ASH Clinical News July 2017 V2 - Page 14

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 .
• 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 717 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 four open-label , clinical trials in which patients received DARZALEX either 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 reactions a
48
5
0
0
0
0
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 3
Grade 4
All Grades
Grade 3
Grade 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 ).
DARZALEX ® ( daratumumab ) injection
Adverse reactions resulted in discontinuations for 7 % ( n = 18 ) of patients in the DVd arm versus 9 % ( n = 22 ) in the Vd arm .
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
6 0 30 3 < 1
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 peripheral b
22
1
0
13
0
0
Pyrexia
16
1
0
11
1
0
Infections and infestations
Upper respiratory
44
tract infection c
Nervous system disorders Peripheral sensory
47
5
0
38
6
< 1
neuropathy
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 3
Grade 4
Any Grade
Grade 3
Grade 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 . Monotherapy The safety data reflect exposure to DARZALEX in 156 adult patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg / kg in three open-label , clinical trials . 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 5 . Table 6 describes Grade 3 – 4 laboratory abnormalities reported at a rate of ≥10 %.
Table 5 : Adverse reactions with incidence ≥10 % in patients with
multiple myeloma treated with DARZALEX 16 mg / kg
DARZALEX 16 mg / kg
N = 156
Incidence (%)
Adverse Reaction
Any Grade
Grade 3
Grade 4
Infusion reaction a
48
3
0
General disorders and administration site conditions
Fatigue
39
2
0
Pyrexia
21
1
0
Chills
10
0
0
Respiratory , thoracic and mediastinal disorders
Cough
21
0
0
Nasal congestion
17
0
0
Dyspnea
15
1
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
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. • 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 cortico- steroids. 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 broncho- dilators 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. 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