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    Miscellaneous Monoclonal Antibodies that Target Cell Surface Receptors

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-CD38 monoclonal antibody
    Used as monotherapy or in combination with other agents for 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. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). 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. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.[60311] 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 2 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).[61025] 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 1/2 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.[60312]

    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. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). 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. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.[60311] 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 3 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.[61207] 

    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 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). 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). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. 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 3 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. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). 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. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. 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 1b 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.

    For the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with bortezomib, melphalan, and prednisone.
    Intravenous dosage
    Adults

    16 mg/kg (actual body weight) IV weekly on weeks 1 to 6 (6 doses), 16 mg/kg IV every 3 weeks on weeks 7 to 54 (16 doses), and then 16 mg/kg IV every 4 weeks starting on week 55 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). 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). Omit the prednisone dose on days when dexamethasone is administered as a premedication. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion unless there is a scheduled prednisone dose on this day. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Daratumumab was administered in combination with VMP consisting of bortezomib 1.3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and 1.3 mg/m2 subcutaneously once weekly on weeks 1, 2, 4, and 5 of cycles 2 to 9; melphalan 9 mg/m2 orally daily on days 1, 2, 3, and 4 on cycles 1 to 9; and prednisone 60 mg/m2 orally daily on days 1, 2, 3, and 4 on cycles 1 to 9 was evaluated in a randomized, phase 3 trial (the ALCYONE trial; n = 706). VMP treatment cycles were repeated every 6 weeks. Dexamethasone 20 mg IV or PO was substituted for prednisone on day 1 of each cycle. In the ALCYONE trial (median follow-up of 40.1 months), the primary endpoint of PFS time was significantly higher with daratumumab plus VMP compared VMP alone (36.4 months vs. 19.3 months; hazard ratio (HR) = 0.42; 95% CI, 0.34 to 0.51; p less than 0.0001) in adult patients (median age, 71 years; range, 40 to 93 years) with multiple myeloma who were ineligible for high-dose chemotherapy with stem-cell transplant (SCT) due to coexisting conditions or age of 65 years or older and who had not received prior systemic therapy or SCT. At the time of this analysis, the median overall survival time was significantly improved in patients in the daratumumab plus VMP arm compared with the VMP alone arm (median time not reached in either arm; HR = 0.6; 95% CI, 0.46 to 0.8; p = 0.0003).

    For the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, 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 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression. The first dose on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). 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). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.[60311] 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 3 trial (n = 737; MAIA trial). In this trial (median follow-up time, 28 months), the median progression-free survival time was significantly improved in the daratumumab plus lenalidomide and dexamethasone arm compared with the lenalidomide and dexamethasone arm (time not reached vs. 31.9 months; hazard ratio = 0.56; 95% CI, 0.43 to 0.73, p less than 0.001) in patients (median age, 73 years; range, 45 to 90 years) with newly diagnosed multiple myeloma who were ineligible for a stem-cell transplant. In patients with a reduced creatinine clearance of 30 to 50 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.

    For the treatment of newly diagnosed multiple myeloma in patients who are eligible for autologous stem-cell transplant, in combination with bortezomib, thalidomide, and dexamethasone (DVTd).
    Intravenous dosage
    Adults 65 years and younger

