Data from FDA - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE DARZALEX is indicated: in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. 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. DARZALEX is a CD38-directed cytolytic antibody indicated: in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant 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. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. Patients with a history of severe hypersensitivity to daratumumab or any of the components of the formulation. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are also described elsewhere in the labeling: Infusion reactions [see Warning and Precautions (5.1)]. Neutropenia [see Warning and Precautions (5.3)]. Thrombocytopenia [see Warning and Precautions (5.4)]. The most frequently reported adverse reactions (incidence ≥20%) 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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 1166 patients with multiple myeloma including 872 patients from three Phase 3 active-controlled trials who received DARZALEX in combination with either lenalidomide and dexamethasone (DRd, n=283; POLLUX), bortezomib and dexamethasone (DVd, n=243; CASTOR) or bortezomib, melphalan and prednisone (D-VMP, n=346; ALCYONE), and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide and dexamethasone (DPd, n=103; EQUULEUS), in combination with lenalidomide and dexamethasone (n=35), or as monotherapy (n=156). Newly Diagnosed Multiple Myeloma Combination Treatment with Bortezomib, Melphalan and Prednisone Adverse reactions described in Table 5 reflect exposure to DARZALEX (D-VMP arm) for a median treatment duration of 14.7 months (range: 0 to 25.8 months) and median treatment duration of 12 months (range: 0.1 to 14.9 months) for the VMP group in ALCYONE. The most frequent adverse reactions (≥20% with at least 5% greater frequency in the D-VMP arm) were infusion reactions, upper respiratory tract infection and edema peripheral. 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 5: Adverse reactions reported in ≥10% of patients and with at least a 5% greater frequency in the D-VMP arm in ALCYONE Body System Adverse Reaction D-VMP (N=346) VMP (N=354) Any Grade (%) Grade 3 (%) Grade 4 (%) Any Grade (%) Grade 3 (%) Grade 4 (%) Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below. 28 4 1 0 0 0 General disorders and administration site conditions Edema peripheraledema peripheral, generalized edema, peripheral swelling 21 1 < 1 14 1 0 Infections and infestations Upper respiratory tract infectionupper 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. 48 5 0 28 3 0 Pneumoniapneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis 16 12 < 1 6 5 < 1 Respiratory, thoracic and mediastinal disorders Coughcough, productive cough 16 < 1 0 8 < 1 0 Dyspneadyspnea, dyspnea exertional 13 2 1 5 1 0 Vascular disorders Hypertensionhypertension, blood pressure increased 10 4 < 1 3 2 0 Laboratory abnormalities worsening during treatment from baseline listed in Table 6. Table 6: Treatment-emergent hematology laboratory abnormalities in ALCYONE D-VMP (N=346) % VMP (N=354) % Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone Anemia 47 18 0 50 21 0 Thrombocytopenia 88 27 11 88 26 16 Neutropenia 86 34 10 87 32 11 Lymphopenia 85 46 12 83 44 9 Relapsed/Refractory Multiple Myeloma Combination Treatment with Lenalidomide Adverse reactions described in Table 7 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 POLLUX. 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 (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 7: 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) % Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Key: D=daratumumab, Rd=lenalidomide-dexamethasone. Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below. 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 infectionupper 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 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 Coughcough, productive cough, allergic cough 30 0 0 15 0 0 Dyspneadyspnea, dyspnea exertional 21 3 < 1 12 1 0 Laboratory abnormalities worsening during treatment from baseline listed in Table 8. Table 8: Treatment-emergent hematology laboratory abnormalities in POLLUX DRd (N=283) % Rd (N=281) % Any Grade Grade 3 Grade 4 Any Grades Grade 3 Grade 4 Key: D=Daratumumab, Rd=lenalidomide-dexamethasone. 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 Combination Treatment with Bortezomib Adverse reactions described in Table 9 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 CASTOR. 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. Table 9: 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) % Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Key: D=daratumumab, Vd=bortezomib-dexamethasone. Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below. 