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DARZALEX ® ( daratumumab ) injection , for intravenous use Brief Summary of Full Prescribing Information
INDICATIONS AND USAGE DARZALEX is indicated :
• in combination with lenalidomide and dexamethasone , or bortezomib and dexamethasone , for the treatment of patients with multiple myeloma who have received at least one prior therapy .
• in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor .
• as monotherapy , for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor ( PI ) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent .
CONTRAINDICATIONS None . WARNINGS AND PRECAUTIONS Infusion Reactions DARZALEX can cause severe infusion reactions . Approximately half of all patients experienced a reaction , most during the first infusion .
Infusion reactions can also occur with subsequent infusions . Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX . Prior to the introduction of post-infusion medication in clinical trials , infusion reactions occurred up to 48 hours after infusion .
Severe reactions have occurred , including bronchospasm , hypoxia , dyspnea , hypertension , laryngeal edema and pulmonary edema . Signs and symptoms may include respiratory symptoms , such as nasal congestion , cough , throat irritation , as well as chills , vomiting and nausea . Less common symptoms were wheezing , allergic rhinitis , pyrexia , chest discomfort , pruritus , and hypotension [ see Adverse Reactions ].
Pre-medicate patients with antihistamines , antipyretics and corticosteroids . Frequently monitor patients during the entire infusion . Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed . Permanently discontinue DARZALEX therapy for life-threatening ( Grade 4 ) reactions . For patients with Grade 1 , 2 , or 3 reactions , reduce the infusion rate when re-starting the infusion [ see Dosage and Administration ( 2.1 ) in Full Prescribing Information ].
To reduce the risk of delayed infusion reactions , administer oral corticosteroids to all patients following DARZALEX infusions [ see Dosage and Administration ( 2.2 ) in Full Prescribing Information ]. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications . Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease .
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 1 [ see References ]. The determination of a patient ’ s ABO and Rh blood type are not impacted [ see Drug Interactions ].
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 .
Neutropenia DARZALEX may increase neutropenia induced by background therapy [ see Adverse Reactions ].
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 . DARZALEX dose delay may be required to allow recovery of neutrophils . No dose reduction of DARZALEX is recommended . Consider supportive care with growth factors .
Thrombocytopenia DARZALEX may increase thrombocytopenia induced by background therapy [ see Adverse Reactions ].
Monitor complete blood cell counts periodically during treatment according to manufacturer ’ s prescribing information for background therapies . DARZALEX dose delay may be required to allow recovery of platelets . No dose reduction of DARZALEX is recommended . Consider supportive care with transfusions .
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 ]. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein .
ADVERSE REACTIONS The following serious adverse reactions are also described elsewhere in the labeling :
• Infusion reactions [ see Warning and Precautions ].
• Neutropenia [ see Warning and Precautions ].
• Thrombocytopenia [ see Warning and Precautions ].
Adverse Reactions in Clinical Trials 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 .
DARZALEX ® ( daratumumab ) injection
The safety data described below reflects exposure to DARZALEX ( 16 mg / kg ) in 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received DARZALEX in combination with either lenalidomide ( DRd , n = 283 ; Study 3 ) or bortezomib ( DVd , n = 243 ; Study 4 ) and five open-label , clinical trials in which patients received DARZALEX either in combination with pomalidomide ( DPd , n = 103 ; Study 5 ), in combination with lenalidomide ( n = 35 ), or as monotherapy ( n = 156 ).
Combination Treatment with Lenalidomide Adverse reactions described in Table 1 reflect exposure to DARZALEX ( DRd arm ) for a median treatment duration of 13.1 months ( range : 0 to 20.7 months ) and median treatment duration of 12.3 months ( range : 0.2 to 20.1 months ) for the lenalidomide group ( Rd ) in Study 3 . The most frequent adverse reactions ( ≥20 %) were infusion reactions , diarrhea , nausea , fatigue , pyrexia , upper respiratory tract infection , muscle spasms , cough and dyspnea . The overall incidence of serious adverse reactions was 49 % for the DRd group compared with 42 % for the Rd group . Serious adverse reactions with at least a 2 % greater incidence in the DRd arm compared to the Rd arm were pneumonia ( 12 % vs Rd 10 %), upper respiratory tract infection ( 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 1 : Adverse reactions reported in ≥ 10 % of patients and with
at least a 5 % frequency greater in the DRd arm in Study 3
Adverse Reaction
DRd ( N = 283 ) %
Rd ( N = 281 ) %
Any Grade
Grade 3
Grade 4
Any Grade
Grade 3
Grade 4
Infusion
48 5 0 0 0 0 reactions a
Gastrointestinal disorders Diarrhea 43 5 0 25 3 0 Nausea 24 1 0 14 0 0 Vomiting 17 1 0 5 1 0 General disorders and administration site conditions Fatigue 35 6 < 1 28 2 0 Pyrexia 20 2 0 11 1 0 Infections and infestations
Upper respiratory tract infection b 65 6 < 1 51 4 0
Musculoskeletal and connective tissue disorders Muscle spasms 26 1 0 19 2 0 Nervous system disorders Headache 13 0 0 7 0 0 Respiratory , thoracic and mediastinal disorders Cough c 30 0 0 15 0 0 Dyspnea d 21 3 < 1 12 1 0
Key : D = daratumumab , Rd = lenalidomide-dexamethasone . a Infusion reaction includes terms determined by investigators to be
related to infusion , see description of Infusion Reactions below . b 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 c cough , productive cough , allergic cough
d dyspnea , dyspnea exertional
Laboratory abnormalities worsening during treatment from baseline listed in Table 2 .