    16 mg/kg (actual body weight) IV weekly on weeks 1 to 8 (cycles 1 and 2; total of 8 doses), then 16 mg/kg IV every other week starting week 9 through week 16 (cycles 3 and 4; total of 4 doses). Therapy is then interrupted for high dose chemotherapy and autologous stem cell transplant (ASCT), followed by daratumumab 16 mg/kg IV consolidation every 2 weeks on weeks 1 to 8 (cycles 5 and 6; total of 4 doses). In the clinical trial, the consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. Daratumumab is administered in combination with bortezomib (1.3 mg/m2 IV or SC on days 1, 4, 8, and 11 every 4 weeks during induction [cycles 1 to 4] and consolidation [cycles 5 and 6]), thalidomide (100 mg PO once daily during bortezomib cycles), and dexamethasone (40 mg IV or PO on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1 and 2; 40 mg on days 1 and 2, then 20 mg on days 8, 9, 15, and 16 of cycles 3 and 4; and 20 mg on days 1, 2, 8, 9, 15, and 16 in cycles 5 and 6). The first dose of daratumumab on week 1 may be split over 2 consecutive days (i.e., 8 mg/kg IV on day 1 and 8 mg/kg IV on day 2). Hold daratumumab 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). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion; however, if dexamethasone is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. Treatment with DVT-d significantly improved the overall response rate at Day 100 post-transplant compared with those who received bortezomib, thalidomide, and dexamethasone (VTd) in a multicenter, randomized, phase 3 trial (CASSIOPEIA) (92.6% vs. 89.9%); the stringent complete response rate was also significantly improved in the DVTd arm (28.9% vs. 20.3%). After a median follow-up of 18.8 months, the median progression-free survival had not been reached in either arm; however, the reduction in the risk of progression or death was significantly reduced by 53% in the DVTd arm compared with VTd.[64528] [60311]

    For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with carfilzomib and dexamethasone.
    Intravenous dosage
    Adults

    8 mg/kg (actual body weight) IV on days 1 and 2, 16 mg/kg IV weekly on weeks 2 to 8 (7 doses), 16 mg/kg IV every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg IV every 4 weeks starting on week 25. Administer in combination with IV carfilzomib (20 mg/m2 and 56 mg/m2 twice weekly regimen or 20 mg/m2 and 70 mg/m2 once weekly regimen) and PO/IV dexamethasone until disease progression or unacceptable toxicity. 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). Give the treatment dexamethasone dose as the daratumumab premedication steroid when these drugs are scheduled on the same day. Consider giving a low-dose oral corticosteroid (equivalent to methylprednisolone 20 mg or less) on the day after every infusion. Short and long-acting bronchodilators and/or inhaled corticosteroids may be administered in patients with a history of chronic obstructive pulmonary disease; consider discontinuing these medications if the patient has no major infusion reaction with the first 4 infusions. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy. At a median follow-up time of about 17 months, the median progression-free survival was significantly improved in patients with relapsed or refractory multiple myeloma who received carfilzomib 20 mg/m2 and 56 mg/m2 twice weekly regimen, daratumumab, and dexamethasone compared with carfilzomib and dexamethasone alone (median time not reached vs. 15.8 months; hazard ratio = 0.63; 95% CI, 0.46 to 0.85; p = 0.0027) in a multicenter, randomized (2:1), open-label, phase 3 trial (n = 466; the CANDOR trial). At a median follow-up time of 16.6 months (range, 0.5 to 27.4 months), the overall response rate was 84% (complete response rate, 33%) in patients with relapsed or refractory multiple myeloma who received carfilzomib 20 mg/m2 and 70 mg/m2 once weekly regimen, daratuzumab, and dexamethasone in a multicenter, multi-arm, phase 1b trial (n = 85; EQUULEUS trial).

    For the treatment of newly diagnosed multiple myeloma in patients who are eligible for autologous stem-cell transplant, in combination with bortezomib, lenalidomide, and dexamethasone†.
    Intravenous dosage
    Adults 70 years and younger

    16 mg/kg IV on days 1, 8, and 15 repeated every 21 days on cycles 1, 2, 3, and 4 followed by high-dose chemotherapy and an autologous stem-cell transplant and then 2 additional cycles of daratumumab 16 mg/kg IV day 1 repeated every 21 days (cycles 5 and 6) plus lenalidomide, bortezomib, and dexamethasone (VRd regimen) was evaluated in a randomized, phase 2 trial (the GRIFFIN trial; n = 207). VRd treatment consisted of lenalidomide 25 mg orally daily on days 1 to 14; bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16 repeated every 21 days for 6 cycles. Maintenance therapy was given for up to 2 years and consisted of daratumumab 16 mg/kg IV on day 1 repeated every 4 or 8 weeks and lenalidomide 10 mg PO daily on days 1 to 21 (increased to 15 mg after 3 cycles if tolerated) repeated every 28 days. Patients received premedication with acetaminophen (650 mg to 1,000 mg PO), an antihistamine (H1-receptor agonist), and montelukast 10 mg orally prior to the first daratumumab infusion and then as necessary prior to subsequent infusions. Patients with mild asthma, mild chronic obstructive pulmonary disease, or a higher risk of respiratory complications (e.g., patients with a FEV1 of less than 80%) could receive post-infusion medications (e.g., antihistamines, short-acting beta-2 adrenergic receptor agonist, inhaled corticosteroids, long-acting bronchodilators, and/or long-acting beta-2 adrenergic receptor agonists). 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. Begin antiviral prophylaxis within 1 week of starting daratumumab and continue for 3 months after therapy.

