DOSING & ADMINISTRATION FOR DARZALEX (daratumumab)

Transcription

1 JUNE 2017 UPDATE DOSING & ADMINISTRATION FOR DARZALEX (daratumumab)

2 Indications and mechanisms of action 1 How DARZALEX is supplied DARZALEX (daratumumab) 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 doublerefractory to a PI and an immunomodulatory agent DARZALEX is a first-in-class monoclonal antibody that targets CD38 1 CD38 is expressed on hematopoietic cells, other cell types and tissues, and is over-expressed on multiple myeloma cells 1,2 DARZALEX inhibits tumor cell growth through immunemediated, direct on-tumor, and immunoregulatory actions. DARZALEX may also have an effect on normal cells Warnings and precautions include: infusion reactions, interference with serological testing, neutropenia, thrombocytopenia, and interference with determination of complete response. In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%). DARZALEX in combination with lenalidomide and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were neutropenia (36%) and lymphopenia (42%). Dosage form and strengths 1 DARZALEX is a colorless to pale yellow, preservative-free solution for intravenous (IV) infusion DARZALEX is supplied in single-use vials 100 mg/5 ml (20 mg/ml) 1 Storage mg/20 ml (20 mg/ml) Store in a refrigerator at 2 C to 8 C (36 F to 46 F) Do not freeze or shake. Protect from light. This product contains no preservative In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). DARZALEX in combination with bortezomib and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were lymphopenia (41%) and thrombocytopenia (28%). 2

3 (cont d) In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence 20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). 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%). DARZALEX as monotherapy: treatment-emergent Grade 3-4 hematology laboratory abnormalities >20% was lymphopenia (30%). In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in 5% patients included pneumonia (7%). DARZALEX in combination with pomalidomide and dexamethasone: treatment-emergent hematology Grade 3-4 laboratory abnormalities 20% were anemia (30%), neutropenia (36%, 46%), and lymphopenia (45%, 26%). 3

4 DARZALEX (daratumumab) + lenalidomide + dexamethasone (DRd) DOSING & SAFETY

5 DARZALEX (daratumumab) + Rd dosing Important information 1 DARZALEX should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur Recommended dosage and schedule 1 If a planned dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval DARZALEX is given as an intravenous (IV) infusion after dilution at 16 mg/kg of actual body weight, with pre- and post-infusion medications See table on next page Revlimid (lenalidomide) is given orally on days 1 21 of each cycle* Dexamethasone 40 mg is given orally or IV once a week On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion For patients on a reduced dexamethasone dose, the entire 20-mg dose was given as a DARZALEX pre-infusion medication Revlimid is a registered trademark of Celgene Corporation. * Please refer to the lenalidomide Prescribing Information for more detailed information about lenalidomide dosing. Dexamethasone dosing may be modified for various patient populations. Please see the DARZALEX Prescribing Information for more information. 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 an infusion. 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. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue 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. To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. 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. 5

6 DARZALEX (daratumumab) + Rd dosing schedule Dosing frequency of DARZALEX decreases throughout the course of therapy 1 DRUG INTERACTIONS Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab. Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib. 6

7 Established safety profile with DARZALEX (daratumumab) + Rd Safety demonstrated in combination with Rd The most frequent adverse reactions (ARs) ( 20%) with DARZALEX + Rd were infusion reactions (48%), diarrhea (43%), nausea (24%), fatigue (35%), pyrexia (20%), upper respiratory tract infection (65%), muscle spasms (26%), cough (30%), and dyspnea (21%) 1 Serious ARs with at least a 2% greater incidence in the DARZALEX + Rd 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) Infusion reaction includes terms determined by investigators to be related to infusion. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; 5%) were nasal congestion, cough, chills, throat irritation, nausea and vomiting 1 Neutropenia DARZALEX may increase neutropenia induced by background therapy. 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. 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. Grade 3 and 4 infections between study arms: 28% vs 23% with DARZALEX + Rd vs Rd alone, respectively 1 Discontinuation rates due to ARs with DARZALEX -based combination therapy were similar to Rd alone (7% vs 8%, respectively) 1 7

