Medical Editor: John P. Cunha, DO, FACOEP
What Is Darzalex?
Darzalex (daratumumab) injection is a human CD38-directed monoclonal antibody indicated 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.
What Are Side Effects of Darzalex?
Darzalex may cause serious side effects including:
- hives,
- difficulty breathing,
- swelling of your face, lips, tongue, or throat,
- dizziness,
- itchiness,
- nausea,
- headache,
- stuffy nose,
- runny nose,
- cough,
- fever,
- chills,
- wheezing,
- tight feeling in your throat,
- cough with yellow or green mucus,
- stabbing chest pain,
- wheezing,
- shortness of breath,
- numbness,
- tingling,
- burning pain,
- tiredness,
- mouth sores,
- skin sores,
- easy bruising,
- unusual bleeding,
- pale skin,
- cold hands and feet, and
- lightheadedness
Get medical help right away, if you have any of the symptoms listed above.
Common side effects of Darzalex include:
- infusion site reactions,
- fatigue,
- nausea,
- back pain,
- fever,
- cough,
- upper respiratory tract infection,
- chills,
- nasal congestion,
- shortness of breath,
- joint pain,
- muscle pain,
- pain in the extremities,
- runny or stuffy nose,
- sore throat,
- pneumonia,
- nausea,
- vomiting,
- diarrhea,
- constipation,
- loss of appetite,
- headache,
- high blood pressure, and
- anemia.
Seek medical care or call 911 at once if you have the following serious side effects:
- Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
- Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.
Dosage for Darzalex
The recommended dose of Darzalex is 16 mg/kg body weight and dosing follows a set schedule. Patients are pre-medicated with corticosteroids, antipyretics, and antihistamines.
What Drugs, Substances, or Supplements Interact with Darzalex?
Darzalex may interact with other drugs. Tell your doctor all medications and supplements you use.
Darzalex During Pregnancy and Breastfeeding
Tell your doctor if you are pregnant, plan to become pregnant, or become pregnant while taking Darzalex. It is unknown if Darzalex passes into breast milk. Consult your doctor before breastfeeding.
Additional Information
Our Darzalex (daratumumab) injection Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
SLIDESHOW
Understanding Cancer: Metastasis, Stages of Cancer, and More See SlideshowGet emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, itchy, nauseated, or if you have a headache, stuffy nose, runny nose, cough, fever, chills, wheezing, trouble breathing, or a tight feeling in your throat.
Call your doctor at once if you have:
- cough with yellow or green mucus;
- stabbing chest pain, wheezing, feeling short of breath;
- numbness, tingling, burning pain; or
- low blood cell counts--fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath.
Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.
Common side effects may include:
- nausea, constipation, diarrhea;
- fever;
- shortness of breath;
- nerve problems causing tingling, numbness, or pain;
- feeling tired or weak;
- swelling in your hands, ankles, or feet; or
- cold symptoms such as stuffy nose, sneezing, cough, sore throat.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Infusion-related reactions [see WARNINGS AND PRECAUTIONS].
- Neutropenia [see WARNINGS AND PRECAUTIONS].
- Thrombocytopenia [see WARNINGS AND PRECAUTIONS].
Clinical Trials Experience
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 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.
Newly Diagnosed Multiple Myeloma Ineligible For Autologous Stem Cell Transplant
Combination Treatment With Lenalidomide And Dexamethasone (DRd)
The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies]. Adverse reactions described in Table 7 reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).
Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).
