NDC 57894-505 Darzalex Iv

Daratumumab

NDC Product Code 57894-505

NDC 57894-505-05

Package Description: 1 VIAL, SINGLE-DOSE in 1 BOX > 5 mL in 1 VIAL, SINGLE-DOSE

NDC 57894-505-20

Package Description: 1 VIAL, SINGLE-DOSE in 1 BOX > 20 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Darzalex Iv with NDC 57894-505 is a a human prescription drug product labeled by Janssen Biotech, Inc.. The generic name of Darzalex Iv is daratumumab. The product's dosage form is injection, solution, concentrate and is administered via intravenous form.

Dosage Form: Injection, Solution, Concentrate - A sterile preparation for parenteral use which, upon the addition of suitable solvents, yields a solution conforming in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Darzalex Iv Active Ingredient(s)

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This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Administration Route(s)

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The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • CD38-directed Cytolytic Antibody - [EPC] (Established Pharmacologic Class)
  • CD38-directed Antibody Interactions - [MoA] (Mechanism of Action)
  • Antibodies -
  • Monoclonal - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Janssen Biotech, Inc.
Labeler Code: 57894
FDA Application Number: BLA761036 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-15-2021 What is the Start Marketing Date?
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Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Darzalex Iv Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

  • DARZALEX is indicated:in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.as monotherapy, 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.

2.1 Recommended Dose And Schedule

  • Administer pre-infusion and post-infusion medications [see Dosage and Administration (2.2)].Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.4, 2.5)].DARZALEX should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur [see Warnings and Precautions (5.1)].

Other

Monotherapy and Combination Therapy with Lenalidomide or Pomalidomide and Low-Dose Dexamethasone (4-week cycle regimens)The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule in Table 1:Table 1: DARZALEX dosing schedule for monotherapy and in combination with lenalidomide or pomalidomide (4-week cycle dosing regimens)WeeksScheduleWeeks 1 to 8weekly (total of 8 doses)Weeks 9 to 24First dose of the every-2-week dosing schedule is given at week 9every two weeks (total of 8 doses)Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at week 25every four weeksFor dosing instructions of combination agents administered with DARZALEX, see Clinical Studies (14.1, 14.3) and manufacturer's prescribing information.

Combination Therapy with Bortezomib and Dexamethasone (3-week cycle regimen)The recommended dose of DARZALEX is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule in Table 2:Table 2: DARZALEX dosing schedule with bortezomib (3-week cycle dosing regimen)WeeksScheduleWeeks 1 to 9weekly (total of 9 doses)Weeks 10 to 24First dose of the every-3-week dosing schedule is given at week 10every three weeks (total of 5 doses)Week 25 onwards until disease progressionFirst dose of the every-4-week dosing schedule is given at week 25every four weeksFor dosing instructions of combination agents administered with DARZALEX see Clinical Studies (14.2) and manufacturer's prescribing information.

Missed DARZALEX DosesIf a planned dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.

  • Infusion Rates and Management of Infusion ReactionsAdminister DARZALEX infusion intravenously at the infusion rate described below in Table 3. Consider incremental escalation of the infusion rate only in the absence of infusion reactions.Table 3:Infusion rates for DARZALEX administrationDilution volumeInitial rate (first hour)Rate incrementConsider incremental escalation of the infusion rate only in the absence of infusion reactions.Maximum rateFirst infusion1000 mL50 mL/hour50 mL/hour every hour200 mL/hourSecond infusionUse a dilution volume of 500 mL only if there were no Grade 1 (mild) or greater infusion reactions during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion.500 mL50 mL/hour50 mL/hour every hour200 mL/hourSubsequent infusionsUse a modified initial rate for subsequent infusions (i.e. third infusion onwards) only if there were no Grade 1 (mild) or greater infusion reactions during a final infusion rate of ≥100 mL/hr in the first two infusions. Otherwise, continue to use instructions for the second infusion.500 mL100 mL/hour50 mL/hour every hour200 mL/hourFor 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 [see Warnings and Precautions (5.1)].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 (Table 3).Grade 3 (severe): Once reaction symptoms resolve, consider restarting the 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 outlined in Table 3. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction.Grade 4 (life threatening): Permanently discontinue DARZALEX treatment.