8 Safety demonstrated in combination with Rd * 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. Note: ARs that occurred in 10% of patients and with at least 5% greater frequency in the DARZALEX + Rd arm are listed. 8

9 DARZALEX (daratumumab) + bortezomib + dexamethasone (DVd) DOSING & SAFETY

10 DARZALEX (daratumumab) + Vd dosing Important information 1 DARZALEX should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur Recommended dosage and schedule 1 DARZALEX is given as an intravenous (IV) infusion after dilution at 16 mg/kg of actual body weight, with pre- and post-infusion medications See table on next page Velcade (bortezomib) is administered by subcutaneous injection or IV infusion on days 1, 4, 8, and 11 of each cycle for a total of 8 cycles* Dexamethasone 20 mg is given orally once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total of 8 cycles On the days of DARZALEX infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication and was continued as a pre-medication after Vd discontinuation For patients on a reduced dexamethasone dose, the entire 20-mg dose was given as a DARZALEX pre-infusion medication If a planned dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval Interference with Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumabmediated 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. The determination of a patient s ABO and Rh blood type are not impacted. 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. Velcade is a registered trademark of Millennium Pharmaceuticals, Inc. * Please refer to the bortezomib Prescribing Information for more detailed information about twice-weekly bortezomib dosing. Dexamethasone dosing may be modified for various patient populations. Please see the DARZALEX Prescribing Information for more information. 10

11 DARZALEX + Vd dosing schedule Dosing frequency of DARZALEX decreases throughout the course of therapy 1 Note: Bortezomib and dexamethasone dosing should be stopped after 8 cycles. DRUG INTERACTIONS Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab. Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib. 11

12 Established safety profile with DARZALEX (daratumumab) + Vd Safety demonstrated in combination with Vd The most frequent adverse reactions (ARs) (>20%) with DARZALEX + Vd were infusion reactions (45%), diarrhea (32%), peripheral edema (22%), upper respiratory tract infection (44%), peripheral sensory neuropathy (47%), cough (27%), and dyspnea (21%) 1 Serious ARs with at least a 2% greater incidence in the DARZALEX + Vd 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) Infusion reaction includes terms determined by investigators to be related to infusion. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; 5%) were nasal congestion, cough, chills, throat irritation, nausea and vomiting 1 Neutropenia DARZALEX may increase neutropenia induced by background therapy. 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. 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. Grade 3 and 4 infections were similar between study arms: 21% vs 19% with DARZALEX + Vd vs Vd alone, respectively 1 Discontinuation rates due to ARs with DARZALEX -based combination therapy were similar to Vd alone (7% vs 9%, respectively) 1 12

13 Safety demonstrated in combination with Vd *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. Note: ARs that occurred in 10% of patients and with at least 5% greater frequency in the DARZALEX + Vd arm are listed. 13

14 DARZALEX (daratumumab) + pomalidomide + dexamethasone (DPd) DOSING & SAFETY

15 DARZALEX (daratumumab) + Pd dosing In patients with 2 prior lines of therapy including lenalidomide and a proteasome inhibitor (PI) 1 Dosing schedule based on a phase 1b, open-label trial 1,4 DARZALEX in combination with Pomalyst (pomalidomide) and dexamethasone (Pd) [N=103] 1 Important information 1 DARZALEX should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur If a planned dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval Recommended dosage and schedule 1 DARZALEX is given as an intravenous (IV) infusion after dilution at 16 mg/kg of actual body weight, with pre- and post-infusion medications See table on next page Pomalyst (pomalidomide) is given orally on days 1 21 of each cycle* Dexamethasone 40 mg is given orally or IV once a week On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a preinfusion medication and the remainder given the day after the infusion For patients on a reduced dexamethasone dose, the entire 20-mg dose was given as a DARZALEX pre-infusion medication DRUG INTERACTIONS Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab. Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib. Pomalyst is a registered trademark of Celgene Corporation. * Please refer to the pomalidomide Prescribing Information for more detailed information about pomalidomide dosing. Dexamethasone dosing may be modified for various patient populations. Please see the DARZALEX Prescribing Information for more information. 15

