ASH Clinical News September 2016 | Page 52
DARZALEX® (daratumumab) injection, for intravenous use
Brief Summary of Full Prescribing Information
DARZALEX® (daratumumab) injection
DARZALEX® (daratumumab) injection
INDICATIONS AND USAGE
DARZALEX is 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.
This indication is approved under accelerated approval based
on response rate [see Clinical Studies (14) in Full Prescribing
Information]. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in confirmatory
trials.
Table 1: Adverse reactions with incidence ≥10% in patients with
multiple myeloma treated with DARZALEX 16 mg/kg
(continued)
DARZALEX 16 mg/kg
N=156
Incidence (%)
System Organ Class
Adverse Reaction
Any Grade Grade 3 Grade 4
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
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
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 [see Clinical Considerations]. The
estimated background risk of major birth defects and miscarriage for
the indicated population is unknown. 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 Considerations
Fetal/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 and decreased
bone density. Defer administering live vaccines to neonates and
infants exposed to DARZALEX in utero until a hematology evaluation
is completed.
Data
Animal 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 Summary
There is no information regarding the presence of daratumumab
in human milk, the effects on the breastfed infant, 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
Contraception
To 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 Use
Safety and effectiveness of DARZALEX in pediatric patients have not
been established.
Geriatric Use
Of the 156 patients on the recommended dose, 45% were 65 years
of age or older, and 10% were 75 years of age or older. No overall
differences in safety or effectiveness were observed between
these patients and younger patients [see Clinical Studies (14) in Full
Prescribing Information].
Renal Impairment
Based on a population pharmacokinetic (PK) analysis no dosage
adjustment is necessary for patients with pre-existing renal
impairment [see Clinical Pharmacology (12.3) in Full Prescribing
Information].
Hepatic Impairment
Based on a population PK analysis, no dosage adjustments
are necessary for patients with mild hepatic impairment (Total
Bilirubin [TB] 1.0× to 1.5× upper limit of normal [ULN] or aspartate
aminotransferase [AST] >ULN). Daratumumab has not been studied
in patients with moderate to severe hepatic impairment (TB >1.5× ULN
and any AST) [see Clinical Pharmacology (12.3) in Full Prescribing
Information].
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Infusion Reactions
DARZALEX 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, and hypertension. Signs and symptoms may include
respiratory symptoms, such as cough, wheezing, larynx and throat
tightness and irritation, laryngeal edema, pulmonary edema, nasal
congestion, and allergic rhinitis. Less common symptoms were
hypotension, headache, rash, urticaria, pruritus, nausea, vomiting,
and chills [see Adverse Reactions].
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 [see Dosage and Administration (2.1) in Full
Prescribing Information].
To reduce the risk of delayed infusion reactions, administer oral
corticosteroids to all patients the first and second day after all
infusions. Patients with a history of obstructive pulmonary disorders
may require additional post-infusion medications to manage
respiratory complications. Consider prescribing short- and longacting bronchodilators and inhaled corticosteroids for patients with
obstructive pulmonary disorders.
Interference with Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results
in a positive Indirect Antiglobulin Test (Coombs test). Daratumumabmediated 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 serum1 [see References]. The determination of a patient’s
ABO and Rh blood type are not impacted [see Drug Interactions].
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.
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 [see Drug Interactions]. This interference
can impact the determination of complete response and of disease
progression in some patients with IgG kappa myeloma protein.
ADVERSE REACTIONS
The following serious adverse reactions are also described
elsewhere in the labeling:
• Infusion reactions [see Warning and Precautions].
Adverse Reactions in Clinical Trials
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 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 20.4 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 1. Table 2 describes Grade 3–4 laboratory abnormalities
reported at a rate of ≥10%.
Table 1: Adverse reactions with incidence ≥10% in patients with
multiple myeloma treated with DARZALEX 16 mg/kg
DARZALEX 16 mg/kg
N=156
Incidence (%)
System Organ Class
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
Table 2: Treatment Emergent Grade 3-4 laboratory abnormalities
(≥10%)
Daratumumab 16 mg/kg (N=156)
All Grade (%) Grade 3 (%) Grade 4 (%)
Anemia
45
19
0
Thrombocytopenia
48
10
8
Neutropenia
60
17
3
Lymphopenia
72
30
10
Infusion Reactions
The incidence of any grade infusion reactions was 46% with the
first infusion of DARZALEX, 5% with the second infusion, and 4%
with subsequent infusions. None of the reactions with second or
subsequent infusions were Grade 3 or higher.
The median time to onset of a reaction was 1.5 hours (range: 0.02 to
9.3 hours). The incidence of infusion interruptions due to reactions
was 37%. Median durations of infusion for the 1st, 2nd and subsequent
infusions were 7.0, 4.6 and 3.4 hours respectively.
Severe infusion reactions included bronchospasm, dyspnea, hypoxia,
and hypertension (<2% each). Common any grade adverse infusion
reactions (≥5%) were nasal congestion, cough, chills, rhinitis allergic,
throat irritation, dyspnea, and nausea.
Herpes Zoster Virus Reactivation
Prophylaxis for Herpes Zoster Virus reactivation was recommended
for patients in some clinical trials of DARZALEX. Systemic antiviral medications were used in 73% of patients. Herpes zoster was
reported in 3% of patients.
Immunogenicity
As with all therapeutic proteins, there is the potential for
immunogenicity. In an open-label, clinical trial of patients with
relapsed or refractory multiple myeloma treated with DARZALEX,
111 patients were evaluated for anti-therapeutic antibody
(ATA) responses to daratumumab at multiple time points during
treatment and up to 8 weeks following the end of treatment using
an electrochemiluminescence-based immunoassay. Following the
start of DARZALEX treatment, none of the patients tested positive for
anti-daratumumab antibodies. However, this assay has limitations
in detecting anti-daratumumab antibodies in the presence of high
concentrations of daratumumab; therefore, the incidence of antibody
development might not have been reliably determined.
Immunogenicity data are highly dependent on the sensitivity and
specificity of the test methods used. Additionally, the observed
incidence of a positive result in a test method may be influenced
by several factors, including sample handling, timing of sample
collection, drug interference, concomitant medication and the
underlying disease. Therefore, comparison of the incidence of
antibodies to daratumumab with the incidence of antibodies to other
products may be misleading.
DRUG INTERACTIONS
No drug interaction studies have been performed.
Effects of Daratumumab on Laboratory Tests
Interference with Indirect Antiglobulin Tests (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
binding1 [see References] or genotyping. Since the Kell blood group
system is also sensitive to DTT treatment, K-negative units should
be supplied after ruling out or identifying alloantibodies using DTTtreated RBCs.
If an emergency transfusion is required, non-cross-matched ABO/
RhD-compatible RB Cs can be given 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). This can lead to false
positive SPE and IFE assay results 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, consider other methods to
evaluate the depth of response.
OVERDOSAGE
The dose of DARZALEX at which severe toxicity occurs is not known.
In the event of an overdose, monitor patients for any signs or
symptoms of adverse effects and provide appropriate supportive
treatment.
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).
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient
Information).
Infusion Reactions
Advise patients to seek immediate medical attention for any of the
following signs and symptoms of infusion reactions:
• itchy, runny or blocked nose; chills, nausea, throat irritation,
cough, headache, shortness of breath or difficulty breathing [see
Warnings and Precautions and Adverse Reactions].
Interference with Laboratory Tests
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.
Manufactured by:
Janssen Biotech, Inc.
Horsham, PA 19044
U.S. License Number 1864
© Janssen Biotech, Inc., 2015
040929-160226