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Daratumumab

Medically reviewed by Drugs.com. Last updated on May 12, 2020.

Pronunciation

(dar a TOOM ue mab)

Index Terms

  • JNJ-54767414

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Darzalex: 100 mg/5 mL (5 mL); 400 mg/20 mL (20 mL)

Brand Names: U.S.

  • Darzalex

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD38
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Daratumumab is an IgG1κ human monoclonal antibody directed against CD38. CD38 is a cell surface glycoprotein which is highly expressed on myeloma cells, yet is expressed at low levels on normal lymphoid and myeloid cells (Lokhorst 2015). By binding to CD38, daratumumab 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, antibody dependent cell mediated cytotoxicity, and antibody dependent cellular phagocytosis.

Distribution

Central: Monotherapy: 4.7 ± 1.3 L; Combination therapy: 4.4 ± 1.5 L

Excretion

Clearance: 171.4 ± 95.3 mL/day

Half-Life Elimination

18 ± 9 days

Special Populations Note

Body weight: Central volume of distribution and clearance increase with increasing body weight.

Use: Labeled Indications

Multiple myeloma (newly diagnosed):

Treatment of newly diagnosed multiple myeloma (in combination with bortezomib, thalidomide, and dexamethasone) in adults who are eligible for autologous stem cell transplant.

Treatment of newly diagnosed multiple myeloma (in combination with bortezomib, melphalan, and prednisone) in adults who are ineligible for autologous stem cell transplant.

Treatment of newly diagnosed multiple myeloma (in combination with lenalidomide and dexamethasone) in adults who are ineligible for autologous stem cell transplant.

Multiple myeloma (relapsed/refractory):

Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and lenalidomide) in adults who have received at least 1 prior therapy.

Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and bortezomib) in adults who have received at least 1 prior therapy.

Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and carfilzomib) in patients who have received 1 to 3 prior therapies.

Treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone and pomalidomide) in adults who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor.

Treatment of relapsed or refractory multiple myeloma (as monotherapy) in adults who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent.

Off Label Uses

Systemic light chain amyloidosis (relapsed)

Data from a small, multicenter, phase 2 study support the use of daratumumab (as a single agent) for the treatment of light chain amyloidosis (based on the primary endpoint of very good partial response [VGPR]) in previously treated patients who had either relapsed or not reached VGPR [Roussel 2020)]. Data from another small phase II study also support the use of single agent daratumumab in the treatment of relapsed light chain amyloidosis in patients who had received at least 1 prior treatment regimen [Sanchorawala 2020].

Contraindications

History of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any component of the formulation.

Dosing: Adult

Note: Premedicate 1 to 3 hours prior to each infusion with a corticosteroid, an oral antipyretic, and an oral or IV antihistamine (see Premedications below). Postinfusion, administer an oral corticosteroid to all patients to reduce the risk of delayed infusion reactions (see Postinfusion medications below). To prevent herpes zoster reactivation, initiate antiviral prophylaxis within 1 week after starting daratumumab and continue for 3 months following completion of daratumumab treatment. Per the manufacturer, daratumumab dosing should be based on actual body weight. Type and screen (blood type) prior to daratumumab initiation. Do not substitute daratumumab (IV) with daratumumab/hyaluronidase (for subcutaneous use); products have different dosing and are not interchangeable.

The initial daratumumab dose (16 mg/kg on week 1) may be divided over 2 consecutive days (by administering 8 mg/kg/day on days 1 and 2 of week 1 of therapy) to facilitate administration.

Multiple myeloma (newly diagnosed): IV: Note: Refer to specific protocol or to dexamethasone, lenalidomide, thalidomide, bortezomib, melphalan, and/or prednisone monographs for dosing when used in combination with daratumumab.

In combination with bortezomib, melphalan, and prednisone (D-VMP regimen; in patients ineligible for autologous stem cell transplant) (Mateos 2018; Mateos 2020):

Weeks 1 to 6: 16 mg/kg once weekly for 6 doses.

Weeks 7 to 54: 16 mg/kg once every 3 weeks for 16 doses.

Weeks 55 and beyond: 16 mg/kg once every 4 weeks until disease progression.

In combination with lenalidomide and low-dose dexamethasone (DRd regimen; in patients ineligible for autologous stem cell transplant) (Facon 2019):

Weeks 1 to 8: 16 mg/kg once weekly for 8 doses.

Weeks 9 to 24: 16 mg/kg once every 2 weeks for 8 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks until disease progression.

