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Darzalex

Generic Name: Daratumumab
Class: Antineoplastic Agents
Chemical Name: Disulfide with human monoclonal 3003-005 κ-chain, anti-(human CD38 (antigen)) (human monoclonal 3003-005 heavy chain), immunoglobulin G1, dimer
Molecular Formula: C6466H9996N1724O2010S42
CAS Number: 945721-28-8

Introduction

Antineoplastic agent; a recombinant humanized anti-CD38 monoclonal antibody.1 2 5 12

Uses for Darzalex

Multiple Myeloma

Treatment of multiple myeloma in patients who have received ≥3 prior therapies, including proteasome inhibitor and immunomodulatory agent, or in those with disease refractory to proteasome inhibitor and immunomodulatory agent1 (designated an orphan drug by FDA for use in multiple myeloma).3

Accelerated approval based on overall response rate.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Darzalex Dosage and Administration

General

  • Administer in setting where emergency equipment and appropriate medical support for treating infusion-related reactions is available.1

Premedication for Infusion-related Reactions

  • Administer IV corticosteroid (e.g., methylprednisolone 100 mg or equivalent dose of other intermediate- or long-acting corticosteroid) approximately 1 hour prior to each daratumumab infusion.1

  • Also administer oral antipyretic (e.g., acetaminophen 650 mg or 1 g) and oral or IV antihistamine (e.g., diphenhydramine hydrochloride 25–50 mg or equivalent) approximately 1 hour prior to each daratumumab infusion.1

  • Reduction of corticosteroid dosage (e.g., methylprednisolone from 100 mg to 60 mg or equivalent) may be considered following second infusion.1

Post-infusion Medication for Infusion-related Reactions

  • Administer oral corticosteroid (e.g., methylprednisolone 20 mg or equivalent) the first and second days following each daratumumab infusion.1

  • For patients with history of COPD, consider therapy with short- and long-acting bronchodilators and inhaled corticosteroids; discontinue inhaled post-infusion medications if major infusion-related reactions do not occur during or following the first 4 infusions.1

Antiviral Prophylaxis

  • Risk of herpes zoster.1 To prevent reactivation of latent virus, consider antiviral prophylaxis (e.g., acyclovir) within 1 week of initiating daratumumab therapy and continue for 3 months after the last dose.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Administer diluted daratumumab solution using polyurethane, polybutadiene, PVC, polypropylene, or polyethylene administration set fitted with flow regulator and a low-protein-binding 0.2- or 0.22-μm inline polyethersulfone filter.1

Do not administer any other drug simultaneously in the same IV line.1

Discard any unused portion of injection concentrate or diluted solution; vials of daratumumab injection concentrate contain no preservative and are intended for single use only.1

Dilution

Must be diluted prior to IV infusion.1

To prepare first dose: Remove volume of diluent equal to total required volume of injection concentrate from a 1-L bag of 0.9% sodium chloride injection.1 Slowly add total required volume of injection concentrate to diluent in the infusion bag.1 Mix the diluted solution by gentle inversion; do not shake.1

To prepare subsequent doses: Remove volume of diluent equal to total required volume of injection concentrate from a 500-mL bag of 0.9% sodium chloride injection.1 Slowly add total required volume of injection concentrate to diluent in the infusion bag.1 Mix the diluted solution by gentle inversion; do not shake.1

Complete infusion within 15 hours of dilution.1

Rate of Administration

Dose 1: Infuse solution at initial rate of 50 mL/hour; if infusion-related events do not occur, infusion rate may be increased in increments of 50 mL/hour every hour to maximum rate of 200 mL/hour.1

Dose 2: Infuse solution at initial rate of 50 mL/hour; if grade 1 or greater infusion-related events did not occur during the first 3 hours of the first infusion, infusion rate may be increased in increments of 50 mL/hour every hour to maximum rate of 200 mL/hour.1

Subsequent doses: Infuse solution at initial rate of 100 mL/hour; if grade 1 or greater infusion-related events did not occur during a final infusion rate of ≥100 mL/hour during the first 2 infusions, infusion rate may be increased in increments of 50 mL/hour every hour to maximum rate of 200 mL/hour.1

Interrupt infusion if an infusion-related reaction of any severity occurs.1 If reaction is grade 4 in severity, do not resume the infusion.1

For the first and second occurrence of grade 3 infusion-related reactions, resume infusion at a rate that is no more than 50% of the previous infusion rate once reaction improves to grade 2 or less; increase the infusion rate as tolerated in increments and intervals appropriate for the treatment dose.1 For the third occurrence of grade 3 infusion-related reactions, permanently discontinue therapy.1