    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.[60311]

    Intravenous Administration

    Daratumumab is available as a 20 mg/mL solution in 100 mg/5 mL and 400 mg/mL vials; each of these vial strengths has 2 National Drug Codes (NDCs).
    Dilute prior to administration; vials of the same strength with different NDCs may be admixed in the same infusion bag.
    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 (week 1), dilute the calculated amount in 0.9% sodium chloride injection to a total infusion bag volume of 1,000 mL for a single-dose infusion (16 mg/kg) or 500 mL for split-dose infusions (8 mg/kg). For subsequent infusions, dilute the calculated amount in 0.9% sodium chloride injection to a total infusion bag volume of 500 mL. Following a single-dose infusion (16 mg/kg), reduce the total infusion bag volume to 500 mL only if there were no grade 1 or higher infusion reactions during the previous week.
    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: Week 1 infusion(s): start at 50 mL/hour, increase by 50 mL/hour every hour to a maximum rate of 200 mL/hour.Week 2 infusion (following a single 16 mg/kg dose infusion only): 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 previous week.
    Do not save or store unused daratumumab for reuse.[60311]

    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

    Infusion-related reactions (IRRs) have been reported with daratumumab therapy. IRRs may be life-threatening or fatal and severe reactions may include anaphylaxis, bronchospasm, hypoxia, dyspnea, hypertension, headache, tachycardia, laryngeal edema, and pulmonary edema. Most reactions occur during the first infusion. Use is contraindicated in patients who have a history of a severe hypersensitivity reaction with daratumumab or any other component of the product. Monitor patients frequently during the daratumumab infusion for signs and symptoms of IRRs. Hold therapy and initiate appropriate medical support if an IRRs 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 IRRs occur during or within 4 hours from the end of the infusion. Symptoms of IRRs 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. 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. 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. If daratumumab test interference is suspected, consider using a FDA-approved IFE assay to distinguish daratumumab from any remaining endogenous M-protein in patient serum.

    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.

    Hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation may occur during or following treatment with daratumumab; fatal cases were reported. Monitor patients with a history of HBV infection for signs and symptoms of HBV reactivation prior to, during, and after daratumumab therapy.

    Hereditary fructose intolerance

    Daratumumab contains sorbitol; therefore, administer daratumumab cautiously in patients with hereditary fructose intolerance.

    Geriatric

    In clinical studies evaluating daratumumab therapy (n = 1,213), serious adverse events (i.e., pneumonia, sepsis) occurred more often in geriatric patients aged 65 years or older who received daratumumab compared with younger patients. In one randomized clinical trial (n = 308), fatal adverse reactions were reported in 14% of patients aged 65 years or older who received carfilzomib, daratumumab, and dexamethasone compared with 6% of patients aged less than 65 years.

    Pregnancy, vaccination

    Daratuzumab may cause fetal harm if administered during pregnancy based on its mechanism of action and data from target antigen CD38 knockout animal models. Immunoglobulin G1 monoclonal antibodies are transferred across the placenta; therefore, daratumumab may cause fetal CD38-positive, immune-cell depletion and decreased bone density. Birth defects or fetal death may occur when daratumumab is used in combination with thalidomide or a thalidomide analog (e.g., lenalidomide and pomalidomide). Prior to administering a live vaccination, evaluate hematologic parameters in neonates and infants whose mother received daratumumab during pregnancy.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during daratumumab treatment. Pregnancy testing should be performed when daratumumab is used in combination with thalidomide or a thalidomide analog (e.g., lenalidomide and pomalidomide) per the labeling requirements of those agents. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 3 months after the last daratumumab dose. Women who become pregnant while receiving daratumumab should be apprised of the potential hazard to the fetus.