In combination with thalidomide, bortezomib, and dexamethasone (DVTd regimen; in patients eligible for autologous stem cell transplant) (Moreau 2019):

Induction:

Weeks 1 to 8: 16 mg/kg once weekly for 8 doses.

Weeks 9 to 16: 16 mg/kg once every 2 weeks for 4 doses.

Consolidation (following autologous stem cell transplant):

Weeks 1 to 8: 16 mg/kg once every 2 weeks for 4 doses.

Multiple myeloma (relapsed/refractory): IV: Note: Refer to specific protocol or to dexamethasone, lenalidomide, bortezomib, carfilzomib, and/or pomalidomide monographs for dosing when used in combination with daratumumab.

Monotherapy:

Weeks 1 to 8: 16 mg/kg once weekly for 8 doses.

Weeks 9 to 24: 16 mg/kg once every 2 weeks for 8 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks until disease progression.

In combination with lenalidomide and low-dose dexamethasone (DRd regimen; Dimopoulos 2016):

Weeks 1 to 8: 16 mg/kg once weekly for 8 doses.

Weeks 9 to 24: 16 mg/kg once every 2 weeks for 8 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks until disease progression.

In combination with pomalidomide and low-dose dexamethasone (DPd regimen; Chari 2017):

Weeks 1 to 8: 16 mg/kg once weekly for 8 doses.

Weeks 9 to 24: 16 mg/kg once every 2 weeks for 8 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks until disease progression.

In combination with bortezomib and dexamethasone (DVd regimen; Palumbo 2016):

Weeks 1 to 9: 16 mg/kg once weekly for 9 doses.

Weeks 10 to 24: 16 mg/kg once every 3 weeks for 5 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks until disease progression.

In combination with carfilzomib and dexamethasone (DKd regimen; Chari 2019; Dimopoulos 2020):

Week 1: 8 mg/kg on days 1 and 2.

Weeks 2 to 8: 16 mg/kg once weekly for 7 doses.

Weeks 9 to 24: 16 mg/kg once every 2 weeks for 8 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks until disease progression.

Missed dose: If a dose is missed, administer as soon as possible and adjust the schedule accordingly (maintain the treatment interval).

Premedications: Administer 1 to 3 hours prior to each daratumumab infusion. If dexamethasone is the background regimen-specific corticosteroid, the dexamethasone treatment dose will serve as the corticosteroid premedication on daratumumab infusion days. Do not administer additional background regimen-specific corticosteroids (eg, prednisone) on daratumumab infusion days when patients receive dexamethasone (or equivalent) as a premedication.

Corticosteroid:

Monotherapy: Methylprednisolone 100 mg IV (or equivalent intermediate- or long-acting corticosteroid); following the second infusion, consider reducing the dose (eg, methylprednisolone 60 mg [IV or oral] or equivalent).

Combination therapy: IV or Oral: Dexamethasone 20 mg (or equivalent) prior to each daratumumab infusion

plus

Antipyretic: Oral: Acetaminophen 650 to 1,000 mg plus

Antihistamine: IV or Oral: Diphenhydramine 25 to 50 mg or equivalent.

The following premedication regimen has also been reported (Hofmeister 2016):

First infusion: Acetaminophen 325 mg orally, diphenhydramine 25 mg orally or IV, dexamethasone 20 mg IV, montelukast 10 mg orally, and famotidine 20 mg IV.

Subsequent infusions: Acetaminophen 325 mg orally, diphenhydramine 25 mg IV, and dexamethasone 20 mg IV.

Postinfusion medication:

Monotherapy: Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after each daratumumab administration.

Combination therapy: Consider administering oral methylprednisolone at ≤20 mg (or equivalent intermediate- or long-acting corticosteroid) beginning the day after each daratumumab infusion. If dexamethasone or prednisone is administered the day after the daratumumab infusion as part of background combination chemotherapy regimen, additional postinfusion corticosteroid therapy may not be necessary.

Patients with a history of chronic obstructive pulmonary disease: Also consider short- and long-acting bronchodilators and inhaled corticosteroids postinfusion. If no major infusion reactions occur during the first 4 daratumumab infusions, consider discontinuing these additional inhaled postinfusion medications.

Systemic light chain amyloidosis, relapsed (off-label use): IV:

Monotherapy (Roussel 2020; Sanchorawala 2020; refer to protocols for premedication, infusion, and additional details):

Weeks 1 to 8: 16 mg/kg once weekly for 8 doses.

Weeks 9 to 24: 16 mg/kg once every 2 weeks for 8 doses.