16 DARZALEX + Pd dosing schedule Dosing frequency of DARZALEX decreases throughout the course of therapy 1 Cycles 1 2 (each lasting 28 days) Total of 8 DARZALEX doses Day DARZALEX weekly pomalidomide dexamethasone Rest Cycles 3 6 (each lasting 28 days) Total of 8 DARZALEX doses Day DARZALEX every 2 weeks pomalidomide dexamethasone Rest Cycle 7+ (each lasting 28 days) Day DARZALEX every 4 weeks pomalidomide dexamethasone Rest Continue DARZALEX + Pd until disease progression or unacceptable toxicity DRUG INTERACTIONS Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab. Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib. 16

17 Established safety profile with DARZALEX (daratumumab) + Pd Safety demonstrated in combination with Pd The most frequent adverse reactions (ARs) (>20%) with DARZALEX + Pd were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%) The overall incidence of serious adverse reactions was 49% Serious adverse reactions reported in 5% of patients included pneumonia (7%) Infusion reaction includes terms determined by investigators to be related to infusion. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; 5%) were nasal congestion, cough, chills, throat irritation, vomiting, and nausea 1 Anemia Treatment-emergent hematology laboratory abnormalities 1 Thrombocytopenia Neutropenia Lymphopenia DARZALEX + Pd N=103 Any grade Grade 3 Grade 4 (%) (%) (%) Discontinuation rates due to ARs with DPd therapy was 13% Neutropenia DARZALEX may increase neutropenia induced by background therapy. 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. 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. 17

18 Safety demonstrated in combination with Pd Adverse reactions with incidence 10% 1 DARZALEX + Pd N=103 Adverse reactions with incidence 10% 1 (cont d) DARZALEX + Pd N=103 AR Any grade (%) Grade 3 (%) Grade 4 (%) AR Any grade (%) Grade 3 (%) Grade 4 (%) Infusion reactions* Gastrointestinal disorders Diarrhea Constipation Nausea Vomiting General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Non-cardiac chest pain Pain Infections and infestations Upper respiratory tract infection Pneumonia Metabolism and nutrition disorders Hypokalemia Hyperglycemia Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Back pain Arthralgia Pain in extremity Bone pain Musculoskeletal chest pain Nervous system disorders Dizziness Tremor Headache Psychiatric disorders Insomnia Anxiety Respiratory, thoracic, and mediastinal disorders Cough Dyspnea Nasal congestion * Infusion reaction includes terms determined by investigators to be related to infusion. See description of infusion reactions on pages 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. 18

19 MONOTHERAPY (single agent) DOSING & SAFETY

20 DARZALEX (daratumumab) dosing Important information 1 DARZALEX should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur If a planned dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval Recommended dosage and schedule 1 DARZALEX is given as an intravenous (IV) infusion after dilution at 16 mg/kg of actual body weight, with pre- and post-infusion medications See table on next page Administer DARZALEX only as an IV infusion after dilution 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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. 20

21 DARZALEX dosing schedule Dosing frequency of DARZALEX decreases throughout the course of therapy 1 DRUG INTERACTIONS Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab. Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib. 21

22 Established safety profile with DARZALEX (daratumumab)* * Safety data were pooled from 3 open-label clinical studies of relapsed/refractory patients treated with 16 mg/kg DARZALEX (N=156). 1 Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. Infusion reaction includes terms determined by investigators to be related to infusion. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; 5%) were nasal congestion, cough, chills, throat irritation, nausea and vomiting 1 Adverse reactions resulted in treatment delay for 24 patients (15%), most frequently for infections. Adverse reactions resulted in discontinuations for 6 patients (4%) Neutropenia DARZALEX may increase neutropenia induced by background therapy. 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. 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. 22