  • Pre-infusion MedicationAdminister the following pre-infusion medications to reduce the risk of infusion reactions to all patients 1–3 hours prior to every infusion of DARZALEX:Corticosteroid (long-acting or intermediate-acting) Monotherapy:Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).Combination therapy:Administer 20 mg dexamethasone prior to every DARZALEX infusion [Clinical Studies (14)].Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions.Antipyretics (oral acetaminophen 650 to 1000 mg)Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

  • Post-infusion MedicationAdminister post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows: Monotherapy:Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) on each of the 2 days following all DARZALEX infusions (beginning the day after the infusion).Combination therapy:Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent, the day after the DARZALEX infusion.However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed [see Clinical Studies (14)].In addition, for any patients with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued.

Prophylaxis for Herpes Zoster ReactivationInitiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following treatment [see Adverse Reactions (6.1)].

Combination Treatment with LenalidomideAdverse reactions described in Table 4 reflect exposure to DARZALEX (DRd arm) for a median treatment duration of 13.1 months (range: 0 to 20.7 months) and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide group (Rd) in Study 3. The most frequent adverse reactions (≥20%) were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea. The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (12% vs Rd 10%), upper respiratory tract infection (7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each).Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.Table 4: Adverse reactions reported in ≥ 10% of patients and with at least a 5% frequency greater in the DRd arm in Study 3Adverse ReactionDRd (N=283) %Rd (N=281) %Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4Key: D=daratumumab, Rd=lenalidomide-dexamethasone.Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below.4850000Gastrointestinal disorders  Diarrhea43502530  Nausea24101400  Vomiting1710510General disorders and administration site conditions  Fatigue356< 12820  Pyrexia20201110Infections and infestations  Upper respiratory tract infectionupper 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 infection656< 15140Musculoskeletal and connective tissue disorders  Muscle spasms26101920Nervous system disorders  Headache1300700Respiratory, thoracic and mediastinal disorders  Coughcough, productive cough, allergic cough30001500  Dyspneadyspnea, dyspnea exertional213< 11210Laboratory abnormalities worsening during treatment from baseline listed in Table 5.Table 5: Treatment-emergent hematology laboratory abnormalities in Study 3DRd (N=283) %Rd (N=281) %Any GradeGrade 3Grade 4All GradesGrade 3Grade 4Key: D=Daratumumab, Rd=lenalidomide-dexamethasone.Anemia5213057190Thrombocytopenia737667105Neutropenia92361787328Lymphopenia95421087326

Combination Treatment with BortezomibAdverse reactions described in Table 6 reflect exposure to DARZALEX (DVd arm) for a median treatment duration of 6.5 months (range: 0 to 14.8 months) and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib group (Vd) in Study 4. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group. Serious adverse reactions 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).Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.Table 6: Adverse reactions reported in ≥ 10% of patients and with at least a 5% frequency greater in the DVd arm Study 4Adverse ReactionDVd (N=243) %Vd (N=237) %Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4Key: D=daratumumab, Vd=bortezomib-dexamethasone.Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below.4590000Gastrointestinal disorders  Diarrhea323< 12210  Vomiting1100400General disorders and administration site conditions  Edema peripheraledema peripheral, edema, generalized edema, peripheral swelling22101300  Pyrexia16101110Infections and infestations  Upper respiratory tract infectionupper 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 infection4460303< 1Nervous system disorders  Peripheral sensory neuropathy4750386< 1Respiratory, thoracic and mediastinal disorders  Coughcough, productive cough, allergic cough27001400  Dyspneadyspnea, dyspnea exertional21401110Laboratory abnormalities worsening during treatment are listed in Table 7.Table 7: Treatment-emergent hematology laboratory abnormalities in Study 4DVd (N=243) %Vd (N=237) %Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4Key: D=Daratumumab, Vd=bortezomib-dexamethasone.Anemia4813056140Thrombocytopenia902819852213Neutropenia58123405< 1Lymphopenia8941781243

