DARZALEX® + Velcade® (bortezomib) + melphalan + prednisone
Important Safety Information
CONTRAINDICATIONS
DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.
WARNINGS AND PRECAUTIONS
Infusion-Related Reactions
DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision.
When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.
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 if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. 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-related 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.
Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX® infusion. If ocular symptoms occur, interrupt DARZALEX® infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX®.
Interference With Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®.
Neutropenia and Thrombocytopenia
DARZALEX® may increase neutropenia and thrombocytopenia 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. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets.
Interference With Determination of Complete Response
Daratumumab is a human immunoglobulin G (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.
Embryo-Fetal Toxicity
Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose.
The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.
ADVERSE REACTIONS
The most frequently reported adverse reactions (incidence ≥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. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.
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cp-60862v8
Adverse events reported with DARZALEX® + VMP in NDMM transplant-ineligible patients1
| Adverse reactions with incidence ≥10%1 | ||||||
|---|---|---|---|---|---|---|
|
DARZALEX® + VMP n=346 |
VMP n=354 |
|||||
| Adverse reaction (AR) |
Any grade (%) |
Grade 3 (%) |
Grade 4 (%) |
Any grade (%) |
Grade 3 (%) |
Grade 4 (%) |
| Infusion reactions | 28 | 4 | 1 | 0 | 0 | 0 |
| General disorders and administration site conditions | ||||||
| Peripheral edema* | 21 | 1 | <1 | 14 | 1 | 0 |
| Infections and infestations | ||||||
| Upper respiratory tract infection† | 48 | 5 | 0 | 28 | 3 | 0 |
| Pneumonia‡ | 16 | 12 | <1 | 6 | 5 | <1 |
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Cough§ | 16 | <1 | 0 | 8 | <1 | 0 |
| Dyspnea∥ | 13 | 2 | 1 | 5 | 1 | 0 |
| Vascular disorders | ||||||
| Hypertension¶ | 10 | 4 | <1 | 3 | 2 | 0 |
*Edema peripheral, generalized edema, peripheral swelling.
†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.
‡Pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis.
§Cough, productive cough.
IlDyspnea, dyspnea exertional.
¶Hypertension, blood pressure increased.
Note: ARs that occurred in ≥10% of patients and with at least 5% greater frequency in the DARZALEX® + VMP arm are listed.1
- Infusion reaction includes terms determined by investigators to be related to infusion. 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 nausea1
Safety profile demonstrated in combination with VMP1
-
The most frequent ARs (≥20% with at least 5% greater frequency in the DVMP arm) were infusion reactions, upper respiratory tract infection, and peripheral edema1
- Serious adverse reactions with at least a 2% greater incidence in the DARZALEX® + VMP arm compared with the VMP arm were pneumonia (DVMP 11% vs VMP 4%), upper respiratory tract infection (DVMP 5% vs VMP 1%), and pulmonary edema (DVMP 2% vs VMP 0%)
DVMP = DARZALEX® + bortezomib + melphalan + prednisone.
| Treatment-emergent hematology laboratory abnormalities1 | ||||||
|---|---|---|---|---|---|---|
|
DARZALEX® + 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 |
- Grade 3 or 4 infections were 23% with DARZALEX® + VMP vs 15% with VMP alone1
Discontinuation rates due to ARs with DARZALEX® combination therapy in NDMM transplant-ineligible patients2
4.9%DARZALEX® + VMP
vs
9.3%VMP Alone
Interference with serological testing1
- DARZALEX® binds to CD38 found on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). DARZALEX®-mediated positive Indirect Antiglobulin Test may persist for up to 6 months after the last DARZALEX® infusion
- DARZALEX® 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 is not impacted
- Type and screen patients prior to starting treatment, and inform blood banks when a patient is being treated with DARZALEX® and for 6 months after treatment has stopped
In the event of a planned transfusion, notify blood transfusion centers of the interference with serological testing1
Find out more about interference with serological testing for patients being treated with DARZALEX®
Provide this document to patients to let healthcare professionals know that the patient is being treated with DARZALEX®
42% of patients treated experienced an infusion reaction1,3#
- DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation1
- For 40% of patients, infusion reactions (any grade) occurred with the first infusion; for 2% of patients, with the second infusion; and for 4% of patients, with subsequent infusions1
- Median time to onset of an infusion reaction was 1.4 hours (range: 0 to 72.8 hours)1
- Incidence of infusion modification due to reactions was 37%1
- DARZALEX® can cause severe and/or serious infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were Grade 1-21
- 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 nausea1
- For infusion reactions of any grade/severity, immediately interrupt the DARZALEX® infusion and manage symptoms. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care1
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.1
| Recommended management of infusion reactions1 | |
|---|---|
| Infusion reaction grade | Dose interruptions/modifications |
|
Grade 1 & 2 (mild to moderate) |
Once reaction symptoms resolve:
If the patient does not experience any further reaction symptoms:
|
|
Grade 3 (severe) |
Once symptoms resolve:
If the patient does not experience additional symptoms:
In the event of recurrence of Grade 3 symptoms:
If the patient experiences a third occurrence of a Grade 3 or higher infusion reaction:
|
|
Grade 4 (life threatening) |
Permanently discontinue DARZALEX® |
Infusion reactions of any grade or severity may be managed by interruption, modification, and/or discontinuation of the infusion.1