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 peripheraledema peripheral, edema, generalized edema, peripheral swelling 22 1 0 13 0 0 Pyrexia 16 1 0 11 1 0 Infections and infestations Upper respiratory tract infectionupper 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 44 6 0 30 3 < 1 Nervous system disorders Peripheral sensory neuropathy 47 5 0 38 6 < 1 Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 27 0 0 14 0 0 Dyspneadyspnea, dyspnea exertional 21 4 0 11 1 0 Laboratory abnormalities worsening during treatment are listed in Table 10. Table 10: Treatment-emergent hematology laboratory abnormalities in CASTOR DVd (N=243) % Vd (N=237) % Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Key: D=Daratumumab, Vd=bortezomib-dexamethasone. 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 Combination Treatment with Pomalidomide Adverse reactions described in Table 11 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in EQUULEUS. 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 11: Adverse reactions with incidence ≥10% reported in EQUULEUS Body System DPd (N=103) Adverse Reaction Any Grade (%) Grade 3 (%) Grade 4 (%) Key: D=Daratumumab, Pd=pomalidomide-dexamethasone. Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below. 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 peripheraledema, edema peripheral, peripheral swelling. 17 4 0 Asthenia 15 0 0 Non-cardiac chest pain 15 0 0 Pain 11 0 0 Infections and infestations Upper respiratory tract infectionacute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection 50 4 1 Pneumonialung infection, pneumonia, pneumonia aspiration 15 8 2 Metabolism and nutrition disorders Hypokalemia 16 3 0 Hyperglycemia 13 5 1 Decreased appetite 11 0 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 Nervous system disorders Dizziness 21 2 0 Tremor 19 3 0 Headache 17 0 0 Psychiatric disorders Insomnia 23 2 0 Anxiety 13 0 0 Respiratory, thoracic and mediastinal disorders Coughcough, productive cough, allergic cough 43 1 0 Dyspneadyspnea, dyspnea exertional 33 6 1 Nasal congestion 16 0 0 Laboratory abnormalities worsening during treatment are listed in Table 12. Table 12: Treatment-emergent hematology laboratory abnormalities in EQUULEUS DPd (N=103) % Any Grade Grade 3 Grade 4 Key: D=Daratumumab, Pd=pomalidomide-dexamethasone. Anemia 57 30 0 Thrombocytopenia 75 10 10 Neutropenia 95 36 46 Lymphopenia 94 45 26 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 13. Table 14 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%. Table 13: 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 reactionInfusion reaction includes terms determined by investigators to be related to infusion, see below. 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 Infections and infestations Upper respiratory tract infection 20 1 0 Nasopharyngitis 15 0 0 PneumoniaPneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. 11 6 0 Gastrointestinal disorders Nausea 27 0 0 Diarrhea 16 1 0 Constipation 15 0 0 Vomiting 14 0 0 Metabolism and nutrition disorders Decreased appetite 15 1 0 Nervous system disorders Headache 12 1 0 Vascular disorders Hypertension 10 5 0 Table 14: Treatment emergent Grade 3–4 laboratory abnormalities (≥10%) Daratumumab 16 mg/kg (N=156) Any Grade (%) Grade 3 (%) Grade 4 (%) Anemia 45 19 0 Thrombocytopenia 48 10 8 Neutropenia 60 17 3 Lymphopenia 72 30 10 Infusion Reactions In clinical trials (monotherapy and combination treatments; N=1166) the incidence of any grade infusion reactions was 40% with the first infusion of DARZALEX, 2% with the second infusion, and 4% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion reaction with second or subsequent infusions. Grade 4 infusion reactions were reported in 2/1166 (0.2%) of patients. The median time to onset of a reaction was 1.4 hours (range: 0 to 72.8 hours). The incidence of infusion modification due to reactions was 37%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7.0, 4.3, and 3.4 hours respectively. Severe infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions included nasal congestion, cough, chills, throat irritation, vomiting and nausea. 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 In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; D-VMP:23%, VMP:15%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 3% versus 2% of patients in the DRd and Rd groups respectively, 4% versus 3% of patients in the DVd and Vd groups respectively, 1% each in the D-VMP and VMP groups respectively, and in 5% of patients receiving DPd. Fatal infections were generally balanced between the DARZALEX containing regimens and active control arms (<2%) in the controlled studies and were primarily due to pneumonia and sepsis. 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to daratumumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 of the 411 combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of DARZALEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System disorders: Anaphylactic reaction

