Daratumumab

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Daratumumab
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: AKT

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Overview

Daratumumab is an antineoplastic agent that is FDA approved for the treatment of multiple myeloma. Common adverse reactions include fatigue, headache, nausea, diarrhea, constipation, decreased appetite, vomiting, lymphocytopenia, neutropenia, thrombocytopenia, anemia, back pain, arthralgia, leg pain, musculoskeletal chest pain, cough, nasal congestion, dyspnea, nasopharyngitis, pneumonia, and infusion-related reaction.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Daratumumab is indicated for, in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone, treatment of patients with multiple myeloma who have received at least one prior therapy; for, in combination with pomalidomide and dexamethasone, treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor; and as monotherapy, for the treatment of patients with multiple myeloma who have received at least three 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.

Multiple Myeloma

  • Administer post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows:
  • Administer post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows:
  • Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting daratumumab and continue for 3 months following treatment.
  • Dosing Information
  • For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion and manage symptoms. Management of infusion reactions may further require reduction in the rate of infusion, or treatment discontinuation of daratumumab as outlined below:
    • Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 3).
    • Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 3. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction.
    • Grade 4 (life threatening): Permanently discontinue daratumumab treatment.
  • No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity.
  • Daratumumab is for single use only. Prepare the solution for infusion using aseptic technique as follows:
    • Calculate the dose (mg), total volume (mL) of daratumumab solution required and the number of daratumumab vials needed based on patient actual body weight.
    • Check that the daratumumab solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
    • Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of daratumumab solution.
    • Withdraw the necessary amount of daratumumab solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 3. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
    • Gently invert the bag/container to mix the solution. Do not shake.
    • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
    • Since daratumumab does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) 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, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light. Do not freeze.
  • Administer daratumumab as follows:
    • If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.
    • Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.
    • Do not infuse daratumumab concomitantly in the same intravenous line with other agents.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Daratumumab Test in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Daratumumab Test in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding indications and dosing of daratumumab in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Daratumumab Test in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Daratumumab Test in pediatric patients.

Contraindications

There is limited information regarding contraindications of daratumumab.

Warnings

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Daratumumab Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Daratumumab Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Daratumumab Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Daratumumab in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daratumumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Daratumumab during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Daratumumab in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Daratumumab in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Daratumumab in geriatric settings.

Gender

There is no FDA guidance on the use of Daratumumab with respect to specific gender populations.

Race

There is no FDA guidance on the use of Daratumumab with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Daratumumab in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Daratumumab in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Daratumumab in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Daratumumab in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Daratumumab Administration in the drug label.

Monitoring

There is limited information regarding Daratumumab Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Daratumumab and IV administrations.

Overdosage

There is limited information regarding Daratumumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Daratumumab Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Daratumumab Mechanism of Action in the drug label.

Structure

There is limited information regarding Daratumumab Structure in the drug label.

Pharmacodynamics

There is limited information regarding Daratumumab Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Daratumumab Pharmacokinetics in the drug label.

Nonclinical Toxicology

No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

Clinical Studies

Combination treatment with Lenalidomide and Dexamethasone===== Study 3, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the daratumumab and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

Study 3 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (hazard ratio [HR]=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd. Figure 1: Kaplan-Meier Curve of PFS in Study 3

This image is provided by the National Library of Medicine.

Additional efficacy results from Study 3 are presented in Table 12 below.

This image is provided by the National Library of Medicine.

In responders, the median time to response was 1 month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group.

With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group.

Combination treatment with Bortezomib and Dexamethasone

Study 4, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd). Bortezomib was administered by SC injection or IV infusion at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of daratumumab infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone] dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas daratumumab was given until disease progression. However, dexamethasone 20 mg was continued as a daratumumab pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information.

A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the daratumumab and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an immunomodulatory agent (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were in general well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd arm respectively refractory to lenalidomide. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

Study 4 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. Figure 2: Kaplan-Meier Curve of PFS in Study 4

This image is provided by the National Library of Medicine.

Additional efficacy results from Study 4 are presented in Table 13 below.

This image is provided by the National Library of Medicine.

In responders, the median time to response was 0.8 months (range: 0.7 to 4 months) in the DVd group and 1.5 months (range: 0.7 to 5 months) in the Vd group. The median duration of response had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ to 12+ months) in the Vd group.

With a median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in the Vd group were observed.

Combination treatment with Pomalidomide and Dexamethasone

Study 5 was an open-label trial in which 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent, received 16 mg/kg daratumumab in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/ week (reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication.

The median patient age was 64 years (range: 35 to 86 years) with 8% of patients ≥75 years of age. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.

Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see table 14).

This image is provided by the National Library of Medicine.

The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months).

Monotherapy

Study 1, was an open-label trial evaluating daratumumab monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, daratumumab 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.

The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents.

Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see table 15).

This image is provided by the National Library of Medicine.

The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months).

Study 2 was an open-label dose escalation trial evaluating daratumumab monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, daratumumab 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.

The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents.

Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months).

How Supplied

Daratumumab is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as:

  • NDC 57894-502-05 contains one 100 mg/5 mL single-dose vial
  • NDC 57894-502-20 contains one 400 mg/20 mL single-dose vial

Storage

Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze or shake. Protect from light. This product contains no preservative.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

  • Infusion Reactions
  • Neutropenia
    • Advise patients that if they have a fever, they should contact their healthcare professional.
  • Thrombocytopenia
    • Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding.
  • Interference with laboratory tests
    • Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking daratumumab, in the event of a planned transfusion.
    • Advise patients that daratumumab can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response.

Precautions with Alcohol

Alcohol-Daratumumab Test interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Darzalex

Look-Alike Drug Names

There is limited information regarding daratumumab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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