No Information Provided
None.
The following serious adverse reactions are also described elsewhere in the labeling:
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 PrednisoneAdverse 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 (%) |
|
| Infusion reactionsa | 28 | 4 | 1 | 0 | 0 | 0 |
| General disorders and administration site conditions | ||||||
| Edema peripheralb | 21 | 1 | < 1 | 14 | 1 | 0 |
| Infections and infestations | ||||||
| Upper respiratory tract infectionc | 48 | 5 | 0 | 28 | 3 | 0 |
| Pneumoniad | 16 | 12 | < 1 | 6 | 5 | < 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Coughe | 16 | < 1 | 0 | 8 | < 1 | 0 |
| Dyspneaf | 13 | 2 | 1 | 5 | 1 | 0 |
| Vascular disorders | ||||||
| Hypertensiong | 10 | 4 | < 1 | 3 | 2 | 0 |
|
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone a Infusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below. b edema peripheral, generalized edema, peripheral swelling c upper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection. d pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis e cough, productive cough f dyspnea, dyspnea exertional g hypertension, blood pressure increased |
||||||
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 | |
| 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 |
| Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone |
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 | |
| Infusion reactionsa | 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 infectionb | 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 | ||||||
| Coughc | 30 | 0 | 0 | 15 | 0 | 0 |
| Dyspnead | 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 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 | |
| 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. |
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 | |
| Infusion reactionsa | 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 peripheralb | 22 | 1 | 0 | 13 | 0 | 0 |
| Pyrexia | 16 | 1 | 0 | 11 | 1 | 0 |
| Infections and infestations | ||||||
| Upper respiratory tract infectionc | 44 | 6 | 0 | 30 | 3 | < 1 |
| Nervous system disorders | ||||||
| Peripheral sensory neuropathy | 47 | 5 | 0 | 38 | 6 | < 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Coughd | 27 | 0 | 0 | 14 | 0 | 0 |
| Dyspneae | 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 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 | |
| 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. |
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 Adverse Reaction |
DPd (N=103) | ||
| Any Grade (%) | Grade 3 (%) | Grade 4 (%) | |
| Infusion reactionsa | 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 peripheralb | 17 | 4 | 0 |
| Asthenia | 15 | 0 | 0 |
| Non-cardiac chest pain | 15 | 0 | 0 |
| Pain | 11 | 0 | 0 |
| Infections and infestations | |||
| Upper respiratory tract infectionc | 50 | 4 | 1 |
| Pneumoniad | 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 | |||
| Coughe | 43 | 1 | 0 |
| Dyspneaf | 33 | 6 | 1 |
| Nasal congestion | 16 | 0 | 0 |
|
Key: D=Daratumumab, Pd=pomalidomide-dexamethasone. a Infusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below. b edema, edema peripheral, peripheral swelling. c acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection d lung infection, pneumonia, pneumonia aspiration e cough, productive cough, allergic cough f dyspnea, dyspnea exertional |
|||
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 | |
| Anemia | 57 | 30 | 0 |
| Thrombocytopenia | 75 | 10 | 10 |
| Neutropenia | 95 | 36 | 46 |
| Lymphopenia | 94 | 45 | 26 |
| Key: D=Daratumumab, Pd=pomalidomide-dexamethasone. |
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 reactiona | 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 |
| Pneumoniab | 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 |
|
a Infusion reaction includes terms determined by investigators to be related to infusion, see below. b Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. |
|||
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 |
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 ReactivationProphylaxis 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.
InfectionsIn 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.
ImmunogenicityAs 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 w
DARZALEX is indicated:
NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.
Cardiac ElectrophysiologyDARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.
Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg of DARZALEX in combination with other treatments, increases in area under the concentration-time curve (AUC) were more than dose-proportional.
Following the recommended dose of 16 mg/kg when DARZALEX was administered as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) value at the end of weekly dosing, was approximately 2.7 to 3-fold higher compared to the mean serum Cmax following the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 ± 332 µg/mL when DARZALEX was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when DARZALEX was administered as combination therapy. When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean ± SD ratio of Cmax at steady-state to Cmax after the first dose was 1.6 ± 0.5.