For grade 1 and 2 infusion-related reactions, resume infusion at a rate that is no more than 50% of the previous rate once reaction resolves; increase infusion rate as tolerated in increments and intervals appropriate for the treatment dose.1

Dosage

Adults

Multiple Myeloma
IV

16 mg/kg once a week for 8 weeks (weeks 1–8), followed by every 2 weeks for 16 weeks (weeks 9–24), then every 4 weeks thereafter (from week 25 onward).1

Continue therapy until disease progression or unacceptable toxicity occurs.1

If a dose is missed or delayed, administer the dose as soon as possible.1 Adjust administration schedule to maintain appropriate dosage interval.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration 1–1.5 times the ULN or AST concentration above ULN): No dosage adjustment required.1

Moderate or severe hepatic impairment: Not studied.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No specific dosage recommendations.1

Cautions for Darzalex

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Infusion-related Effects

Infusion-related reactions (sometimes serious) reported.1 Generally more frequent during the first infusion than during subsequent infusions of daratumumab.1 Such reactions generally occurred during or within 4 hours of infusion; also occurred up to 48 hours after infusion without post-infusion medications.1

Premedication recommended with antihistamine, antipyretic, and corticosteroid prior to daratumumab infusions.1 (See Premedication for Infusion-related Reactions under Dosage and Administration.)

Post-infusion medication recommended with oral corticosteroid.1 Patients with history of COPD may require additional medications (e.g., inhaled bronchodilator or corticosteroid) following administration of daratumumab.1 (See Post-infusion Medication for Infusion-related Reactions under Dosage and Administration.)

Monitor patients frequently during drug infusions for manifestations of infusion-related reactions.1

Reduce infusion rate or temporarily interrupt or permanently discontinue the infusion depending on severity of reaction; institute medical management as necessary.1 (See Rate of Administration under Dosage and Administration.)

If life-threatening infusion-related reactions occur, permanently discontinue therapy.1

Interference with Serologic Testing

Positive indirect antiglobulin (Coombs') test results reported following administration of daratumumab; pan-agglutination may persist for up to 6 months following last infusion.1 4 10 Detection of antibodies to minor antigens may be masked during therapy; determination of ABO and Rh blood type not affected.1

Perform blood typing and screening prior to initiation of therapy.1 If blood transfusion is required, notify blood centers of serologic test interference and treatment with daratumumab.1 If blood typing and screening occur after initiation of therapy, use genotyping or dithiothreitol (DTT) to treat reagent RBCs to disrupt daratumumab binding.1 8 9

Administer K-negative units to patients after ruling out or identifying alloantibodies using DTT-treated RBCs.1 9 If immediate transfusion is required, can administer non-cross-matched ABO/RhD blood type-compatible RBCs according to local blood center practices.1

Interference with Serum Protein Electrophoresis and Immunofixation Electrophoresis Assays

Daratumumab may interfere with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) assays used for clinical monitoring of endogenous monoclonal immunoglobulins such as myeloma (M) protein.1 6 7 11 Daratumumab-specific IFE reflex assay (DIRA) may be used to separate the migration of daratumumab and endogenous M-protein.7 11

Daratumumab may cause false-positive IFE assay results and misinterpretation of tumor response.1 Consider other methods to evaluate level of tumor response in patients persistently achieving very good partial responses.1

Immunogenicity

There is potential for immunogenicity with daratumumab.1 Development of binding antibodies to daratumumab not detected to date.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women, but daratumumab may cause fetal harm.1 Because human IgG crosses the placenta, adverse effects may occur in infants born to pregnant women treated with daratumumab.1

Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Advice to Patients.)

Possible myeloid- or lymphoid-cell depletion in infants born to pregnant women treated with daratumumab; avoid live vaccines in these infants until completion of hematologic evaluation.1

Lactation

Not known whether daratumumab is distributed into milk; however, human IgG is distributed into milk.1

Effects of drug on nursing infants or on human milk production unknown.1

Consider benefits of breast-feeding and importance of drug to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety or efficacy relative to younger patients.1

Hepatic Impairment

Systemic exposure not altered by mild hepatic impairment; dosage adjustment not necessary in such patients.1 (See Special Populations under Pharmacokinetics.)