Table 7: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in MAIA
| Body System Adverse Reaction |
DRd (N=364) |
Rd (N=365) |
||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Gastrointestinal disorders | ||||||
| Diarrhea | 57 | 7 | 0 | 46 | 4 | 0 |
| Constipation | 41 | 1 | <1 | 36 | <1 | 0 |
| Nausea | 32 | 1 | 0 | 23 | 1 | 0 |
| Vomiting | 17 | 1 | 0 | 12 | <1 | 0 |
| Infections | ||||||
| Upper respiratory tract infectiona | 52 | 2 | <1 | 36 | 2 | <1 |
| Bronchitisb | 29 | 3 | 0 | 21 | 1 | 0 |
| Pneumoniac | 26 | 14 | 1 | 14 | 7 | 1 |
| Urinary tract infection | 18 | 2 | 0 | 10 | 2 | 0 |
| General disorders and administration site conditions | ||||||
| Infusion-related reactionsd | 41 | 2 | <1 | 0 | 0 | 0 |
| Peripheral edemae | 41 | 2 | 0 | 33 | 1 | 0 |
| Fatigue | 40 | 8 | 0 | 28 | 4 | 0 |
| Asthenia | 32 | 4 | 0 | 25 | 3 | <1 |
| Pyrexia | 23 | 2 | 0 | 18 | 2 | 0 |
| Chills | 13 | 0 | 0 | 2 | 0 | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 34 | 3 | <1 | 26 | 3 | <1 |
| Muscle spasms | 29 | 1 | 0 | 22 | 1 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Dyspneaf | 32 | 3 | <1 | 20 | 1 | 0 |
| Coughg | 30 | <1 | 0 | 18 | 0 | 0 |
| Nervous system disorders | ||||||
| Peripheral sensory neuropathy | 24 | 1 | 0 | 15 | 0 | 0 |
| Headache | 19 | 1 | 0 | 11 | 0 | 0 |
| Paresthesia | 16 | 0 | 0 | 8 | 0 | 0 |
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 22 | 1 | 0 | 15 | <1 | <1 |
| Hyperglycemia | 14 | 6 | 1 | 8 | 3 | 1 |
| Hypocalcemia | 14 | 1 | <1 | 9 | 1 | 1 |
| Vascular disorders | ||||||
| Hypertensionh | 13 | 6 | <1 | 7 | 4 | 0 |
| Key: D=daratumumab, Rd=lenalidomide-dexamethasone. a Acute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection b Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis cAtypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis d Infusion-related reaction includes terms determined by investigators to be related to infusion e Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling f Dyspnea, Dyspnea exertional g Cough, Productive cough h Blood pressure increased, Hypertension |
||||||
Laboratory abnormalities worsening during treatment from baseline listed in Table 8.
Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA
| DRd (N=364) |
Rd (N=365) |
|||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Leukopenia | 90 | 30 | 5 | 82 | 20 | 4 |
| Neutropenia | 91 | 39 | 17 | 77 | 28 | 11 |
| Lymphopenia | 84 | 41 | 11 | 75 | 36 | 6 |
| Thrombocytopenia | 67 | 6 | 3 | 58 | 7 | 4 |
| Anemia | 47 | 13 | 0 | 57 | 24 | 0 |
| Key: D=daratumumab, Rd=lenalidomide-dexamethasone. | ||||||
Combination Treatment With Bortezomib, Melphalan And Prednisone
The safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies]. Adverse reactions described in Table 9 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.
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 9: 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) |
||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Infections | ||||||
| Upper respiratory tract infectiona | 48 | 5 | 0 | 28 | 3 | 0 |
| Pneumoniab | 16 | 12 | < 1 | 6 | 5 | < 1 |
| General disorders and administration site conditions | ||||||
| Infusion-related reactionsc | 28 | 4 | 1 | 0 | 0 | 0 |
| Peripheral edemad | 21 | 1 | < 1 | 14 | 1 | 0 |
| 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 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 b pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis c Infusion-related reaction includes terms determined by investigators to be related to infusion d edema peripheral, generalized edema, peripheral swelling e cough, productive cough f dyspnea, dyspnea exertional g hypertension, blood pressure increased |
||||||
Laboratory abnormalities worsening during treatment from baseline listed in Table 10.
Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE
| D-VMP (N=346) |
VMP (N=354) |
|||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Thrombocytopenia | 88 | 27 | 11 | 88 | 26 | 16 |
| Neutropenia | 86 | 34 | 10 | 87 | 32 | 11 |
| Lymphopenia | 85 | 46 | 12 | 83 | 44 | 9 |
| Anemia | 47 | 18 | 0 | 50 | 21 | 0 |
| Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone | ||||||
Newly Diagnosed Multiple Myeloma Eligible For Autologous Stem Cell Transplant
Combination Treatment With Bortezomib, Thalidomide And Dexamethasone (DVTd)
The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.