23 Indications and INDICATIONS 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 IMPORTANT SAFETY INFORMATION 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 an infusion. 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. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue 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. Infusion Reactions (cont d) To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and longacting 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. The determination of a patient s ABO and Rh blood type are not impacted. 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. 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 neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors. Thrombocytopenia DARZALEX may increase thrombocytopenia induced by background therapy. 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. Please see additional on page 24 23

24 Indications and (cont d) 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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. Adverse Reactions The most frequently reported adverse reactions (incidence 20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection. In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%). DARZALEX in combination with lenalidomide and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were neutropenia (36%) and lymphopenia (42%). In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). DARZALEX in combination with bortezomib and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were lymphopenia (41%) and thrombocytopenia (28%). Adverse Reactions (cont d) In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence 20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). 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%). DARZALEX as monotherapy: treatmentemergent Grade 3-4 hematology laboratory abnormalities 20% was lymphopenia (30%). In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in 5% patients included pneumonia (7%). DARZALEX in combination with pomalidomide and dexamethasone: treatment-emergent hematology Grade 3-4 laboratory abnormalities 20% were anemia (30%), neutropenia (36%, 46%), and lymphopenia (45%, 26%). DRUG INTERACTIONS Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab. Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib Please see additional on page 23 24

25 DARZALEX (daratumumab) administration Preparation for administration 1 Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (ml) of DARZALEX solution required, and number of DARZALEX vials needed based on patient s actual body weight Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration, or foreign particles are present Remove a volume of 0.9% Sodium Chloride Injection, USP, from the infusion bag/container that is equal to the required volume of DARZALEX solution Withdraw necessary amount of DARZALEX solution and dilute to appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP. Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE). Dilute under appropriate conditions. Discard any unused portion left in the vial Gently invert the bag/container to mix the solution. Do not shake Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as DARZALEX is a protein. Do not use if visibly opaque particles, discoloration, or foreign particles are observed Since DARZALEX does not contain a preservative, administer the diluted solution immediately at room temperature, 15 C to 25 C (59 F to 77 F), and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time) If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions, 2 C to 8 C (36 F to 46 F), and protected from light. Do not freeze Adverse Reactions The most frequently reported adverse reactions (incidence 20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection. In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%). DARZALEX in combination with lenalidomide and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were neutropenia (36%) and lymphopenia (42%). In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). DARZALEX in combination with bortezomib and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were lymphopenia (41%) and thrombocytopenia (28%). 25

26 DARZALEX (daratumumab) administration (cont d) Administration 1 If stored in the refrigerator, allow the solution to come to room temperature. Administer diluted solution by intravenous (IV) infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, nonpyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements Do not infuse DARZALEX concomitantly in the same IV line with other agents Adverse Reactions In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence 20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). 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%). DARZALEX as monotherapy: treatmentemergent Grade 3-4 hematology laboratory abnormalities 20% was lymphopenia (30%). In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in 5% patients included pneumonia (7%). DARZALEX in combination with pomalidomide and dexamethasone: treatment-emergent hematology Grade 3-4 laboratory abnormalities 20% were anemia (30%), neutropenia (36%, 46%), and lymphopenia (45%, 26%). 26

27 Infusion rates for DARZALEX (daratumumab) Slower rate of infusion for the first DARZALEX dose is recommended, as infusion reactions are more likely to occur with the first infusion 1 * Use a dilution volume of 500 ml only if there were no Grade 1 (mild) or greater infusion reactions during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 ml and instructions for the first infusion. Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if there were no Grade 1 (mild) or greater infusion reactions during a final infusion rate of 100 ml/hour in the first two infusions. Otherwise, continue to use instructions for the second infusion. Consider incremental escalation of the infusion rate only in the absence of infusion reactions. 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 an infusion. 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. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue 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. Median infusion duration decreased considerably after the first infusion across all trials (n=820) 1 First infusion was 7.0 hours Second infusion was 4.3 hours Subsequent infusions were 3.5 hours Administration of pre- and post-infusion medications is recommended to reduce the risk of infusion reactions (see pages 40 41) 1 27