Weeks 25 and beyond: 16 mg/kg once every 4 weeks thereafter until disease progression or unacceptable toxicity, for up to 24 months.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Note: Refer to specific protocol or to dexamethasone, prednisone, lenalidomide, thalidomide, bortezomib, carfilzomib, melphalan, or pomalidomide monographs for dosing adjustment for toxicity when used in combination with daratumumab.

Hematologic toxicity: No dose reductions of daratumumab are recommended; consider withholding daratumumab infusion to allow for neutrophil and/or platelet recovery.

Infusion reactions: Immediately interrupt daratumumab infusion for reaction of any severity. Manage symptoms as clinically appropriate.

Grade 1 or 2 (mild to moderate) infusion reaction: Once symptoms resolve, resume the daratumumab infusion at no more than 50% of the rate at which the reaction occurred. If no further reactions are observed, may escalate the infusion rate as appropriate up to the maximum rate of 200 mL/hour (see "Administration").

Grade 3 (severe) infusion reaction: Once symptoms resolve, consider resuming the daratumumab infusion at no more than 50% of the rate at which the reaction occurred. If no further reactions are observed, may escalate the infusion rate as appropriate (see "Administration"). If a grade 3 reaction recurs, repeat the steps above. Permanently discontinue daratumumab if a grade 3 infusion reaction occurs for the third time.

Grade 4 (anaphylactic reaction or life-threatening) infusion reaction: Permanently discontinue daratumumab.

Reconstitution

Daratumumab (for IV administration) and daratumumab/hyaluronidase (for subcutaneous administration) are not interchangeable; check vial labels to prevent medication errors.

Determine the appropriate dose and volume of daratumumab required (based on patient's actual body weight); daratumumab should be colorless to pale yellow (do not use if opaque particles, discoloration, or other foreign particles are observed). Remove the volume of 0.9% sodium chloride injection from the infusion bag that is equal to the required volume of the daratumumab dose. Add the appropriate daratumumab volume to a 500 mL or 1,000 mL 0.9% sodium chloride bag; dilution volume depends on dose (single dose vs split dose, or if initial vs subsequent dose). Gently invert to mix (do not shake). Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE). If the diluted solution is refrigerated prior to use, allow to come to room temperature before administration. After dilution, may develop very small translucent to white proteinaceous particles; do not use if discolored or if visibly opaque or foreign particles are observed.

Administration

Note: Check label to ensure appropriate product is administered (daratumumab [IV] and daratumumab/hyaluronidase [SubQ] are different products and are not interchangeable).

IV: For IV infusion only. Do not administer IV push or as a bolus. Premedicate with a corticosteroid, acetaminophen, and an IV or oral antihistamine (see "Dosing") 1 to 3 hours prior to administration. Infuse in an environment equipped to monitor for and manage infusion reactions. Administer with an infusion set fitted with a flow regulator and with an inline, sterile, nonpyrogenic, low protein-binding polyethersulfone filter (0.22 or 0.2 micrometer). Polyurethane, polybutadiene, polyvinylchloride, polypropylene, or polyethylene administration sets are required. Do not mix with or infuse with other medications.

The manufacturer recommends not exceeding first, second, and subsequent infusion rates listed below. Begin infusion immediately after infusion bag reaches room temperature (if refrigerated). Infusion should be completed within 15 hours. Interrupt infusion for any severity of infusion reaction; if the reaction resolves, may resume infusion (see "Dosage Adjustment for Toxicity"). If infusion cannot be completed, do not save unused portion for reuse. Postinfusion, administer an oral corticosteroid to all patients to reduce the risk of delayed infusion reactions (see "Dosing"). In patients with a history of obstructive pulmonary disorder, consider short- and long-acting bronchodilators and inhaled corticosteroids postinfusion.

Infusion rate:

Week 1 infusion (500 mL [split-dose infusion; 8 mg/kg on days 1 and 2] or 1,000 mL volume [single-dose infusion; 16 mg/kg on day 1]): Infuse at 50 mL/hour for the first hour. If no infusion reactions occur, may increase the rate by 50 mL/hour every hour (maximum rate: 200 mL/hour).

Week 2 infusion (500 mL volume; 16 mg/kg): Use a dilution volume of 500 mL only if there were no infusion reactions during the previous week's infusion. Otherwise, continue to use a dilution volume of 1,000 mL. Infuse at 50 mL/hour for the first hour. If no infusion reactions occur, may increase the rate by 50 mL/hour every hour (maximum rate: 200 mL/hour).