Serious adverse reactions with a 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%).
Table 11: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DVTd Arm in CASSIOPEIA
| Body System Adverse Reaction |
DVTd (N=536) |
VTd (N=538) |
||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| General disorders and administration site conditions | ||||||
| Infusion-related reactionsa | 35 | 3 | <1 | 0 | 0 | 0 |
| Pyrexia | 26 | 2 | <1 | 21 | 2 | 0 |
| Gastrointestinal disorders | ||||||
| Nausea | 30 | 4 | 0 | 24 | 2 | <1 |
| Vomiting | 16 | 2 | 0 | 10 | 2 | 0 |
| Infections | ||||||
| Upper respiratory tract infectionb | 27 | 1 | 0 | 17 | 1 | 0 |
| Bronchitisc | 20 | 1 | 0 | 13 | 1 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Coughd | 17 | 0 | 0 | 9 | 0 | 0 |
| Vascular disorders | ||||||
| Hypertension | 10 | 4 | 0 | 5 | 2 | 0 |
| Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone. a Infusion-related reaction includes terms determined by investigators to be related to infusion b Laryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection c Bronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis d Cough, Productive cough |
||||||
Note: Hematology laboratory related toxicities were excluded and reported separately in the table below
Table 12: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA
| DVTd (N=536) |
VTd (N=538) |
|||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Lymphopenia | 95 | 44 | 15 | 91 | 37 | 10 |
| Leukopenia | 82 | 14 | 10 | 57 | 6 | 9 |
| Thrombocytopenia | 81 | 9 | 5 | 58 | 8 | 3 |
| Neutropenia | 63 | 19 | 14 | 41 | 10 | 9 |
| Anemia | 36 | 4 | 0 | 35 | 5 | 0 |
| Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone. | ||||||
Relapsed/Refractory Multiple Myeloma
Combination Treatment With Lenalidomide And Dexamethasone
The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Clinical Studies]. Adverse reactions described in Table 13 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd).
Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. 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 13: 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) |
||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Infections | ||||||
| Upper respiratory tract infectiona | 65 | 6 | < 1 | 51 | 4 | 0 |
| General disorders and administration site conditions | ||||||
| Infusion-related reactionsb | 48 | 5 | 0 | 0 | 0 | 0 |
| Fatigue | 35 | 6 | < 1 | 28 | 2 | 0 |
| Pyrexia | 20 | 2 | 0 | 11 | 1 | 0 |
| Gastrointestinal disorders | ||||||
| Diarrhea | 43 | 5 | 0 | 25 | 3 | 0 |
| Nausea | 24 | 1 | 0 | 14 | 0 | 0 |
| Vomiting | 17 | 1 | 0 | 5 | 1 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Coughc | 30 | 0 | 0 | 15 | 0 | 0 |
| Dyspnead | 21 | 3 | < 1 | 12 | 1 | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Muscle spasms | 26 | 1 | 0 | 19 | 2 | 0 |
| Nervous system disorders | ||||||
| Headache | 13 | 0 | 0 | 7 | 0 | 0 |
| Key: D=daratumumab, Rd=lenalidomide-dexamethasone. a 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 b Infusion-related reaction includes terms determined by investigators to be related to infusion c cough, productive cough, allergic cough d dyspnea, dyspnea exertional |
||||||
Laboratory abnormalities worsening during treatment from baseline listed in Table 14.
Table 14: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUX
| DRd (N=283) |
Rd (N=281) |
|||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Lymphopenia | 95 | 42 | 10 | 87 | 32 | 6 |
| Neutropenia | 92 | 36 | 17 | 87 | 32 | 8 |
| Thrombocytopenia | 73 | 7 | 6 | 67 | 10 | 5 |
| Anemia | 52 | 13 | 0 | 57 | 19 | 0 |
| Key: D=daratumumab, Rd=lenalidomide-dexamethasone. | ||||||
Combination Treatment With Bortezomib And Dexamethasone
The safety of DARZALEX in combination with bortezomib and dexamethasone was evaluated in CASTOR [see Clinical Studies]. Adverse reactions described in Table 15 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm.
Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. 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 15: 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) |
||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Nervous system disorders | ||||||
| Peripheral sensory neuropathy | 47 | 5 | 0 | 38 | 6 | < 1 |
| General disorders and administration site conditions | ||||||
| Infusion-related reactionsa | 45 | 9 | 0 | 0 | 0 | 0 |
| Peripheral edemab | 22 | 1 | 0 | 13 | 0 | 0 |
| Pyrexia | 16 | 1 | 0 | 11 | 1 | 0 |
| Infections | ||||||
| Upper respiratory tract infectionc | 44 | 6 | 0 | 30 | 3 | < 1 |
| Gastrointestinal disorders | ||||||
| Diarrhea | 32 | 3 | < 1 | 22 | 1 | 0 |
| Vomiting | 11 | 0 | 0 | 4 | 0 | 0 |
| 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-related reaction includes terms determined by investigators to be related to infusion 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 16.
Table 16: Treatment-Emergent Hematology Laboratory Abnormalities in CASTOR
| DVd (N=243) |
Vd (N=237) |
|||||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Thrombocytopenia | 90 | 28 | 19 | 85 | 22 | 13 |
| Lymphopenia | 89 | 41 | 7 | 81 | 24 | 3 |
| Neutropenia | 58 | 12 | 3 | 40 | 5 | < 1 |
| Anemia | 48 | 13 | 0 | 56 | 14 | 0 |
| Key: D=daratumumab, Vd=bortezomib-dexamethasone. | ||||||
Combination Treatment With Twice-Weekly (20/56 mg/m²) Carfilzomib And Dexamethasone
The safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Clinical Studies]. Adverse reactions described in Table 17 reflect exposure to DARZALEX for a median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd).
Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%).
Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia.
Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%.
Table 17: Adverse Reactions (≥15%) in Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone (DKd) in CANDOR
| Adverse Reaction | DKd (N=308) |
Kd (N=153) |
||
| All Grades (%) | Grades 3 or 4 (%) | All Grades (%) | Grades 3 or 4 (%) | |
| General Disorders and Administration Site Conditions | ||||
| Infusion-related reactionsa | 41 | 12 | 28 | 5 |
| Fatigueb | 32 | 11 | 28 | 8 |
| Pyrexia | 20 | 1.9 | 15 | 0.7 |
| Infections | ||||
| Respiratory tract infectionc | 40g | 7 | 29 | 3.3 |
| Pneumonia | 18g | 13 | 12 | 9 |
| Bronchitis | 17 | 2.6 | 12 | 1.3 |
| Blood and lymphatic system disorders | ||||
| Thrombocytopeniad | 37 | 25 | 30 | 16 |
| Anemiae | 33 | 17 | 31 | 14 |
| Gastrointestinal disorders | ||||
| Diarrhea | 32 | 3.9 | 14 | 0.7 |
| Nausea | 18 | 0 | 13 | 0.7 |
| Vascular Disorders | ||||
| Hypertension | 31 | 18 | 28 | 13 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Coughf | 21 | 0 | 21 | 0 |
| Dyspnea | 20 | 3.9 | 22 | 2.6 |
| Psychiatric disorders | ||||
| Insomnia | 18 | 3.9 | 11 | 2 |
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 16 | 1.9 | 10 | 1.3 |
| Key: D=daratumumab; Kd=carfilzomib-dexamethasone a The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration. b Fatigue includes fatigue and asthenia. c Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. d Thrombocytopenia includes platelet count decreased and thrombocytopenia. e Anemia includes anemia, hematocrit decreased and hemoglobin decreased. f Cough includes productive cough and cough. g Includes fatal adverse reactions. |
||||
Adverse Reactions Occurring At A Frequency Of < 15%
- Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia
- Cardiac disorders: atrial fibrillation
- Gastrointestinal disorders: vomiting, constipation
- General disorders and administration site conditions: peripheral edema, asthenia, chills
- Infections: influenza, urinary tract infection, sepsis, septic shock
- Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration
- Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain
- Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndrome
- Respiratory, thoracic and mediastinal disorders: pulmonary edema
- Skin and subcutaneous tissue disorders: rash, pruritus
Combination Treatment With Once-Weekly (20/70 mg/m²) Carfilzomib And Dexamethasone
The safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Clinical Studies]. Adverse reactions described in Table 18 reflect exposure to DARZALEX for a median treatment duration of 19.8 months (range: 0.3 to 34.5 months).
Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.
Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient.
Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively.
Table 18: Adverse Reactions (≥15%) of Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone in EQUULEUS
| Adverse Reaction | DKd (N=85) |
|
| All Grades (%) | Grades 3 or 4 (%) | |
| Blood and lymphatic system disorders | ||
| Thrombocytopeniaa | 68 | 32 |
| Anemiab | 52 | 21 |
| Neutropeniac | 31 | 21 |
| Lymphopeniad | 29 | 25 |
| General disorder and administration site conditions | ||
| Fatiguee | 54 | 18 |
| Infusion-related reactionsf | 53 | 12 |
| Pyrexia | 37 | 1.2 |
| Infections | ||
| Respiratory tract infectiong | 53 | 3.5 |
| Bronchitis | 19 | 0 |
| Nasopharyngitis | 18 | 0 |
| Influenza | 17 | 3.5 |
| Gastrointestinal disorders | ||
| Nausea | 42 | 1.2 |
| Vomiting | 40 | 1.2 |
| Diarrhea | 38 | 2.4 |
| Constipation | 17 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 35 | 3.5 |
| Coughh | 33 | 0 |
| Vascular disorders | ||
| Hypertension | 33 | 20 |
| Psychiatric disorders | ||
| Insomnia | 33 | 4.7 |
| Nervous system disorders | ||
| Headache | 27 | 1.2 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 25 | 0 |
| Pain in extremity | 15 | 0 |
| Key: D=daratumumab; Kd=carfilzomib-dexamethasone a Thrombocytopenia includes platelet count decreased and thrombocytopenia. b Anemia includes anemia, hematocrit decreased and hemoglobin decreased. c Neutropenia includes neutrophil count decreased and neutropenia. d Lymphopenia includes lymphocyte count decreased and lymphopenia e Fatigue includes fatigue and asthenia. f The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration. g Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. h Cough includes productive cough and cough. |
||
Adverse Reactions Occurring At A Frequency Of < 15%
- Blood and lymphatic system disorders: leukopenia, febrile neutropenia
- Cardiac disorders: atrial fibrillation
- Gastrointestinal disorders: pancreatitis
- General disorders and administration site conditions: peripheral edema, chills
- Infections: pneumonia, urinary tract infection, sepsis, septic shock
- Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia
- Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia
- Nervous system disorders: dizziness, paresthesia, peripheral sensory neuropathy
- Skin and subcutaneous tissue disorders: pruritus, rash
Combination Treatment With Pomalidomide And Dexamethasone
The safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Clinical Studies]. Adverse reactions described in Table 19 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months).
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 19: Adverse Reactions With Incidence ≥10% Reported in EQUULEUS
| Adverse Reaction | DPd (N=103) |
||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| General disorders and administration site conditions | |||
| Fatigue | 50 | 10 | 0 |
| Infusion-related reactionsa | 50 | 4 | 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 | |||
| Upper respiratory tract infectionc | 50 | 4 | 1 |
| Pneumoniad | 15 | 8 | 2 |
| Respiratory, thoracic and mediastinal disorders | |||
| Coughe | 43 | 1 | 0 |
| Dyspneaf | 33 | 6 | 1 |
| Nasal congestion | 16 | 0 | 0 |
| Gastrointestinal disorders | |||
| Diarrhea | 38 | 3 | 0 |
| Constipation | 33 | 0 | 0 |
| Nausea | 30 | 0 | 0 |
| Vomiting | 21 | 2 | 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 |
| Psychiatric disorders | |||
| Insomnia | 23 | 2 | 0 |
| Anxiety | 13 | 0 | 0 |
| Nervous system disorders | |||
| Dizziness | 21 | 2 | 0 |
| Tremor | 19 | 3 | 0 |
| Headache | 17 | 0 | 0 |
| Metabolism and nutrition disorders | |||
| Hypokalemia | 16 | 3 | 0 |
| Hyperglycemia | 13 | 5 | 1 |
| Decreased appetite | 11 | 0 | 0 |
| Key: D=daratumumab, Pd=pomalidomide-dexamethasone. a Infusion-related reaction includes terms determined by investigators to be related to infusion 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 20.
