Established Safety Profile with DARZALEX® + Vd

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DARZALEX® + Velcade® (bortezomib) + dexamethasone

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 Reactions – 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 1-2. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy 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 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 Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®.

Neutropenia – DARZALEX® may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.

In patients who received DARZALEX® in combination with bortezomib, melphalan, and prednisone (DVMP), the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (48%), infusion reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (58%), neutropenia (44%), and thrombocytopenia (38%).

In patients who received DARZALEX® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were neutropenia (53%) and lymphopenia (52%).

In patients who received DARZALEX® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (48%) and thrombocytopenia (47%).

In patients who received DARZALEX® in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Treatment-emergent hematology Grade 3-4 laboratory abnormalities ≥20% were anemia (30%), neutropenia (82%), and lymphopenia (71%).

In patients who received DARZALEX® as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The overall incidence of serious adverse reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (40%) and neutropenia (20%).

DRUG INTERACTIONS
Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX® did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX® with bortezomib or pomalidomide did not affect the pharmacokinetics of bortezomib or pomalidomide.

Please see full Prescribing Information.

cp-60862v1

 

Adverse Reactions

Adverse reactions with incidence ≥10%1
  DARZALEX® + VMP
n=243
VMP
n=237
Adverse reaction (AR) Any grade
(%)
Grade 3
(%)
Grade 4
(%)
Any grade
(%)
Grade 3
(%)
Grade 4
(%)
Infusion reactions 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 Peripheral* 22 1 0 13 1 0
Pyrexia 16 1 0 11 1 0
Infections and infestations
Upper respiratory tract infection 44 6 0 30 3 <1
Nervous system disorders
Peripheral sensory neuropathy 47 5 0 38 6 <1
Respiratory, thoracic, and mediastinal disorders
Cough§ 27 0 0 14 0 0
Dyspnea 21 4 0 11 1 0

*Edema peripheral, edema, generalized edema, peripheral swelling.

Upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection.

Cough, productive cough, allergic cough.

§Dyspnea, dyspnea exertional.

Note: ARs that occurred in >10% of patients and with at least 5% greater frequency in the DARZALEX® + Vd arm are listed.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 were nasal congestion, cough, chills, throat irritation, vomiting, and nausea1
 

Safety profile demonstrated in combination with Vd

  • The most frequent ARs (>20%) with DARZALEX® + Vd (DVd) were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough, and dyspnea1
    • Serious ARs 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)
Treatment-emergent hematology laboratory abnormalities1
  DARZALEX® + Vd
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
  • Grade 3/4 infections were similar between study arms: 21% vs 19% with DARZALEX® + Vd and Vd, respectively1
  • Discontinuation rates due to ARs with DARZALEX® + Vd were similar to Vd alone (7% vs 9%, respectively)1

 

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 reaction1,2II

  • 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

 

IIInfusion reaction information in the bullets above includes patients in DARZALEX® monotherapy and combination therapy clinical trials (N=1166).1
 

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:
  • Resume the infusion at no more than half the rate at which the reaction occurred

If the patient does not experience any further reaction symptoms:

  • Infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour
Grade 3
(severe)
Once symptoms resolve:
  • Consider restarting infusion at no more than half the rate at which the reaction occurred

If the patient does not experience additional symptoms:

  • Resume infusion rate escalation at increments and intervals as appropriate

In the event of recurrence of Grade 3 symptoms:

  • Repeat the procedure above

If the patient experiences a third occurrence of a Grade 3 or higher infusion reaction:

  • Permanently discontinue DARZALEX®
Grade 4
(life threatening)
Permanently discontinue DARZALEX®

Infusion reactions of any grade or severity may be managed by interruption, modification, and/or discontinuation of infusion.1