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  • CLASSES

    Immunomodulators, Monoclonal Antibodies

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-CD38 monoclonal antibody
    Used as monotherapy or in combination with lenalidomide/dexamethasone, bortezomib/dexamethasone, or pomalidomide/dexamethasone in patients with multiple myeloma
    Type and cross-match patient blood prior to starting treatment

    COMMON BRAND NAMES

    DARZALEX

    HOW SUPPLIED

    DARZALEX Intravenous Inj Sol: 1mL, 20mg

    DOSAGE & INDICATIONS

    For the treatment of multiple myeloma.
    NOTE: The FDA has designated daratumumab as an orphan drug for the treatment of multiple myeloma.
    For the treatment of multiple myeloma in patients who have received at least 3 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.
    Intravenous dosage
    Adults

    16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO and diphenhydramine 25 to 50 mg (or equivalent) PO or IV prior to every infusion, and methylprednisolone 100 mg (or equivalent) IV prior to the first and second infusions and methylprednisolone 60 mg IV (or equivalent IV or PO) prior to subsequent infusions. All patients should receive an oral corticosteroid (equivalent to methylprednisolone 20 mg) for 2 days beginning the day after every infusion; consider giving bronchodilators and inhaled corticosteroids following the first 4 infusions in patients with a history of obstructive pulmonary disorder. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. The overall response rate (ORR) was 29.2% in patients with relapsed or refractory multiple myeloma who received daratumumab (median of 4 cycles; range, 1 to 16 cycles) in a multinational, nonrandomized, phase II trial (n = 106; SIRIUS trial); the CR rate was 2.8%. The median time to response and median response duration were 1 month (range, 0.9 to 5.6 months) and 7.4 months, respectively. At a median follow-up time of 9.3 months (range, 0.5 to 14.4 months), the median progression-free survival (PFS) time was 3.7 months and the median overall survival (OS) time had not been reached. The 12-month OS rate was 64.8%. Patients (median age, 63.5 years; range, 31 to 84 years) in this study had received a median of 5 prior therapies (range, 2 to 14 therapies); 97% of patients were refractory to the last line of therapy and 80% of patients had previously received an autologous stem cell transplantation (ASCT). The ORR was 36% and the median PFS time was 5.6 months in 42 patients with previously treated multiple myeloma who received daratumumab (16 mg/kg IV cohort) in a multicenter, open-label, phase I/II trial. Patients in this dose cohort had received a median of 4 prior therapies (range, 2 to 12 therapies); 76% of patients had refractory disease to the last therapy and 74% of patients had received a prior ASCT.

    For the treatment of multiple myeloma in patients who have received at least 1 prior therapy, in combination with bortezomib and dexamethasone.
    Intravenous dosage
    Adults

    16 mg/kg (actual body weight) IV weekly on weeks 1 to 9 (9 doses), 16 mg/kg IV every 3 weeks on weeks 10 to 24 (5 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (given IV prior to the first infusion; oral administration may be considered thereafter). Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion unless the regimen already has a scheduled dexamethasone dose on this day. Bronchodilators and inhaled corticosteroids may be administered following the first 4 infusions in patients with a history of obstructive pulmonary disorder. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. Daratumumab was given in combination with bortezomib (1.3 mg/m2 as a subcutaneous injection or IV infusion on days 1, 4, 8, and 11) and dexamethasone (20 mg PO/IV on days 1, 2, 4, 5, 8, 9, 11, and 12) repeated every 3 weeks for 8 cycles of therapy in a multinational, randomized, open-label, phase III trial (n = 498; CASTOR trial). Dexamethasone was administered prior to daratumumab when these drugs were scheduled on the same day and was continued as a pre-infusion medication as long as daratumumab was continued. Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years, with a body-mass index less than 18.5, or who had poorly controlled diabetes mellitus or a prior intolerance to glucocorticoid therapy. 