Table 2 : Treatment-emergent hematology laboratory abnormalities in Study 3
DRd ( N = 283 ) % Rd ( N = 281 ) %
Any Grade Grade Any Grade Grade
Grade 3 4 Grade 3 4 Anemia 52 13 0 57 19 0
Thrombocytopenia 73 7 6 67 10 5 Neutropenia 92 36 17 87 32 8 Lymphopenia 95 42 10 87 32 6
Key : D = Daratumumab , Rd = lenalidomide-dexamethasone . Combination Treatment with Bortezomib Adverse reactions described in Table 3 reflect exposure to DARZALEX ( DVd arm ) for a median treatment duration of 6.5 months ( range : 0 to 14.8 months ) and median treatment duration of 5.2 months ( range : 0.2 to 8.0 months ) for the bortezomib group ( Vd ) in Study 4 . The most frequent adverse reactions (> 20 %) were infusion reactions , diarrhea , peripheral edema , upper respiratory tract infection , peripheral sensory neuropathy , cough and dyspnea . The overall incidence of serious adverse reactions was 42 % for the DVd group compared with 34 % for the Vd group . 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 .
DARZALEX ® ( daratumumab ) injection
Table 3 : Adverse reactions reported in ≥ 10 % of patients and with
at least a 5 % frequency greater in the DVd arm Study 4
Adverse Reaction
DVd ( N = 243 ) %
Vd ( N = 237 ) %
Any Grade
Grade 3
Grade 4
Any Grade
Grade 3
Grade 4
Infusion reactions a
45
9
0
0
0
0
Gastrointestinal disorders
Diarrhea
32
3
< 1
22
1
0
Vomiting
11
0
0
4
0
0
General disorders and administration site conditions
Edema
22
1
0
13
0
peripheral b
Pyrexia
16
1
0
11
1
0
Infections and infestations
Upper respiratory tract infection c
44
6
0
30
3
< 1
Nervous system disorders
Peripheral sensory neuropathy
47
5
0
38
6
< 1
Respiratory , thoracic and mediastinal disorders
Cough d
27
0
0
14
0
0
Dyspnea e
21
4
0
11
1
0
Key : D = daratumumab , Vd = bortezomib-dexamethasone . a Infusion reaction includes terms determined by investigators to be
related to infusion , see description of Infusion Reactions below . b edema peripheral , edema , generalized edema , peripheral swelling
c 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 d cough , productive cough , allergic cough
e dyspnea , dyspnea exertional
Laboratory abnormalities worsening during treatment are listed in Table 4 .
Table 4 : Treatment-emergent hematology laboratory abnormalities in Study 4
DVd ( N = 243 ) % Vd ( N = 237 ) % Any Grade Grade Any Grade Grade Grade 3 4 Grade 3 4 Anemia 48 13 0 56 14 0
Thrombocytopenia 90 28 19 85 22 13 Neutropenia 58 12 3 40 5 < 1 Lymphopenia 89 41 7 81 24 3
Key : D = Daratumumab , Vd = bortezomib-dexamethasone .
Combination Treatment with Pomalidomide Adverse reactions described in Table 5 reflect exposure to DARZALEX , pomalidomide and dexamethasone ( DPd ) for a median treatment duration of 6 months ( range : 0.03 to 16.9 months ) in Study 5 . The most frequent adverse reactions (> 20 %) were infusion reactions , diarrhea , constipation , nausea , vomiting , fatigue , pyrexia , upper respiratory tract infection , muscle spasms , back pain , arthralgia , dizziness , insomnia , cough and dyspnea . 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 5 : Adverse reactions with incidence ≥10 % reported
in Study 5
Body System
DPd ( N = 103 )
Adverse Reaction
Any Grade (%)
Grade 3 (%)
Grade 4 (%)
Infusion reactions a
50
4
0
Gastrointestinal disorders Diarrhea
38
3
0
Constipation
33
0
0
Nausea
30
0
0
Vomiting
21
2
0
General disorders and administration site conditions
Fatigue
50
10
0
Pyrexia
25
1
0
Chills
20
0
0
Edema peripheral b
17
4
0
Asthenia
15
0
0
Non-cardiac chest pain
15
0
0
Pain
11
0
0
Infections and infestations Upper respiratory tract infection c
50
4
1
Pneumonia d
15
8
2
Metabolism and nutrition disorders
Hypokalemia
16
3
0
Hyperglycemia
13
5
1
Decreased appetite
11
0
0