28 48% of patients experienced an infusion reaction Across all trials (n=820), most infusion reactions occurred during the first infusion 1 For 46% of patients, infusion reactions (any grade) occurred with the first infusion, 2% of patients with the second infusion, and 3% of patients with subsequent infusions 1 The median time to onset of an infusion reaction was 1.4 hours (range: 0.02 to 72.8 hours) 1 Incidence of infusion modification due to reactions was 42% 1 DARZALEX (daratumumab) can cause severe infusion reactions. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; 5%) were nasal congestion, cough, chills, throat irritation, vomiting, and nausea 1 Infusion reactions of any grade or severity may be managed by interruption, modification, and/or discontinuation of the infusion 1 Infusion reactions by grade (n=820) 1 Infusion Reactions (cont d) To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and longacting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. 28

29 Management of infusion reactions Infusion reactions of any grade or severity may be managed by interruption, modification, and/or discontinuation of the infusion 1 For infusion reactions of any grade/severity, immediately interrupt the DARZALEX (daratumumab) infusion and manage symptoms. Management of infusion reactions may further require reduction in the rate of infusion or treatment discontinuation of DARZALEX as outlined below 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 an infusion. 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. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue 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. To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and longacting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. 29

30 Important information before administering DARZALEX (daratumumab) Interference with serological testing 1 DARZALEX binds to CD38 found on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test) that may persist for up to 6 months after the last DARZALEX infusion Reminders Type and screen patients before starting DARZALEX Inform blood banks when a patient is taking DARZALEX Identify any DARZALEX -treated blood samples Ask patients to tell other healthcare professionals that they have taken DARZALEX Adverse Reactions The most frequently reported adverse reactions (incidence 20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection. In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%). DARZALEX in combination with lenalidomide and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were neutropenia (36%) and lymphopenia (42%). Prophylaxis for herpes zoster reactivation 1 Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment Pre-infusion medications are recommended 1 Pre-infusion medications To reduce the risk of infusion reactions, administer approximately 1 3 hours prior to every infusion as follows: for monotherapy, intravenous (IV) methylprednisolone 100 mg, or equivalent. Following the second infusion, the dose of corticosteroid may be reduced (oral or IV methylprednisolone 60 mg) for combination therapy, IV dexamethasone 20 mg prior to the first infusion and IV or oral dexamethasone 20 mg prior to subsequent infusions oral antipyretics (acetaminophen 650 mg to 1000 mg), plus oral or IV antihistamine (diphenhydramine 25 mg to 50 mg or equivalent) Note: On DARZALEX infusion days in combination therapy clinical trials, 20 mg of the dexamethasone dose was given as a pre-infusion medication. For patients on a reduced dexamethasone dose, the entire 20-mg dose was given as a DARZALEX pre-infusion medication. In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence 20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). DARZALEX in combination with bortezomib and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% were lymphopenia (41%) and thrombocytopenia (28%). 30

31 Post-infusion medications are recommended Post-infusion medications To reduce the risk of delayed infusion reactions, administer after every infusion as follows 1 : oral corticosteroid for monotherapy, 20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards on each of the 2 days following all DARZALEX (daratumumab) infusions (beginning the day after the infusion) for combination therapy, 20 mg of methylprednisolone or equivalent the day after the DARZALEX infusion; however, if a background regimen-specific corticosteroid (eg, dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed Note: For patients with a history of chronic obstructive pulmonary disease, consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued. 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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence 20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). 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%). DARZALEX as monotherapy: treatment-emergent Grade 3-4 hematology laboratory abnormalities 20% was lymphopenia (30%). In patients In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in 5% patients included pneumonia (7%). DARZALEX in combination with pomalidomide and dexamethasone: treatment-emergent hematology Grade 3-4 laboratory abnormalities 20% were anemia (30%), neutropenia (36%, 46%), and lymphopenia (45%, 26%). 31