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Daratumumab

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) [contains mouse (murine) and/or hamster protein]

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

Half-Life Elimination

Monotherapy: 18 ± 9 days; Combination therapy: 23 ± 12 days

Special Populations Note

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

Use: Labeled Indications

Multiple myeloma, relapsed/refractory: Treatment of multiple myeloma (in combination with dexamethasone and either lenalidomide or bortezomib) in patients who have received at least one prior therapy; treatment of multiple myeloma (as monotherapy) in patients 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.

Contraindications

There are no contraindications listed in the US labeling.

Canadian labeling: Hypersensitivity to daratumumab or any component of the formulation

Dosing: Adult

Note: Premedicate approximately 1 hour prior to infusion with a corticosteroid, an oral antipyretic, and an oral or IV antihistamine (see Premedications below). Post-infusion, administer an oral corticosteroid to all patients to reduce the risk of delayed infusion reactions (see Post-infusion medications below). To prevent herpes zoster reactivation, initiate antiviral prophylaxis within 1 week after starting daratumumab and continue for 3 months following completion of treatment. Per the manufacturer, daratumumab dosing should be based on actual body weight.

Multiple myeloma, relapsed/refractory: Adults: IV: Note: Refer to specific protocol or to dexamethasone and lenalidomide or bortezomib 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 (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 bortezomib and dexamethasone (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

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 infusion

Corticosteroid:

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

Combination therapy: Dexamethasone 20 mg prior to each infusion; administer IV prior to the first infusion; oral administration may be considered prior to subsequent infusions plus

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

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

Post-infusion medication:

Monotherapy: Administer an oral intermediate- or long-acting corticosteroid (eg, methylprednisolone 20 mg or equivalent) on the first and second day after all infusions.

Combination therapy: Consider administering low-dose oral methylprednisolone (20 mg or less) or equivalent on the first day after the infusion. If dexamethasone is administered the day after the infusion as part of combination chemotherapy, additional post-infusion corticosteroid therapy may not be necessary.

In patients with a history of chronic obstructive pulmonary disease, also consider short- and long-acting bronchodilators and inhaled corticosteroids post-infusion. If no major infusion reactions occur during the first 4 infusions, these additional inhaled post-infusion medications may be discontinued.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 15 to 89 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, CrCl between 15 to 89 mL/minute did not have any meaningful effect on daratumumab pharmacokinetics.

Dosing: Hepatic Impairment

Mild (total bilirubin 1 to 1.5 times ULN and any ALT) or moderate (total bilirubin 1.5 to 3 times ULN and any ALT) impairment: There are no dosage adjustments provided in the manufacturer’s labeling, however, mild or moderate impairment did not have any meaningful effect on daratumumab pharmacokinetics.

Severe impairment (total bilirubin >3 times ULN and any ALT): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Note: Refer to specific protocol or to dexamethasone and lenalidomide or bortezomib monographs for dosing adjustment for toxicity when used in combination with daratumumab.

Hematologic toxicity: No dose reductions of daratumumab are recommended; delay of daratumumab infusion may be required to allow for neutrophil and/or platelet recovery. Supportive care with growth factors and/or platelet transfusions may be necessary.

Infusion reactions: Immediately interrupt 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 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 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 if a grade 3 infusion reaction occurs for the third time.

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

Reconstitution

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 1,000 mL (first infusion) or 500 mL (subsequent infusions) 0.9% sodium chloride bag; 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

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) approximately 60 minutes 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, non-pyrogenic, 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.

Do not exceed infusion rates 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. Post-infusion, 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 post-infusion.

Infusion rate:

First infusion (1,000 mL volume): 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).

Second infusion (500 mL volume): Use a dilution volume of 500 mL only if there were no grade 1 or greater infusion reactions during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1,000 mL and instructions for the first infusion. 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): Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if there were no grade 1 or greater infusion reactions during a final infusion rate of ≥100 mL/hour in the first 2 infusions. Otherwise, continue to use instructions for the second 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).

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

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

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

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

Test Interactions

Daratumumab binds to CD38 on red blood cells and results in a positive indirect antiglobulin test (Coombs test), which may persist for up to 6 months after the last infusion. Daratumumab may also mask antibody detection to minor antigens in the patient’s serum. Mitigation methods include treating reagent red blood cells with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. As the Kell blood group system is also sensitive to DTT, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated red blood cells.

Daratumumab may be detected on both serum protein electrophoresis and immunofixation assays used for multiple myeloma endogenous M-protein monitoring, and may affect the determination of complete response and disease progression of some patients with IgG kappa myeloma protein. In patients with persistent very good partial response, consider other methods to evaluate the depth of treatment response.

Adverse Reactions

Cardiovascular: Hypertension (10%)

Central nervous system: Fatigue (39%), headache (12%), chills (10%)

Gastrointestinal: Nausea (27%), diarrhea (16%), constipation (15%), decreased appetite (15%), vomiting (14%)

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

Infection: Herpes zoster (3%)

Local: Infusion site reaction (first infusion: 46% to 48%; grade 3: 3%; second infusion: 5%; subsequent infusions: 4%)

Neuromuscular & skeletal: Back pain (23%), arthralgia (17%), leg pain (15%), musculoskeletal chest pain (12%)

Respiratory: Cough (21%), upper respiratory (20%), nasal congestion (17%), dyspnea (15%), nasopharyngitis (15%), pneumonia (6% to 11%)

Miscellaneous: Fever (3% to 21%), physical health deterioration (3%)

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 complete blood counts periodically; may require delay of daratumumab infusion to allow for neutrophil and/or platelet recovery. Supportive care with growth factors and/or platelet transfusions may be necessary.

• Infusion reactions: Severe infusion reactions may occur (including 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. Infusion reactions were reported in approximately 50% of patients in clinical trials. Reactions may also be seen during subsequent infusions, and generally occur either during the infusion or within 4 hours of completion; some reactions occurred up to 48 hours after the infusion. Premedication with antihistamines, antipyretics, and corticosteroids is required; interrupt infusion for any reaction and manage as appropriate. Reduce the infusion rate for grade 1, 2, or 3 reaction; permanently discontinue therapy for grade 4 infusion reaction. Administer in a facility with immediate access to resuscitative measures (eg, glucocorticoids, epinephrine, bronchodilators, and/or 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 which 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Interference with serological testing: Through binding to CD38 on red blood cells, 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 red blood cells) 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 therapy initiation.

Monitoring Parameters

Complete blood cell counts periodically; type and screen (blood type) prior to initiating therapy; signs/symptoms of infusion reactions.

Pregnancy Considerations

Animal reproduction studies have not been conducted. Daratumumab is a monoclonal antibody; monoclonal antibodies are known to cross the placenta. Based on the mechanism of action, daratumumab may cause myeloid or lymphoid cell depletion and decreased bone density in the fetus. Females of reproduction potential should use effective contraception during therapy and for 3 months after treatment is complete. The administration of live vaccines should be deferred for neonates and infants exposed to daratumumab in utero until a hematology evaluation can be completed.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, joint pain, pharyngitis, diarrhea, muscle spasms, constipation, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of infusion reaction, shortness of breath, dizziness, passing out, headache, wheezing, coughing, rhinitis, rhinorrhea, nausea, vomiting, angina, severe loss of strength and energy, swelling of arms or legs, burning or numbness feeling, bruising, or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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