    For the treatment of multiple myeloma in patients who have received at least 1 prior therapy, in combination with lenalidomide and dexamethasone.
    Intravenous dosage
    Adults

    16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion unless the regimen already has a scheduled dexamethasone dose on this day (e.g., give the remaining 20 mg of the weekly 40-mg dexamethasone dose as applicable). Bronchodilators and inhaled corticosteroids may be administered following the first 4 infusions in patients with a history of obstructive pulmonary disorder. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. Daratumumab was given in combination with lenalidomide (25 mg PO daily on days 1 to 21 repeated every 28 days) and dexamethasone (40 mg IV/PO once weekly) in a multinational, randomized, open-label, phase III trial (n = 569; POLLUX trial). In patients with a reduced creatinine clearance of 30 to 60 mL/min, the lenalidomide dosage was reduced (10 mg PO daily on days 1 to 21 repeated every 28 days). Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5. In patients receiving full dose dexamethasone, it was administered as 20 mg IV prior to the daratumumab infusion and then 20 mg orally the next day when these drugs were scheduled on the same week; patients receiving a 20 mg/week dexamethasone dose had the entire dose administered prior to the daratumumab infusion.

    For the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor, in combination with pomalidomide and dexamethasone.
    Intravenous dosage
    Adults

    16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (8 doses), 16 mg/kg IV every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression; give daratumumab in combination with pomalidomide (4 mg PO daily on days 1 to 21 repeated every 28 days) and dexamethasone (40 mg IV/PO once weekly or 20 mg PO/IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5) until disease progression. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer the following premedications 1 to 3 hours prior to daratumumab: acetaminophen 650 to 1,000 mg PO, diphenhydramine 25 to 50 mg (or equivalent) PO or IV, and dexamethasone 20 mg prior to every infusion (give IV prior to the first infusion; oral administration may be considered thereafter). Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion unless the regimen already has a scheduled dexamethasone dose on this day (e.g., give the remaining 20 mg of the weekly 40-mg dexamethasone dose as applicable). Bronchodilators and inhaled corticosteroids may be administered following the first 4 infusions in patients with a history of obstructive pulmonary disorder. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. The overall response rate (ORR) was 60% in patients with relapsed or refractory multiple myeloma who received daratumumab, pomalidomide, and low-dose dexamethasone in a nonrandomized, phase Ib trial (n = 103; EQUULEUS trial); the stringent complete response (CR) rate was 8% and the CR rate was 9%. At a median follow-up time of 13.1 months (range, 0.2 to 25.8 months), the median progression-free survival (PFS) and overall survival (OS) times were 8.8 months and 17.5 months, respectively; the estimated 12-month PFS and OS rates were 42% and 66%, respectively. Patients (median age, 64 years; range, 35 to 86 years) in this study had received a median of 4 prior therapies (range, 1 to 13 therapies); 74% of patients had previously received an autologous stem cell transplantation.

    MAXIMUM DOSAGE

    Adults

    16 mg/kg/dose (actual body weight) IV.

    Geriatric

    16 mg/kg/dose (actual body weight) IV.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are necessary for patients with pre-existing mild (total bilirubin level of 1 to 1.5-times the upper limit of normal (ULN) and any ALT level) or moderate (total bilirubin level 1.5 to 3-times the ULN and any ALT level) hepatic impairment based on a population pharmacokinetic analysis. Daratumumab has not been evaluated in patients with severe hepatic impairment (total bilirubin level greater than 3-times the ULN and any ALT level).

    Renal Impairment

    No daratumumab dosage adjustment is necessary for patients with pre-existing renal impairment based on a population pharmacokinetic analysis.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
    The daratumumab solution in single-dose vials is colorless to pale yellow. It is a protein and the diluted solution may develop very small, translucent to white particles; do not use diluted solutions containing visibly opaque particles, discoloration, or foreign particles.

    Intravenous Administration

    Premedication with acetaminophen PO, diphenhydramine IV or PO, and a corticosteroid is required prior to each infusion; hold therapy for infusion-related reactions.
    If a dose is missed, administer daratumumab as soon as possible and adjust the dosing schedule to maintain the treatment interval.
    Initial dilution volume and/or infusion rate differ for first, second, and subsequent infusions; the maximum infusion rate is 200 mL/hour.
     
    Dilution:
    Withdraw the appropriate amount (mL) from the daratumumab 20 mg/mL vials for the calculated dose (use actual body weight); discard any unused portion left in the vial.
    For the first infusion, dilute the calculated amount in 0.9% sodium chloride injection to a total infusion bag volume of 1,000 mL; for subsequent infusions, dilute the calculated amount in 0.9% sodium chloride injection to a total infusion bag volume of 500 mL if there were no grade 1 or higher infusion reactions during the first 3 hours of the first infusion.
    Gently invert the bag to mix the solution but do not shake.
    Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend.
    Storage of admixture: store at room temperature (15 to 25 degrees C or 59 to 77 degrees F) for up to 15 hours (includes infusion time) or for up to 24 hours refrigerated (2 to 8 degrees C or 36 to 46 degrees F) and protected from light; allow refrigerated admixtures to warm to room temperature prior to use.
     