Subsequent infusions (500 mL volume; 16 mg/kg): Use a modified initial rate for subsequent infusions (week 3 onwards) only if there were no infusion reactions during the previous infusion. Otherwise, continue to use instructions for the week 2 infusion. Infuse at 100 mL/hour for the first hour. If no infusion reactions occur, may increase the rate by 50 mL/hour every hour (maximum rate: 200 mL/hour).

Accelerated infusion rate (off-label) (Barr 2018): An accelerated infusion rate was studied (small, single-center study) in patients who have received ≥2 daratumumab doses at the standard infusion rate. Twenty percent of the dose was infused over 30 minutes (200 mL/hour) and the remaining 80% of the dose was then infused over 60 minutes (450 mL/hour), delivering the dose over a total of ~90 minutes. Standard existing premedications were continued (montelukast and famotidine were included in the premedication regimen), but may be tapered over subsequent infusions if tolerated (refer to protocol for details). Vital signs were monitored prior to infusion, every 15 minutes for the first hour, and then at the end of infusion; patients were observed for signs/symptoms of infusion reaction for 30 minutes after the initial accelerated infusion was completed. Prior to implementing the accelerated infusion rate, patients should demonstrate tolerability to a 500 mL infusion.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Do not freeze or shake; protect from light. Solutions diluted for infusion should be administered immediately at room temperature 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, solutions diluted for infusion may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) and protected from light; do not freeze. Discard any unused portion of the solution.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Test Interactions

Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. As the Kell blood group system is also sensitive to DTT, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices.

Daratumumab may be detected on both serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring multiple myeloma monoclonal immunoglobulins (M-proteins); false positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein, and may affect initial assessment of complete response criteria. In patients with persistent very good partial response where daratumumab interference is suspected, consider using a daratumumab-specific IFE assay to distinguish daratumumab from any residual endogenous M protein to evaluate the depth of treatment response.

Adverse Reactions

>10%:

Gastrointestinal: Constipation (15%), decreased appetite (15%), diarrhea (16%), nausea (27%), vomiting (14%)

Hematologic & oncologic: Anemia (45%; grade 3: 19%), lymphocytopenia (72%; grade 3: 30%; grade 4: 10%), neutropenia (60%; grade 3: 17%; grade 4: 3%), thrombocytopenia (48%; grade 3: 10%; grade 4: 8%)

Nervous system: Fatigue (39%), headache (12%)

Neuromuscular & skeletal: Arthralgia (17%), back pain (23%), limb pain (15%), musculoskeletal chest pain (12%)

Respiratory: Cough (21%), dyspnea (15%), nasal congestion (17%), nasopharyngitis (15%), pneumonia (11%), upper respiratory tract infection (20%)

Miscellaneous: Fever (21%), infusion related reaction (48%)

1% to 10%:

Cardiovascular: Hypertension (10%)

Infection: Herpes zoster infection (3%)

Nervous system: Chills (10%)

Miscellaneous: Physical health deterioration (3%)

<1%:

Immunologic: Antibody development

Infection: Reactivation of HBV

Frequency not defined: Hematologic & oncologic: Positive indirect Coombs test

Postmarketing:

Gastrointestinal: Pancreatitis

Hypersensitivity: Anaphylaxis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Daratumumab may increase neutropenia and thrombocytopenia when used in combination with other chemotherapy agents for the treatment of multiple myeloma. Lymphopenia, neutropenia, thrombocytopenia, and anemia (including grade 3 and 4 toxicity) were commonly reported as treatment emergent adverse reactions in clinical trials. Monitor for signs/symptoms of infection and bleeding. Monitor CBCs periodically; consider withholding daratumumab infusion to allow for neutrophil and/or platelet recovery.

• Hepatitis B virus reactivation: Hepatitis B virus (HBV) reactivation has been reported rarely; some cases have been fatal. Monitor for signs/symptoms of HBV reactivation. The American Society of Clinical Oncology hepatitis B screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