Table 20: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUS
| DPd (N=103) |
|||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Neutropenia | 95 | 36 | 46 |
| Lymphopenia | 94 | 45 | 26 |
| Thrombocytopenia | 75 | 10 | 10 |
| Anemia | 57 | 30 | 0 |
| Key: D=daratumumab, Pd=pomalidomide-dexamethasone. | |||
Monotherapy
The safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. 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 21. Table 22 describes Grade 3-4 laboratory abnormalities reported at a rate of ≥10%.
Table 21: Adverse Reactions With Incidence ≥10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg
| Adverse Reaction | DARZALEX (N=156) |
||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| General disorders and administration site conditions | |||
| Infusion-related reactiona | 48 | 3 | 0 |
| Fatigue | 39 | 2 | 0 |
| Pyrexia | 21 | 1 | 0 |
| Chills | 10 | 0 | 0 |
| Gastrointestinal disorders | |||
| Nausea | 27 | 0 | 0 |
| Diarrhea | 16 | 1 | 0 |
| Constipation | 15 | 0 | 0 |
| Vomiting | 14 | 0 | 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 |
| Respiratory, thoracic and mediastinal disorders | |||
| Cough | 21 | 0 | 0 |
| Nasal congestion | 17 | 0 | 0 |
| Dyspnea | 15 | 1 | 0 |
| Infections | |||
| Upper respiratory tract infection | 20 | 1 | 0 |
| Nasopharyngitis | 15 | 0 | 0 |
| Pneumoniab | 11 | 6 | 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-related reaction includes terms determined by investigators to be related to infusion b Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia. |
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Table 22: Treatment-Emergent Grade 3-4 Laboratory Abnormalities (≥10%)
| Daratumumab 16 mg/kg (N=156) |
|||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Lymphopenia | 72 | 30 | 10 |
| Neutropenia | 60 | 17 | 3 |
| Thrombocytopenia | 48 | 10 | 8 |
| Anemia | 45 | 19 | 0 |
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
Grade 3 or 4 infections were reported as follows:
- Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKda: 37%, Kda: 29%; DKdb: 21%
- where carfilzomib 20/56 mg/m² was administered twice-weekly
- where carfilzomib 20/70 mg/m² was administered once-weekly
- Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.
Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients.
Fatal infections (Grade 5) were reported as follows:
- Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKda: 5%, Kda: 3%; DKdb: 0%
- where carfilzomib 20/56 mg/m² was administered twice-weekly
- where carfilzomib 20/70 mg/m² was administered once-weekly
- Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.
Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.
Hepatitis B Virus (HBV) Reactivation
Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.
Other Clinical Trials Experience
The following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection:
Nervous System disorders: Syncope
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 in the studies described below with the incidence of antibodies in other studies or to other daratumumab products may be misleading.
In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, 0.35% (6/1,713) of patients developed treatment-emergent anti-daratumumab antibodies. Of those, 4 patients tested positive for neutralizing antibodies.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of daratumumab. 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, IRR (including deaths)
Gastrointestinal disorders: Pancreatitis
Infections: Cytomegalovirus, Listeriosis
DRUG INTERACTIONS
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] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs.
If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs 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). False positive SPE and IFE assay results may occur 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.
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).
Read the entire FDA prescribing information for Darzalex (Daratumumab Intravenous Injection)
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