Combination Treatment with PomalidomideAdverse reactions described in Table 8 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study 5. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.Table 8: Adverse reactions with incidence ≥10% reported in Study 5Body SystemDPd (N=103)  Adverse ReactionAny Grade (%)Grade 3 (%)Grade 4 (%)Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.  Infusion reactionsInfusion reaction includes terms determined by investigators to be related to infusion, see description of Infusion Reactions below.5040Gastrointestinal disorders  Diarrhea3830  Constipation3300  Nausea3000  Vomiting2120General disorders and administration site conditions  Fatigue50100  Pyrexia2510  Chills2000  Edema peripheraledema, edema peripheral, peripheral swelling.1740  Asthenia1500  Non-cardiac chest pain1500  Pain1100Infections and infestations  Upper respiratory tract infectionacute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection5041  Pneumonialung infection, pneumonia, pneumonia aspiration1582Metabolism and nutrition disorders  Hypokalemia1630  Hyperglycemia1351  Decreased appetite1100Musculoskeletal and connective tissue disorders  Muscle spasms2610  Back pain2560  Arthralgia2220  Pain in extremity1500  Bone pain1340  Musculoskeletal chest pain1320Nervous system disorders  Dizziness2120  Tremor1930  Headache1700Psychiatric disorders  Insomnia2320  Anxiety1300Respiratory, thoracic and mediastinal disorders  Coughcough, productive cough, allergic cough4310  Dyspneadyspnea, dyspnea exertional3361  Nasal congestion1600Laboratory abnormalities worsening during treatment are listed in Table 9.Table 9: Treatment-emergent hematology laboratory abnormalities in Study 5DPd (N=103) %Any GradeGrade 3Grade 4Key: D=Daratumumab, Pd=pomalidomide-dexamethasone.Anemia57300Thrombocytopenia751010Neutropenia953646Lymphopenia944526

MonotherapyThe 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 10. Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.Table 10: Adverse reactions with incidence ≥10% in patients with multiple myeloma treated with DARZALEX 16 mg/kgDARZALEX 16 mg/kgN=156Incidence (%)  Adverse ReactionAny GradeGrade 3Grade 4  Infusion reactionInfusion reaction includes terms determined by investigators to be related to infusion, see below.4830General disorders and administration site conditions  Fatigue3920  Pyrexia2110  Chills1000Respiratory, thoracic and mediastinal disorders  Cough2100  Nasal congestion1700  Dyspnea1510Musculoskeletal and connective tissue disorders  Back pain2320  Arthralgia1700  Pain in extremity1510  Musculoskeletal chest pain1210Infections and infestations  Upper respiratory tract infection2010  Nasopharyngitis1500  PneumoniaPneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.1160Gastrointestinal disorders  Nausea2700  Diarrhea1610  Constipation1500  Vomiting1400Metabolism and nutrition disorders  Decreased appetite1510Nervous system disorders  Headache1210Vascular disorders  Hypertension1050Table 11: Treatment emergent Grade 3–4 laboratory abnormalities (≥10%)Daratumumab 16 mg/kg (N=156)All Grade (%)Grade 3 (%)Grade 4 (%)Anemia45190Thrombocytopenia48108Neutropenia60173Lymphopenia723010

Infusion ReactionsIn 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 ReactivationProphylaxis 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).

InfectionsIn 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.

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 binding1 [see References (15)] 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 DTT-treated 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 TestsDaratumumab 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.

Risk SummaryThere 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 ReactionsImmunoglobulin 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 DataMice 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.

Risk SummaryThere 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.

ContraceptionTo avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of DARZALEX treatment.

Cardiac ElectrophysiologyDARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

DistributionAt the recommended dose of 16 mg/kg, the mean ± SD central volume of distribution was 4.7 ± 1.3 L when DARZALEX was administered as monotherapy and 4.4 ± 1.5 L when DARZALEX was administered as combination therapy.