    Intravenous Infusion:
    Administer daratumumab using an infusion-set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone filter (pore size of 0.2 or 0.22 micrometer); polyurethane, polybutadiene (PBD), PVC, PP, or PE administration sets must be used.
    Do not infuse other drugs concomitantly in the same IV line.
    Administer the diluted infusion intravenously at the appropriate infusion rate as follows:
    First and second infusions: start at 50 mL/hour, increase by 50 mL/hour every hour to a maximum rate of 200 mL/hour.
    Subsequent infusions: start at 100 mL/hour, increase by 50 mL/hour every hour to a maximum rate of 200 mL/hour if there were no grade 1 or higher infusion reactions during the final infusion rate of 100 mL/hour or greater in the first 2 infusions.
    Do not save or store unused daratumumab for reuse.

    STORAGE

    DARZALEX:
    - Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Chronic obstructive pulmonary disease (COPD), infusion-related reactions

    Severe infusion-related reactions (e.g., bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema, and pulmonary edema) have been reported with daratumumab therapy. Monitor patients frequently during the daratumumab infusion for signs and symptoms of infusion-related reactions. Hold therapy and initiate appropriate medical support if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Premedication with acetaminophen, an antihistamine (e.g., diphenhydramine), and a corticosteroid is required prior to each infusion. Additionally, all patients should receive oral corticosteroids after every infusion to reduce the risk of delayed infusion reactions. Consider giving additional post-infusion medications such as short-and long-acting bronchodilators and inhaled corticosteroids in patients with a history of obstructive pulmonary disorder (e.g., chronic obstructive pulmonary disease (COPD)). Reactions may occur up to 48 hours after a daratumumab infusion; however, most infusion-related reactions occur during or within 4 hours from the end of the infusion. Symptoms of infusion-related reactions include nasal congestion, cough, throat irritation, chills, vomiting and nausea; less common symptoms include wheezing, allergic rhinitis, fever, chest discomfort, pruritus, and hypotension.

    Laboratory test interference

    Daratumumab binds to CD38 on red blood cells (RBCs) and may interfere with the ability to determine a patient’s blood type and result in a false positive indirect antiglobulin test (Coombs test); the laboratory test interference may last for up to 6 months after stopping therapy. Additionally, daratumumab can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein which may interfere with the determination of complete response or disease progression in some patients. Patients should have their blood typed and cross-matched prior to starting treatment. In the event of a planned blood transfusion, inform personnel at blood transfusion centers that the patient is receiving daratumumab. If a patient requires an emergency transfusion, non-cross-matched ABO/RhD-compatible RBCs can be given as local blood bank practice dictates. Determination of ABO and Rh blood type are not affected by daratumumab.

    Infection, neutropenia, thrombocytopenia

    Hematologic toxicity such as neutropenia and thrombocytopenia has been reported with daratumumab therapy; the addition of daratumumab to bortezomib/dexamethasone or lenalidomide/dexamethasone therapy may increase the incidence of hematologic toxicity. When daratumumab is given as part of combination therapy, monitor complete blood counts periodically during therapy; the frequency of monitoring depends on recommendations from the manufacturers of the myelosuppressive agents in the regimen (i.e., bortezomib or lenalidomide). Monitor patients who develop neutropenia for signs and symptoms of infection. In patients who develop hematologic toxicity, a daratumumab dose delay may be necessary until blood counts recover; a daratumumab dose reduction is not recommended. Consider supportive care with growth factors or transfusions in these patients.

    Pregnancy, vaccination

    Daratuzumab may cause fetal harm if administered during pregnancy based on its mechanism of action. Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta; therefore, it is possible for daratumumab to cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Prior to administering a live vaccination, evaluate hematologic parameters in neonates and infants whose mother received daratumumab during pregnancy. A reversible reduction in leukocytes was observed in infant cynomolgus monkeys who were exposed in utero to other monoclonal antibodies that affect leukocytes.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during daratumumab treatment. Females should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with daratumumab. Women who become pregnant while receiving daratumumab should be apprised of the potential hazard to the fetus.