    Breast-feeding

    It is not known whether daratumumab is secreted in human milk or if it affects the breastfed child 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. Advise women who are receiving daratumumab in combination with thalidomide or a thalidomide analog (e.g., lenalidomide and pomalidomide) to avoid breast-feeding due to the potential for serious adverse reactions in the breastfed child with this combination therapy.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 15.0-82.0
    lymphopenia / Delayed / 25.0-71.0
    thrombocytopenia / Delayed / 9.0-47.0
    infection / Delayed / 0-37.0
    leukopenia / Delayed / 0-35.0
    anemia / Delayed / 4.0-30.0
    hypertension / Early / 4.0-20.0
    fatigue / Early / 2.0-18.0
    pulmonary edema / Early / 0-15.0
    atrial fibrillation / Early / 0-15.0
    pancreatitis / Delayed / 0-15.0
    leukoencephalopathy / Delayed / 0-15.0
    infusion-related reactions / Rapid / 2.0-12.0
    diarrhea / Early / 1.0-7.0
    dyspnea / Early / 0-7.0
    hyperglycemia / Delayed / 0-7.0
    back pain / Delayed / 0-6.0
    peripheral neuropathy / Delayed / 0-5.0
    insomnia / Early / 0-4.7
    skin cancer / Delayed / 0-4.7
    nausea / Early / 0-4.0
    bone pain / Delayed / 0-4.0
    edema / Delayed / 1.0-4.0
    peripheral edema / Delayed / 1.0-4.0
    influenza / Delayed / 0-3.5
    hypercalcemia / Delayed / 0-3.5
    fever / Early / 1.0-3.0
    tremor / Early / 0-3.0
    hypokalemia / Delayed / 0-3.0
    vomiting / Early / 0-2.0
    musculoskeletal pain / Early / 0-2.0
    arthralgia / Delayed / 0-2.0
    dizziness / Early / 0-2.0
    headache / Early / 0-1.2
    constipation / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    muscle cramps / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    hypocalcemia / Delayed / 0-1.0
    hepatitis B exacerbation / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 0-15.0
    dehydration / Delayed / 0-15.0
    antibody formation / Delayed / 0-0.1
    wheezing / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    hypoxia / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    asthenia / Delayed / 0-28.0
    chills / Rapid / 0-20.0
    nasal congestion / Early / 0-17.0
    paresthesias / Delayed / 0-16.0
    pruritus / Rapid / 0-15.0
    rash / Early / 0-15.0
    anxiety / Delayed / 0-13.0
    syncope / Early / Incidence not known
    throat irritation / Early / Incidence not known
    myalgia / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    ocular pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known whether daratumumab is secreted in human milk or if it affects the breastfed child 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. Advise women who are receiving daratumumab in combination with thalidomide or a thalidomide analog (e.g., lenalidomide and pomalidomide) to avoid breast-feeding due to the potential for serious adverse reactions in the breastfed child with this combination therapy.

    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. The mean estimated terminal half-life value associated with linear clearance was 18 +/- 9 days following daratumumab monotherapy; the mean terminal half-life was similar following daratumumab as combination therapy. Daratumumab clearance decreased with increasing dose and repeated dosing. The mean linear clearance was 171.4 +/- 95.3 mL/day for monotherapy.[60311]

    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 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. A week 1 day 1 split-dose infusion of 8 mg/kg IV resulted in a different pharmacokinetic profile in the first day compared with a single-dose infusion of 16 mg/kg; however, similar Cmax and Cmin concentrations occurred following the administration of the second 8 mg/kg split dose on week 1 day 2.[60311]