EliminationDaratumumab clearance decreased with increasing dose and with multiple dosing. At the recommended dose of 16 mg/kg of DARZALEX as monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day. The mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days when DARZALEX administered as monotherapy and 23 ± 12 days when DARZALEX was administered as combination therapy.

Specific PopulationsThe following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered DARZALEX as monotherapy or as combination therapy: sex, age (31 to 84 years), mild [total bilirubin 1 to 1.5 times upper limit of normal (ULN) and any alanine transaminase (ALT)] and moderate (total bilirubin 1.5 to 3 times ULN and any ALT) hepatic impairment, or renal impairment [Creatinine clearance (CLcr) 15 –89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any ALT) hepatic impairment is unknown. Increasing body weight increased the central volume of distribution and clearance of daratumumab, supporting the body weight-based dosing regimen.

Drug Interactions

Effect of Other Drugs on DaratumumabThe coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other DrugsThe coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib.

  • Infusion ReactionsAdvise 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 (5.1) and Adverse Reactions (6.1)].

  • NeutropeniaAdvise patients that if they have a fever, they should contact their healthcare professional [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

  • ThrombocytopeniaAdvise patients to inform their healthcare professional if they notice signs of bruising or bleeding [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

Interference with Laboratory TestsAdvise 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 (5.2) and Drug Interactions (7.1)].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 (5.5) and Drug Interactions (7.1)].

Manufactured by:Janssen Biotech, Inc.Horsham, PA 19044U.S. License Number 1864© Janssen Biotech, Inc., 2015

2.3 Dose Modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity [see Warnings and Precautions (5.3, 5.4)]. For information concerning drugs given in combination with DARZALEX, see manufacturer's prescribing information.

2.4 Preparation For Administration

  • DARZALEX is for single use only.Prepare the solution for infusion using aseptic technique as follows:Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of DARZALEX solution.Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 3 [see Dosage and Administration (2.1)]. Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.Gently invert the bag/container to mix the solution. Do not shake.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.Since DARZALEX does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time).If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light. Do not freeze.

2.5 Administration

  • If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.

3 Dosage Forms And Strengths

  • DARZALEX is a colorless to pale yellow, preservative-free solution available as:Injection:100 mg/5 mL (20 mg/mL) in a single-dose vial.400 mg/20 mL (20 mg/mL) in a single-dose vial.

4 Contraindications

None.

5.1 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, 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 [see Adverse Reactions (6.1)].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)].To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions [see Dosage and Administration (2.2)]. 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.

5.2 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 serum1 [see References (15)]. The determination of a patient's ABO and Rh blood type are not impacted [see Drug Interactions (7.1)].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.

5.3 Neutropenia

DARZALEX may increase neutropenia induced by background therapy [see Adverse Reactions (6.1)].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.

5.4 Thrombocytopenia

DARZALEX may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1)].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.

5.5 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 (7.1)]. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

6 Adverse Reactions

  • The following serious adverse reactions are also described elsewhere in the labeling:Infusion reactions [see Warning and Precautions (5.1)].Neutropenia [see Warning and Precautions (5.3)].Thrombocytopenia [see Warning and Precautions (5.4)].

6.1 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 described below reflects exposure to DARZALEX (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received DARZALEX in combination with either lenalidomide (DRd, n=283; Study 3) or bortezomib (DVd, n=243; Study 4) and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide (DPd, n=103; Study 5), in combination with lenalidomide (n=35), or as monotherapy (n=156).

6.2 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 anti-daratumumab 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.

8.4 Pediatric Use

Safety and effectiveness of DARZALEX in pediatric patients have not been established.

8.5 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)].

10 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.

11 Description

Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody against CD38 antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.DARZALEX is supplied as a colorless to pale yellow preservative-free solution for intravenous infusion in single-dose vials. The pH is 5.5. DARZALEX must be diluted with 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.4)].Each DARZALEX single-dose 20 mL vial contains 400 mg daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and water for injection.Each DARZALEX single-dose 5 mL vial contains 100 mg daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and water for injection.