    Breast-feeding

    According to the manufacturer, it is not known whether daratumumab is secreted in human milk or if it affects the breast fed infant or milk production. It is known that human IgG is present in human milk; however, published data suggest that only small amounts of antibodies enter the neonatal and infant circulation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 15.0-82.0
    lymphopenia / Delayed / 40.0-71.0
    thrombocytopenia / Delayed / 13.0-47.0
    anemia / Delayed / 13.0-30.0
    fatigue / Early / 0-10.0
    infusion-related reactions / Rapid / 3.0-9.0
    dyspnea / Early / 1.0-7.0
    back pain / Delayed / 0-6.0
    rhinitis / Early / 0-6.0
    pharyngitis / Delayed / 0-6.0
    candidiasis / Delayed / 0-6.0
    infection / Delayed / 0-6.0
    laryngitis / Delayed / 0-6.0
    sinusitis / Delayed / 0-6.0
    tracheitis / Delayed / 0-6.0
    hyperglycemia / Delayed / 0-6.0
    diarrhea / Early / 1.0-5.0
    hypertension / Early / 0-5.0
    peripheral neuropathy / Delayed / 0-5.0
    bone pain / Delayed / 0-4.0
    edema / Delayed / 0-4.0
    peripheral edema / Delayed / 0-4.0
    tremor / Early / 0-3.0
    hypokalemia / Delayed / 0-3.0
    vomiting / Early / 0-2.0
    arthralgia / Delayed / 0-2.0
    musculoskeletal pain / Early / 0-2.0
    fever / Early / 1.0-2.0
    dizziness / Early / 0-2.0
    atrial fibrillation / Early / 0-2.0
    insomnia / Early / 0-2.0
    anorexia / Delayed / 0-1.0
    nausea / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    headache / Early / 0-1.0
    pulmonary edema / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 0-33.0
    chest pain (unspecified) / Early / 0-15.0
    antibody formation / Delayed / 0-0.7
    wheezing / Rapid / Incidence not known
    hypoxia / Early / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    chills / Rapid / 0-20.0
    nasal congestion / Early / 0-17.0
    asthenia / Delayed / 0-15.0
    anxiety / Delayed / 0-13.0
    influenza / Delayed / 0-3.0
    throat irritation / Early / 5.0
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Daratumumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is not known whether daratumumab is secreted in human milk or if it affects the breast fed infant or milk production. It is known that human IgG is present in human milk; however, published data suggest that only small amounts of antibodies enter the neonatal and infant circulation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Daratumumab is a human monoclonal antibody that binds to CD38 IgG1 (kappa subclass), a type II transmembrane glycoprotein, resulting in apotosis via Fc-mediated cross linking, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. CD38 is expressed on myeloid-derived suppressor cells and some regulatory T-cells (CD38+Tregs ); these cells are sensitive to daratumumab.

    PHARMACOKINETICS

    Daratumumab is administered as an IV infusion. In a population pharmacokinetic analysis of daratumumab as monotherapy and as part of combination therapy, the mean central volume of distribution (Vd) values were 4.7 +/- 1.3 L and 4.4 +/- 1.5 L, respectively, and the mean estimated mean terminal half-life values associated with linear clearance were 18 +/- 9 days and 23 +/- 12 days, respectively. Daratumumab clearance decreased with increasing dose and repeated dosing. The mean linear clearance was 171.4 +/- 95.3 mL/day for monotherapy.

    Intravenous Route

    At the end of weekly dosing, the mean daratumumab Cmax level was about 2.7 to 3-times higher than the mean Cmax level following the first dose. Additionally, the mean Cmin level (trough) was 573 +/- 332 micrograms (mcg)/mL when daratumumab was administered as monotherapy and 502 +/- 196 mcg/mL to 607 +/- 231 mcg/mL when daratumumab was administered as part of combination therapy. In a population pharmacokinetic analysis in patients with multiple myeloma, steady state levels were achieved at about 5 months after the daratumumab 16 mg/kg IV every 4-week dosing period (by the 21st infusion); the mean steady-state to first dose Cmax ratio was 1.6 (SD +/- 0.5). The AUC values increased more than dose-proportionally over the range of 1 to 24 mg/kg for monotherapy and 1 to 16 mg/kg for combination therapy.