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