DistributionAt the recommended dose of 16 mg/kg, the mean ± SD central volume of distribution was 4.7 ± 1.3 L when DARZALEX was administered as monotherapy and 4.4 ± 1.5 L when DARZALEX was administered as combination therapy.
EliminationDaratumumab clearance decreased with increasing dose and with multiple dosing. At the recommended dose of 16 mg/kg of DARZALEX as monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day. The mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days when DARZALEX administered as monotherapy and a mean of 22-23 days when DARZALEX was administered as combination therapy.
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. 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 ConsiderationsFetal/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 an decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until a hematology evaluation is completed.
DataAnimal 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.
DARZALEX is a colorless to pale yellow, preservative-free solution available as:
InjectionDARZALEX is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as:
NDC 57894-502-05 contains one 100 mg/5 mL single-dose vial
NDC 57894-502-20 contains one 400 mg/20 mL single-dose vial
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.
REFERENCES
1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).
Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044 U.S. Revised: May 2018.
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Infusion ReactionsDARZALEX 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.
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.
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.
Interference With Serological TestingDaratumumab 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.
NeutropeniaDARZALEX 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.
ThrombocytopeniaDARZALEX may increase thrombocytopenia induced by background therapy.
Monitor complete blood cell counts periodically during treatment according to manufacturer’ 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 ResponseDaratumumab 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.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Infusion ReactionsAdvise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions:
Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking DARZALEX, in the event of a planned transfusion.
Advise patients that DARZALEX can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityNo carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.
Use In Specific Populations Pregnancy Risk SummaryThere 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. 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 ConsiderationsFetal/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 an decreased bone density. Defer administering live vaccines to neonates and infants exposed to DARZALEX in utero until a hematology evaluation is completed.
DataAnimal 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.
Lactation Risk SummaryThere 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.
Females And Males Of Reproductive Potential ContraceptionTo avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of DARZALEX treatment.
Pediatric UseSafety and effectiveness of DARZALEX in pediatric patients have not been established.
Geriatric UseOf 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.
REFERENCES
1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf).
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 54a | every three weeks (total of 16 doses) |
| Week 55 onwards until disease progressionb | every four weeks |
|
a First dose of the every-3-week dosing schedule is given at Week 7 b First dose of the every-4-week dosing schedule is given at Week 55 |
For dosing instructions of combination agents administered with DARZALEX see Clinical Studies.
Relapsed/Refractory Multiple MyelomaMonotherapy 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 24a | every two weeks (total of 8 doses) |
| Week 25 onwards until disease progressionb | every four weeks |
|
a First dose of the every-2-week dosing schedule is given at Week 9 b First dose of the every-4-week dosing schedule is given at Week 25 |
For dosing instructions of combination agents administered with DARZALEX, see Clinical Studies 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 24a | every three weeks (total of 5 doses) |
| Week 25 onwards until disease progressionb | every four weeks |
|
a First dose of the every-3-week dosing schedule is given at Week 10 b First dose of the every-4-week dosing schedule is given at Week 25 |
For dosing instructions of combination agents administered with DARZALEX see Clinical Studies and manufacturer’s prescribing information.
Missed DARZALEX DosesIf 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 ReactionsAdminister 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 incrementa | Maximum rate | |
| First infusion | 1000 mL | 50 mL/hour | 50 mL/hour every hour | 200 mL/hour |
| Second infusionb | 500 mL | 50 mL/hour | 50 mL/hour every hour | 200 mL/hour |
| Subsequent infusionsc | 500 mL | 100 mL/hour | 50 mL/hour every hour | 200 mL/hour |
|
a Consider incremental escalation of the infusion rate only in the absence of infusion reactions. b 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. c 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. |
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.
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:
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].
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.
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.
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 ReactivationInitiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following treatment.
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. For information concerning drugs given in combination with DARZALEX, see manufacturer’s prescribing information.
Preparation For AdministrationDARZALEX is for single use only.
Prepare the solution for infusion using aseptic technique as follows:
The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.
Effect Of Daratumumab On Other DrugsThe coadministration of DARZALEX with bortezomib or pomalidomide did not affect the pharmacokinetics of bortezomib or pomalidomide.
