 0 19 2 0
Nervous system disorders
Headache 13 0 0 7 0 0

Laboratory abnormalities worsening during treatment from baseline listed in Table 14.

Table 14: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUX
DRd (N=283) Rd (N=281)
All Grades(%) Grade 3(%) Grade 4(%) All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
Lymphopenia 95 42 10 87 32 6
Neutropenia 92 36 17 87 32 8
Thrombocytopenia 73 7 6 67 10 5
Anemia 52 13 0 57 19 0

Combination Treatment with Bortezomib and Dexamethasone

The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in CASTOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 15 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm.

Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each).

Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.

Table 15: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DVd Arm CASTOR
Adverse Reaction DVd (N=243) Vd (N=237)
All Grades(%) Grade 3(%) Grade 4(%) All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Vd=bortezomib-dexamethasone.
*
Infusion-related reaction includes terms determined by investigators to be related to infusion
edema peripheral, edema, generalized edema, peripheral swelling
upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection
§
cough, productive cough, allergic cough
dyspnea, dyspnea exertional
Nervous system disorders
Peripheral sensory neuropathy 47 5 0 38 6 < 1
General disorders and administration site conditions
Infusion-related reactions * 45 9 0 0 0 0
Peripheral edema 22 1 0 13 0 0
Pyrexia 16 1 0 11 1 0
Infections
Upper respiratory tract infection 44 6 0 30 3 < 1
Gastrointestinal disorders
Diarrhea 32 3 < 1 22 1 0
Vomiting 11 0 0 4 0 0
Respiratory, thoracic and mediastinal disorders
Cough § 27 0 0 14 0 0
Dyspnea 21 4 0 11 1 0

Laboratory abnormalities worsening during treatment are listed in Table 16.

Table 16: Treatment-Emergent Hematology Laboratory Abnormalities in CASTOR
DVd (N=243) Vd (N=237)
All Grades(%) Grade 3(%) Grade 4(%) All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Vd=bortezomib-dexamethasone.
Thrombocytopenia 90 28 19 85 22 13
Lymphopenia 89 41 7 81 24 3
Neutropenia 58 12 3 40 5 < 1
Anemia 48 13 0 56 14 0

Combination Treatment with Twice-Weekly (20/56 mg/m2) Carfilzomib and Dexamethasone

The safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 17 reflect exposure to DARZALEX for a median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd).

Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%).

Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia.

Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%.

Table 17: Adverse Reactions (≥15%) in Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone (DKd) in CANDOR
Adverse Reaction DKd (N=308) Kd (N=153)
All Grades Grades 3 or 4 All Grades Grades 3 or 4
(%) (%) (%) (%)
Key: D=daratumumab; Kd=carfilzomib-dexamethasone
*
The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration.
Fatigue includes fatigue and asthenia.
Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection.
§
Includes fatal adverse reactions.
Thrombocytopenia includes platelet count decreased and thrombocytopenia.
#
Anemia includes anemia, hematocrit decreased and hemoglobin decreased.
Þ
Cough includes productive cough and cough.
General Disorders and Administration Site Conditions
Infusion-related reactions * 41 12 28 5
Fatigue 32 11 28 8
Pyrexia 20 1.9 15 0.7
Infections
Respiratory tract infection 40§ 7 29 3.3
Pneumonia 18§ 13 12 9
Bronchitis 17 2.6 12 1.3
Blood and lymphatic system disorders
Thrombocytopenia 37 25 30 16
Anemia # 33 17 31 14
Gastrointestinal disorders
Diarrhea 32 3.9 14 0.7
Nausea 18 0 13 0.7
Vascular Disorders
Hypertension 31 18 28 13
Respiratory, Thoracic and Mediastinal Disorders
Cough Þ 21 0 21 0
Dyspnea 20 3.9 22 2.6
Psychiatric disorders
Insomnia 18 3.9 11 2
Musculoskeletal and connective tissue disorders
Back pain 16 1.9 10 1.3

Adverse Reactions Occurring at a Frequency of < 15%

  • Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia
  • Cardiac disorders: atrial fibrillation
  • Gastrointestinal disorders: vomiting, constipation
  • General disorders and administration site conditions: peripheral edema, asthenia, chills
  • Infections: influenza, urinary tract infection, sepsis, septic shock
  • Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration
  • Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain
  • Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paraesthesia, posterior reversible encephalopathy syndrome
  • Respiratory, thoracic and mediastinal disorders: pulmonary edema
  • Skin and subcutaneous tissue disorders: rash, pruritus

Combination Treatment with Once-Weekly (20/70 mg/m2) Carfilzomib and Dexamethasone

The safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)]. Adverse reactions described in Table 18 reflect exposure to DARZALEX for a median treatment duration of 19.8 months (range: 0.3 to 34.5 months).

Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.

Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient.

Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively.

