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DARZALEX ® ( daratumumab ) injection

Laboratory abnormalities worsening during treatment are listed in Table 6 .

Table 6 : Treatment-emergent hematology laboratory abnormalities in Study 5

DPd ( N = 103 ) %

Any Grade Grade 3 Grade 4 Anemia 57 30 0 Thrombocytopenia 75 10 10 Neutropenia 95 36 46 Lymphopenia 94 45 26

Key : D = Daratumumab , Pd = pomalidomide-dexamethasone . Monotherapy 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 20.04 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 7 . Table 8 describes Grade 3 – 4 laboratory abnormalities reported at a rate of ≥10 %.

Table 7 : Adverse reactions with incidence ≥10 % in patients with multiple myeloma treated with DARZALEX 16 mg / kg

DARZALEX 16 mg / kg N = 156

Grade 4

DARZALEX ® ( daratumumab ) injection

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 .

Infusion Reactions

In clinical trials ( monotherapy and combination treatments ; N = 820 ) the incidence of any grade infusion reactions was 46 % with the first infusion of DARZALEX , 2 % with the second infusion , and 3 % with subsequent infusions . Less than 1 % of patients had a Grade 3 infusion reaction with second or subsequent infusions .

The median time to onset of a reaction was 1.4 hours ( range : 0.02 to 72.8 hours ). The incidence of infusion modification due to reactions was 42 %. Median durations of infusion for the 1st , 2nd and subsequent infusions were 7.0 , 4.3 , and 3.5 hours respectively .

Severe ( Grade 3 ) infusion reactions included bronchospasm , dyspnea , laryngeal edema , pulmonary edema , hypoxia , and hypertension . Other adverse infusion reactions ( any Grade , ≥5 %) were nasal congestion , cough , chills , throat irritation , vomiting and nausea .

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 randomized controlled combination therapy studies , herpes zoster was reported in 2 % each in the DRd and Rd groups respectively ( Study 3 ), in 5 % versus 3 % in the DVd and Vd groups respectively ( Study 4 ) and in 2 % of patients receiving DPd ( Study 5 ).

Infections

In patients receiving DARZALEX combination therapy , Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies ( DVd : 21 %, Vd : 19 %; DRd : 28 %, Rd : 23 %; DPd : 28 %). Pneumonia was the most commonly reported severe ( Grade 3 or 4 ) infection across studies . Discontinuations from treatment were reported in 3 % versus 2 % of patients in the DRd and Rd groups respectively , 4 % versus 3 % of patients in the DVd and Vd groups respectively and in 5 % of patients receiving DPd . Fatal infections were reported in 0.8 % to 2 % of patients across studies , primarily due to pneumonia and sepsis .

Immunogenicity

As with all therapeutic proteins , there is the potential for immunogenicity . In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies , none of the 111 evaluable monotherapy patients , and 2 ( 0.7 %) of the 298 combination therapy patients , tested positive for antidaratumumab antibodies . One patient administered DARZALEX as combination therapy , developed transient neutralizing antibodies against daratumumab . 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 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 1 [ 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 RBCs 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 .

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 .

DARZALEX ® ( daratumumab ) injection

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 that received DARZALEX monotherapy at the recommended dose , 45 % were 65 years of age or older , and 10 % were 75 years of age or older . Of 664 patients that received DARZALEX with various combination therapies , 41 % were 65 to 75 years of age , and 9 % 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 ].

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 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 ].

Neutropenia

• Advise patients that if they have a fever , they should contact their healthcare professional [ see Warnings and Precautions and Adverse Reactions ].

Thrombocytopenia

• Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding [ 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 [ see Warnings and Precautions and Drug Interactions ].

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 [ see Warnings and Precautions and Drug Interactions ].

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