DARZALEX® + Pd Safety Profile

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DARZALEX® + Pomalyst® (pomalidomide) + 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-Related Reactions

DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. 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, 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.

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.

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 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.

Please click here to see the full Prescribing Information.

cp-60862v6

 

Adverse Reactions

 

Adverse reactions with incidence ≥10%1
  DARZALEX® + Pd
N=103
Adverse reaction (AR) Any grade
(%)
Grade 3
(%)
Grade 4
(%)
Infusion reactions 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 peripheral* 17 4 0
Asthenia 15 0 0
Non-cardiac chest pain 15 0 0
Pain 11 0 0
Infections and infestations
Upper respiratory tract infection 50 4 1
Pneumonia 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
Cough§ 43 1 0
Dyspnea 33 6 1
Nasal congestion 16 0 0

*Edema, edema peripheral, peripheral swelling.

Acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection.

Lung infection, pneumonia, pneumonia aspiration.

§Cough, productive cough, allergic cough.

ǁDyspnea, dyspnea exertional.

  • 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 Pd

  • The most frequent ARs (≥20%) with DARZALEX® + Pd (DPd) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough, and dyspnea1
    • The overall incidence of serious ARs was 49%. Serious ARs reported in ≥5% of patients included pneumonia (7%)
Treatment-emergent hematology laboratory abnormalities1
  DARZALEX® + Pd
N=103
  Any grade
(%)
Grade 3
(%)
Grade 4
(%)
Anemia 57 30 0
Thrombocytopenia 75 10 10
Neutropenia 95 36 46
Lymphopenia 94 45 26
  • The discontinuation rate due to ARs with DARZALEX® + Pd was 13%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 testing.1

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 reaction1,2¶

  • 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
 
Infusion 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 the infusion.1