Pharmacokinetics not studied in patients with moderate or severe hepatic impairment.1

Renal Impairment

Systemic exposure not altered by mild, moderate, or severe renal impairment, or end-stage renal disease (ESRD); dosage adjustment not necessary in such patients.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Infusion-related reactions,1 2 fatigue,1 nausea,1 back pain,1 cough,1 pyrexia,1 upper respiratory tract infection,1 arthralgia,1 nasal congestion,1 diarrhea,1 constipation,1 dyspnea,1 loss of appetite,1 nasopharyngitis,1 pain in extremity,1 vomiting,1 headache,1 musculoskeletal chest pain,1 pneumonia,1 chills,1 hypertension.1

Laboratory abnormalities: Lymphopenia,1 neutropenia,1 2 thrombocytopenia,1 2 anemia.1 2

Interactions for Darzalex

No formal drug interaction studies to date.1

Darzalex Pharmacokinetics

Absorption

Bioavailability

AUC increases more than dose proportionally over the dosage range of 1–24 mg/kg.1

Steady-state concentrations achieved approximately 5 months following administration every 4 weeks.1

Special Populations

Mild hepatic impairment: Systemic exposure similar to that in patients with normal hepatic function.1

Moderate or severe hepatic impairment: Data not available.1

Mild, moderate, or severe renal impairment or ESRD: Systemic exposure similar to that in patients with normal renal function.1

Age (31–84 years) and gender do not substantially affect daratumumab pharmacokinetics.1

Distribution

Extent

Human IgG crosses the placenta and distributes into milk.1 Not known whether daratumumab is distributed into milk.1 (See Lactation under Cautions.)

Elimination

Half-life

Estimated terminal half-life: 18 days.1

Stability

Storage

Parenteral

Injection Concentrate

2–8°C.1 Do not freeze or shake; protect from light.1

Store diluted solution at 2–8°C; discard after 24 hours.1 Do not freeze; protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Actions

  • IgG1 kappa immunoglobulin produced in mammalian (Chinese hamster ovary) cells.1

  • Binds specifically to antigen CD38, a glycoprotein expressed on surface of normal and malignant hematopoietic stem cells, that triggers host immune responses resulting in cell lysis.1 12 13

  • Mechanism of cell lysis is thought to involve antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).1 2 12 13

Advice to Patients

  • Importance of reading the manufacturer's patient information before beginning treatment and each time the drug is administered.1

  • Risk of infusion-related reactions.1 Importance of immediately reporting signs or symptoms of such reactions (e.g., nasal itching, congestion, or rhinitis; chills, nausea, throat irritation, cough, headache, breathing difficulty, shortness of breath).1

  • Importance of advising patients about the possibility for serologic test interference in the event of a planned blood transfusion and of the need to inform clinicians (e.g., blood center personnel) that they are receiving daratumumab.1

  • Importance of advising patients that daratumumab may affect results of some tests used to determine complete response to the drug and that additional tests may be needed to evaluate the response.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use an effective method of contraception while receiving the drug and for at least 3 months after the last dose.1 If pregnancy occurs, advise women of potential fetal risk.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising women who received daratumumab during pregnancy that infants exposed to the drug in utero should have hematologic evaluation performed before they receive live vaccines.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., respiratory problems, history of herpes zoster).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Daratumumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate, for injection, for IV infusion

20 mg/mL (100 and 400 mg)

Darzalex

Janssen Biotech

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: October 21, 2016
Last reviewed: October 21, 2016
Date modified: November 09, 2016

References

1. Janssen Biotech, Inc. Darzalex (daratumumab) injection for intravenous use prescribing information. Horsham, PA; 2015 Nov.

2. Lonial S, Weiss BM, Usmani SZ et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016; 387:1551-60. [PubMed 26778538]

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 Jun 3.

4. Janssen Biotech, Inc. Understanding Darzalex: Interference with blood compatibility testing. 2016 Jun. From Janssen Biotech for US Healthcare Professionals website.

5. Lokhorst HM, Plesner T, Laubach JP et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015; 373:1207-19. [PubMed 26308596]

6. McCudden C, Axel AE, Slaets D et al. Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference. Clin Chem Lab Med. 2016; 54:1095-104. [PubMed 27028734]

7. van de Donk NW, Otten HG, El Haddad O et al. Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA). Clin Chem Lab Med. 2016; 54:1105-9. [PubMed 26812873]

8. Chapuy CI, Nicholson RT, Aguad MD et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015; 55:1545-54. [PubMed 25764134]

9. van de Donk NW, Janmaat ML, Mutis T et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016; 270:95-112. [PubMed 26864107]

10. Oostendorp M, Lammerts van Bueren JJ, Doshi P et al. When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion. 2015; 55:1555-62. [PubMed 25988285]

11. van de Donk NW, Moreau P, Plesner T et al. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood. 2016; 127:681-95. [PubMed 26631114]

12. Phipps C, Chen Y, Gopalakrishnan S et al. Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol. 2015; 6:120-7. [PubMed 26137203]

13. de Weers M, Tai YT, van der Veer MS et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011; 186:1840-8. [PubMed 21187443]

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