12.1 Mechanism Of Action

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab.

12.2 Pharmacodynamics

NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.

12.3 Pharmacokinetics

Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg of DARZALEX in combination with other treatments, increases in area under the concentration-time curve (AUC) were more than dose-proportional.Following the recommended dose of 16 mg/kg when DARZALEX was administered as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) value at the end of weekly dosing, was approximately 2.7 to 3-fold higher compared to the mean serum Cmax following the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 ± 332 µg/mL when DARZALEX was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when DARZALEX was administered as combination therapy. Daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean ± SD ratio of Cmax at steady-state to Cmax after the first dose was 1.6 ± 0.5.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

14.1 Combination Treatment With Lenalidomide And Dexamethasone

Study 3, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.Study 3 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (hazard ratio [HR]=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd.Figure 1: Kaplan-Meier Curve of PFS in Study 3Additional efficacy results from Study 3 are presented in Table 12 below.Table 12: Additional efficacy results from Study 3Based on Intent-to-treat populationDRd (n=286)Rd (n=283)DRd = daratumumab- lenalidomide-dexamethasone; Rd = lenalidomide-dexamethasoneOverall response (sCR+CR+VGPR+PR)261 (91.3%)211 (74.6%)  p-valuep-value from Cochran Mantel-Haenszel Chi-Squared test.<0.0001  Stringent complete response (sCR)51 (17.8%)20 (7.1%)  Complete response (CR)70 (24.5%)33 (11.7%)  Very good partial response (VGPR)92 (32.2%)69 (24.4%)  Partial response (PR)48 (16.8%)89 (31.4%)In responders, the median time to response was 1 month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group.With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group.

14.2 Combination Treatment With Bortezomib And Dexamethasone

Study 4, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd). Bortezomib was administered by SC injection or IV infusion at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of DARZALEX infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas DARZALEX was given until disease progression. However, dexamethasone 20 mg was continued as a DARZALEX pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information.A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an immunomodulatory agent (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were in general well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd arm respectively refractory to lenalidomide. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.Study 4 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd.Figure 2: Kaplan-Meier Curve of PFS in Study 4Additional efficacy results from Study 4 are presented in Table 13 below.Table 13: Additional efficacy results from Study 4Based on Intent-to-treat populationDVd (n=251)Vd (n=247)DVd = daratumumab- bortezomib-dexamethasone; Vd = bortezomib-dexamethasoneOverall response (sCR+CR+VGPR+PR)199 (79.3%)148 (59.9%)  P-valuep-value from Cochran Mantel-Haenszel Chi-Squared test.<0.0001  Stringent complete response (sCR)11 (4.4%)5 (2.0%)  Complete response (CR)35 (13.9%)16 (6.5%)  Very good partial response (VGPR)96 (38.2%)47 (19.0%)  Partial response (PR)57 (22.7%)80 (32.4%)In responders, the median time to response was 0.8 months (range: 0.7 to 4 months) in the DVd group and 1.5 months (range: 0.7 to 5 months) in the Vd group. The median duration of response had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ to 12+ months) in the Vd group.With a median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in the Vd group were observed.

14.3 Combination Treatment With Pomalidomide And Dexamethasone

Study 5 was an open-label trial in which 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent, received 16 mg/kg DARZALEX in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/ week (reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication.The median patient age was 64 years (range: 35 to 86 years) with 8% of patients ≥75 years of age. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see Table 14).Table 14: Efficacy results for Study 5N=103ORR = sCR+CR+VGPR+PRCI=Confidence IntervalOverall response rate (ORR)95% CI (%)61 (59.2%)(49.1, 68.8)  Stringent complete response (sCR)8 (7.8%)  Complete response (CR)6 (5.8%)  Very good partial response (VGPR)29 (28.2%)  Partial response (PR)18 (17.5%)The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months).