Table 18: Adverse Reactions (≥15%) of Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone in EQUULEUS
Adverse Reaction DKd (N=85)
All Grades (%) Grades 3 or 4 (%)
Key: D=daratumumab; Kd=carfilzomib-dexamethasone
*
Thrombocytopenia includes platelet count decreased and thrombocytopenia.
Anemia includes anemia, hematocrit decreased and hemoglobin decreased.
Neutropenia includes neutrophil count decreased and neutropenia.
§
Lymphopenia includes lymphocyte count decreased and lymphopenia
Fatigue includes fatigue and asthenia.
#
The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration.
Þ
Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection.
ß
Cough includes productive cough and cough.
Blood and lymphatic system disorders
Thrombocytopenia * 68 32
Anemia 52 21
Neutropenia 31 21
Lymphopenia § 29 25
General disorder and administration site conditions
Fatigue 54 18
Infusion-related reactions # 53 12
Pyrexia 37 1.2
Infections
Respiratory tract infection Þ 53 3.5
Bronchitis 19 0
Nasopharyngitis 18 0
Influenza 17 3.5
Gastrointestinal disorders
Nausea 42 1.2
Vomiting 40 1.2
Diarrhea 38 2.4
Constipation 17 0
Respiratory, thoracic and mediastinal disorders
Dyspnea 35 3.5
Cough ß 33 0
Vascular disorders
Hypertension 33 20
Psychiatric disorders
Insomnia 33 4.7
Nervous system disorders
Headache 27 1.2
Musculoskeletal and connective tissue disorders
Back pain 25 0
Pain in extremity 15 0

Adverse Reactions Occurring at a Frequency of < 15%

  • Blood and lymphatic system disorders: leukopenia, febrile neutropenia
  • Cardiac disorders: atrial fibrillation
  • Gastrointestinal disorders: pancreatitis
  • General disorders and administration site conditions: peripheral edema, chills
  • Infections: pneumonia, urinary tract infection, sepsis, septic shock
  • Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia
  • Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia
  • Nervous system disorders: dizziness, paraesthesia, peripheral sensory neuropathy
  • Skin and subcutaneous tissue disorders: pruritus, rash

Combination Treatment with Pomalidomide and Dexamethasone

The safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)]. Adverse reactions described in Table 19 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months).

The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.

Table 19: Adverse Reactions With Incidence ≥10% Reported in EQUULEUS
Adverse Reaction DPd (N=103)
All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Pd=pomalidomide-dexamethasone.
*
Infusion-related reaction includes terms determined by investigators to be related to infusion
edema, edema peripheral, peripheral swelling.
acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection
§
lung infection, pneumonia, pneumonia aspiration
cough, productive cough, allergic cough
#
dyspnea, dyspnea exertional
General disorders and administration site conditions
Fatigue 50 10 0
Infusion-related reactions * 50 4 0
Pyrexia 25 1 0
Chills 20 0 0
Edema peripheral 17 4 0
Asthenia 15 0 0
Non-cardiac chest pain 15 0 0
Pain 11 0 0
Infections
Upper respiratory tract infection 50 4 1
Pneumonia § 15 8 2
Respiratory, thoracic and mediastinal disorders
Cough 43 1 0
Dyspnea # 33 6 1
Nasal congestion 16 0 0
Gastrointestinal disorders
Diarrhea 38 3 0
Constipation 33 0 0
Nausea 30 0 0
Vomiting 21 2 0
Musculoskeletal and connective tissue disorders
Muscle spasms 26 1 0
Back pain 25 6 0
Arthralgia 22 2 0
Pain in extremity 15 0 0
Bone pain 13 4 0
Musculoskeletal chest pain 13 2 0
Psychiatric disorders
Insomnia 23 2 0
Anxiety 13 0 0
Nervous system disorders
Dizziness 21 2 0
Tremor 19 3 0
Headache 17 0 0
Metabolism and nutrition disorders
Hypokalemia 16 3 0
Hyperglycemia 13 5 1
Decreased appetite 11 0 0

Laboratory abnormalities worsening during treatment are listed in Table 20.

Table 20: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUS
DPd(N=103)
All Grades(%) Grade 3(%) Grade 4(%)
Key: D=daratumumab, Pd=pomalidomide-dexamethasone.
Neutropenia 95 36 46
Lymphopenia 94 45 26
Thrombocytopenia 75 10 10
Anemia 57 30 0

Monotherapy

The safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months).

Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients.

Adverse reactions occurring in at least 10% of patients are presented in Table 21. Table 22 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.

Table 21: Adverse Reactions With Incidence ≥10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg
Adverse Reaction DARZALEX(N=156)
All Grades(%) Grade 3(%) Grade 4(%)
*
Infusion-related reaction includes terms determined by investigators to be related to infusion
Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.
General disorders and administration site conditions
Infusion-related reaction * 48 3 0
Fatigue 39 2 0
Pyrexia 21 1 0
Chills 10 0 0
Gastrointestinal disorders
Nausea 27 0 0
Diarrhea 16 1 0
Constipation 15 0 0
Vomiting 14 0 0
Musculoskeletal and connective tissue disorders
Back pain 23 2 0
Arthralgia 17 0 0
Pain in extremity 15 1 0
Musculoskeletal chest pain 12 1 0
Respiratory, thoracic and mediastinal disorders
Cough 21 0 0
Nasal congestion 17 0 0
Dyspnea 15 1 0
Infections
Upper respiratory tract infection 20 1 0
Nasopharyngitis 15 0 0
Pneumonia 11 6 0
Metabolism and nutrition disorders
Decreased appetite 15 1 0
Nervous system disorders
Headache 12 1 0
Vascular disorders
Hypertension 10 5 0
Table 22: Treatment-Emergent Grade 3–4 Laboratory Abnormalities (≥10%)
Daratumumab 16 mg/kg (N=156)
All Grades(%) Grade 3(%) Grade 4(%)
Lymphopenia 72 30 10
Neutropenia 60 17 3
Thrombocytopenia 48 10 8
Anemia 45 19 0

Herpes Zoster Virus Reactivation

Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2–5% of patients receiving DARZALEX.

Infections

Grade 3 or 4 infections were reported as follows:

  • Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKd 1: 37%, Kd 1: 29%; DKd 2: 21%
  • Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1–4% of patients.

Fatal infections (Grade 5) were reported as follows:

  • Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd 1: 5%, Kd 1: 3%; DKd 2: 0%
  • Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.

Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

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