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Pre-medicate with corticosteroids, antipyretics and antihistamines. (2.2) Dilute and administer as an intravenous infusion. (2.4, 2.5) Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule (2.1) Administer post-infusion medications. (2.2) 2.1 Recommended Dose and Schedule Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.2)]. Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.4, 2.5)]. 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 [see Warnings and Precautions (5.1)]. Newly Diagnosed Multiple Myeloma Dosing Schedule for DARZALEX in Combination with Bortezomib, Melphalan and Prednisone (6-week cycle regimen) for Patients Ineligible for Autologous Stem Cell Transplant The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule in Table 1. Table 1: DARZALEX dosing schedule in combination with bortezomib, melphalan and prednisone ([VMP], 6-week cycle dosing regimen) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 54First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 16 doses) Week 55 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 55 every four weeks For dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.1). Relapsed/Refractory Multiple Myeloma Monotherapy and Combination Therapy with Lenalidomide or Pomalidomide and Low-Dose Dexamethasone (4-week cycle regimens) The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule in Table 2: Table 2: DARZALEX dosing schedule for monotherapy and in combination with lenalidomide or pomalidomide (4-week cycle dosing regimens) Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25 every four weeks For dosing instructions of combination agents administered with DARZALEX, see Clinical Studies (14.2) and manufacturer's prescribing information. Combination Therapy with Bortezomib and Dexamethasone (3-week cycle regimen) The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule in Table 3: Table 3: DARZALEX dosing schedule with bortezomib (3-week cycle dosing regimen) Weeks Schedule Weeks 1 to 9 weekly (total of 9 doses) Weeks 10 to 24First dose of the every-3-week dosing schedule is given at Week 10 every three weeks (total of 5 doses) Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at Week 25 every four weeks For dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.2) and manufacturer's prescribing information. Missed DARZALEX Doses 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. Infusion Rates and Management of Infusion Reactions Administer DARZALEX infusion intravenously at the infusion rate described below in Table 4. Consider incremental escalation of the infusion rate only in the absence of infusion reactions. Table 4: Infusion rates for DARZALEX administration Dilution volume Initial rate (first hour) Rate incrementConsider incremental escalation of the infusion rate only in the absence of infusion reactions. Maximum rate First infusion 1000 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Second infusion Use a dilution volume of 500 mL only if there were no 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. 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Subsequent infusions Use a modified initial rate for subsequent infusions (i.e. third infusion onwards) only if there were no infusion reactions during a final infusion rate of ≥100 mL/hr in the first two infusions. Otherwise, continue to use instructions for the second infusion. 500 mL 100 mL/hour 50 mL/hour every hour 200 mL/hour For infusion reactions of any grade/severity, immediately interrupt the DARZALEX 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 [see Warnings and Precautions (5.1)]. Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 4). Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 4. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction. Grade 4 (life threatening): Permanently discontinue DARZALEX treatment. 2.2 Recommended Concomitant Medications Pre-infusion Medication Administer the following pre-infusion medications to reduce the risk of infusion reactions to all patients 1–3 hours prior to every infusion of DARZALEX: Corticosteroid (long-acting or intermediate-acting) Monotherapy: Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg). Combination therapy: Administer 20 mg dexamethasone (or equivalent) prior to every DARZALEX infusion [Clinical Studies (14)]. Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions. Additional background regimen-specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX infusion days when patients receive dexamethasone (or equivalent) as a pre-medication. Antipyretics (oral acetaminophen 650 to 1000 mg) Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent). Post-infusion Medication Administer post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows: Monotherapy: Administer oral corticosteroid (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 infusions (beginning the day after the infusion). Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent, the day after the DARZALEX infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed [see Clinical Studies (14)]. In addition, for any patients with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued. Prophylaxis for Herpes Zoster Reactivation Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following treatment [see Adverse Reactions (6.1)]. 2.3 Dose Modifications No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity [see Warnings and Precautions (5.3, 5.4)]. For information concerning drugs given in combination with DARZALEX, see manufacturer's prescribing information. 2.4 Preparation for Administration DARZALEX is for single use only. Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight. Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other 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 the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 4 [see Dosage and Administration (2.1)]. Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic 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 daratumumab 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–25°C (59°F–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 – 8°C (36°F–46°F) and protected from light. Do not freeze. 2.5 Administration If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, 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 intravenous line with other agents.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no human data to inform a risk with use of DARZALEX during pregnancy. Animal studies have not been conducted. However, there are clinical considerations [see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until a hematology evaluation is completed. Data Animal Data Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect leukocyte populations, infant monkeys had a reversible reduction in leukocytes. 8.2 Lactation Risk Summary There is no information regarding the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for DARZALEX and any potential adverse effects on the breast-fed child from DARZALEX or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of DARZALEX treatment. 8.4 Pediatric Use Safety and effectiveness of DARZALEX in pediatric patients have not been established. 8.5 Geriatric Use Of the 1166 patients that received DARZALEX at the recommended dose, 46% were 65 to 75 years of age, and 15% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14)].

Interactions

7 DRUG INTERACTIONS 7.1 Effects of Daratumumab on Laboratory Tests Interference with Indirect Antiglobulin Tests (Indirect Coombs Test) Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References (15)] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices. Interference with Serum Protein Electrophoresis and Immunofixation Tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.

More information

Category Value
Authorisation number BLA761036
Agency product number 4Z63YK6E0E
Orphan designation No
Product NDC 57894-502
Date Last Revised 20-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1721951
Storage and handling 16.2 Storage and Stability 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.
Marketing authorisation holder Janssen Biotech, Inc.