14.4 Monotherapy

Study 1, was an open-label trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents.Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 15).Table 15: Efficacy results for Study 1N=106ORR = sCR+CR+VGPR+PRCI = confidence intervalOverall response rate (ORR)95% CI (%)31 (29.2%)(20.8, 38.9)  Stringent complete response (sCR)3 (2.8%)  Complete response (CR)0  Very good partial response (VGPR)10 (9.4%)  Partial response (PR)18 (17.0%)The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months).Study 2 was an open-label dose escalation trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents.Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months).

15 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).

16.1 How Supplied

DARZALEX is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as:NDC 57894-502-05 contains one 100 mg/5 mL single-dose vialNDC 57894-502-20 contains one 400 mg/20 mL single-dose vial

16.2 Storage And Stability

Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF).Do not freeze or shake. Protect from light. This product contains no preservative.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Spl Patient Package Insert

  • PATIENT INFORMATIONDARZALEX® (Dar'-zah-lex)(daratumumab)injection, for intravenous useThis Patient Information has been approved by the U.S. Food and Drug Administration.Revised: June/2017What is DARZALEX?DARZALEX is a prescription medicine used to treat multiple myeloma: In combination with the medicines lenalidomide and dexamethasone, or bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma.In combination with the medicines pomalidomide and dexamethasone in people who have received at least two prior medicines to treat multiple myeloma, including lenalidomide and a proteasome inhibitor.Alone in people who have received at least three prior medicines to treat multiple myeloma, including a proteasome inhibitor and an immunomodulatory agent, or did not respond to a proteasome inhibitor and an immunomodulatory agent.It is not known if DARZALEX is safe and effective in children.Before you receive DARZALEX, tell your healthcare provider about all of your medical conditions, including if you: have a history of breathing problemshave had shingles (herpes zoster)are pregnant or plan to become pregnant. DARZALEX may harm your unborn baby. Females who are able to become pregnant should use an effective method of birth control during treatment and for at least 3 months after your final dose of DARZALEX. Talk to your healthcare provider about birth control methods that you can use during this time.are breastfeeding or plan to breastfeed. It is not known if DARZALEX passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will I receive DARZALEX?DARZALEX may be given alone or together with other medicines used to treat multiple myeloma.DARZALEX will be given to you by intravenous (IV) infusion into your vein.Your healthcare provider will decide the time between doses as well as how many treatments you will receive.Your healthcare provider will give you medicines before each dose of DARZALEX and on the first day after each dose of DARZALEX to help reduce the risk of infusion reactions.If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of DARZALEX?DARZALEX may cause serious reactions, including:Infusion reactions. Infusion reactions are common with DARZALEX and can be severe. Your healthcare provider may temporarily stop your infusion or completely stop treatment with DARZALEX if you have infusion reactions. Tell your healthcare provider right away if you get any of the following symptoms:shortness of breath or trouble breathingdizziness or lightheadedness (hypotension)coughwheezingthroat tightnessrunny or stuffy noseheadacheitchingnauseavomitingchillsfeverChanges in blood tests. DARZALEX can affect the results of blood tests to match your blood type. These changes can last for up to 6 months after your final dose of DARZALEX. Your healthcare provider will do blood tests to match your blood type before you start treatment with DARZALEX. Tell all of your healthcare providers that you are being treated with DARZALEX before receiving blood transfusions.Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.The most common side effects of DARZALEX include:tirednessnauseadiarrheashortness of breathfevercoughmuscle spasmsback paincold-like symptoms (upper respiratory infection)nerve damage causing tingling, numbness or painswollen hands ankles or feetTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of DARZALEX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of DARZALEXMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about DARZALEX that is written for health professionals.What are the ingredients in DARZALEX?Active ingredient: daratumumabInactive ingredients: glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, sodium chloride, and water for injectionManufactured by: Janssen Biotech, Inc., Horsham, PA 19044 U.S. License Number 1864For more information, call 1-800-526-7736 or go to www.DARZALEX.com.

* Please review the disclaimer below.