• Infusion reactions: Severe and/or serious infusion reactions may occur (including anaphylactic reactions, bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema, and pulmonary edema), mostly during the first infusion. Signs and symptoms include cough, throat irritation, and nasal congestion, as well as chills, vomiting, and nausea. Less commonly reported symptoms include wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. Most infusion reactions were grade 1 or 2. Reactions may also be seen during subsequent infusions; <1% of patients experienced grade 3 or 4 reaction at week 2 or subsequent infusions. The median duration of infusions (when the dose was not split over 2 days) was ~7, 4, and 3 hours for the week 1, week 2, and subsequent infusions, respectively. Infusion reactions generally occur either during the infusion or within 4 hours of completion; some reactions occurred up to 48 hours after the infusion. Across several clinical trials (including monotherapy and combination therapy), the median time to onset of infusion reactions was 1.5 hours (range: up to 73 hours); approximately one-third of infusions were modified due to infusion reactions. Following daratumumab therapy interruption for autologous stem cell transplant (ASCT), the incidence of infusion reaction was ~11% when reinitiating daratumumab (at the infusion rate/dilution used prior to transplant); symptoms/severity were consistent with week 2 incidences prior to ASCT. Premedication with antihistamines, antipyretics, and corticosteroids is required; interrupt infusion for any reaction and manage as appropriate. The addition of montelukast and famotidine to the premedication regimen has also been reported (Barr 2018; Hofmeister 2016). Reduce the infusion rate for grade 1, 2, or 3 reaction; permanently discontinue therapy for an anaphylactic reaction or life-threatening grade 4 infusion reaction and treat with appropriate emergency care. Administer in a facility with immediate access to resuscitative measures (eg, glucocorticoids, epinephrine, bronchodilators, oxygen). Administer oral corticosteroids to all patients after daratumumab infusion to reduce the risk of delayed infusion reactions. Also consider short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease; monitor closely.

Disease-related concerns:

• Interference with determination of myeloma response: Daratumumab (a human IgG kappa monoclonal antibody) may be detected on serum protein electrophoresis and immunofixation assays that monitor for endogenous M-protein. Interference with these assays by daratumumab may affect the determination of complete response and disease progression in some patients with IgG kappa myeloma protein.

Special populations:

• Elderly: Patients ≥65 years of age experienced a higher incidence of serious adverse reactions, including pneumonia and sepsis.

Other warnings/precautions:

• Do not interchange: Daratumumab (for IV administration) and daratumumab/hyaluronidase (for subcutaneous administration) have different dosing and are not interchangeable.

• Interference with serological testing: Through binding to CD38 on RBCs, daratumumab use may result in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated Coombs test positivity may persist for up to 6 months after the last infusion. In addition, daratumumab (bound to RBCs) masks antibody detection to minor antigens in the patient's serum; ABO and Rh blood type determination are not affected. Notify blood transfusion centers and blood banks that a patient has received daratumumab, and type and screen patients prior to initiation of daratumumab treatment.

Monitoring Parameters

CBCs periodically; type and screen (blood type) prior to initiating therapy. Conduct hepatitis B virus (HBV) screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning systemic anticancer therapy (ASCO [Hwang 2020]). Monitor for signs/symptoms of anaphylactic reaction and infusion reactions. Monitor for signs/symptoms of HBV reactivation, infection, and bleeding.

Accelerated infusion rate (off-label): Monitor vital signs prior to infusion, every 15 minutes for the first hour, and then at the end of infusion; patients were observed for signs/symptoms of infusion reaction for 30 minutes after the initial accelerated infusion was completed (Barr 2018).

Reproductive Considerations

Females of reproductive potential should use effective contraception during therapy and for 3 months after the last daratumumab dose.

Pregnancy Considerations

Daratumumab is a humanized monoclonal antibody (IgG1). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Based on the mechanism of action, daratumumab may cause myeloid or lymphoid cell depletion and decreased bone density in the fetus. The administration of live vaccines should be deferred for neonates and infants exposed to daratumumab in utero until a hematology evaluation can be completed. When using in combination regimens, also refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat multiple myeloma.

• This drug may be used with other drugs to treat your health condition. If you are also taking other drugs, talk with your doctor about the risks and side effects that may happen.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak

• Back pain

• Joint pain

• Pain in arms or legs

• Common cold symptoms

• Nose irritation

• Throat irritation

• Diarrhea

• Throwing up

• Upset stomach

• Muscle spasms

• Constipation

• Trouble sleeping

• Not hungry

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• Infusion reaction

• Shortness of breath

• Dizziness

• Passing out

• Severe headache

• Vision changes

• Low calcium like muscle cramps or spasms, numbness and tingling, or seizures

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit

• Stuffy nose

• Runny nose

• Chest pain

• Swelling of arms or legs

• Burning or numbness feeling

• Bleeding like throwing up blood or vomit that looks like coffee grounds; coughing up blood; blood in your urine; black, red, or tarry stools; bleeding from the gums; menstruation; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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