daratumumab (Rx)

Brand and Other Names:Darzalex
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution, single-use vial

  • 100mg/5mL (20mg/mL)
  • 400mg/20mL (20mg/mL)
  • Requires further dilution prior to administration

Multiple Myeloma

Also see Administration and Dosing Considerations

Newly diagnosed multiple myeloma

  • Combination therapy with bortezomib, melphalan and prednisone
    • Indicated in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT)
    • Weeks 1-6: 16 mg/kg IV infusion once weekly (total of 6 doses) 
    • Weeks 7-54: 16 mg/kg IV infusion every 3 weeks (total of 16 doses)
    • Week 55 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks

Relapsed/refractory multiple myeloma

  • Monotherapy
    • Indicated as monotherapy for multiple myeloma in patients who have received at least 3 lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMiD
    • Weeks 1-8: 16 mg/kg IV infusion once weekly (total of 8 doses) 
    • Weeks 9-24: 16 mg/kg IV infusion every 2 weeks (total of 8 doses)
    • Week 25 onward until disease progression: 16 mg/kg IV infusion every 4 weeks
  • Combination therapy with bortezomib and dexamethasone
    • Indicated in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy
    • Weeks 1-9: 16 mg/kg IV infusion once weekly (total of 9 doses) 
    • Weeks 10-24: 16 mg/kg IV infusion every 3 weeks (total of 5 doses)
    • Week 25 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks
  • Combination therapy with lenalidomide and dexamethasone
    • Indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at 1 prior therapy
    • Weeks 1-8: 16 mg/kg IV infusion once weekly (total of 8 doses) 
    • Weeks 9-24: 16 mg/kg IV infusion every 2 weeks (total of 8 doses)
    • Week 25 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks
  • Combination therapy with pomalidomide and dexamethasone
    • Indicated in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor
    • Weeks 1-8: 16 mg/kg IV infusion once weekly 
    • Weeks 9-24: 16 mg/kg IV infusion every 2 weeks
    • Week 25 onwards until disease progression: 16 mg/kg IV infusion every 4 weeks

Preinfusion and postinfusion medications required (see Administration)

Further dilution required (see Administration)

Dosage Modifications

Infusion reaction (see Administration)

Hematologic toxicity: Dose delay may be required to allow recovery of blood cell counts

No dose reductions are recommended

Renal impairment

  • No dosage adjustment required

Hepatic impairment

  • Mild (total bilirubin [TB] <ULN and AST> ULN, or TB 1.5-3x ULN and any AST): No dose adjustment required
  • Severe (TB >3x ULN and any AST): Not studied

Dosing Considerations

Preinfusion medications

  • Administer preinfusion medications to all patients to reduce risk of infusion reactions 1-3 hr prior to every infusion
  • Do not take additional background regimen-specific corticosteroids (eg, prednisone) on daratumumab infusion days when patients receive dexamethasone (or equivalent) as a premedication
  • Monotherapy
    • PO antipyretics (acetaminophen 650-1000 mg), plus
    • PO or IV antihistamine (diphenhydramine 25-50 mg or equivalent), plus
    • IV corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate-acting or long-acting corticosteroid); following the second infusion, corticosteroid dose may be reduced (methylprednisolone 60 mg IV)
  • Combination therapy
    • PO antipyretics (acetaminophen 650-1000 mg), plus
    • PO or IV antihistamine (diphenhydramine 25-50 mg or equivalent), plus
    • Dexamethasone 20 mg before every infusion; give IV before first infusion; consider oral administration prior to subsequent infusion

Postinfusion medications

  • Monotherapy
    • PO corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) on each of the 2 days following all infusions (beginning the day after the infusion)
  • Combination therapy
    • Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent, the day after daratumumab infusion
    • However, if a background regimen-specific corticosteroid (eg, dexamethasone) is administered the day after, additional postinfusion medications may not be needed
  • History of COPD
    • Consider prescribing postinfusion medications (eg, short- and long-acting bronchodilators, and inhaled corticosteroids); following the first 4 infusions if no major infusion reactions occur, these additional inhaled postinfusion medications may be discontinued

Herpes zoster reactivation prophylaxis

  • Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting daratumumab and continue for 3 months following treatment

Diffuse Large B-cell Lymphoma (Orphan)

Orphan designation for treatment of diffuse large B-cell lymphoma

Sponsor

  • Janssen Research and Development, LLC; 1400 McKean Road, P. O. Box 776; Spring House, Pennsylvania 19477

Amyloidosis (Orphan)

Orphan designation for treatment of systemic amyloid light-chain (AL) amyloidosis

Sponsor

  • Janssen Research & Development, LLC; 920 Routh 202 South; Raritan, New Jersey 08869

Safety and efficacy not established

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Adverse Effects

Adverse reactions listed below are for any grade unless otherwise noted

>10% (Monotherapy)

Lymphopenia (72%)

Neutropenia (60%)

Infusion reaction (48%)

Thrombocytopenia (48%)

Anemia (45%)

Fatigue (39%)

Lymphopenia, Grade 3 (30%)

Nausea (27%)

Back pain (23%)

Pyrexia (21%)

Cough (21%)

Upper respiratory tract infection (20%)

Anemia, Grade 3 (19%)

Neutropenia, Grade 3 (17%)

Nasal congestion (17%)

Arthralgia (17%)

Diarrhea (16%)

Constipation (15%)

Pain in extremity (15%)

Dyspnea (15%)

Nasopharyngitis (15%)

Decreased appetite (15%)

Vomiting (14%)

Musculoskeletal chest pain (12%)

Headache (12%)

Pneumonia (11%)

>10% (Combination therapy)

Combination therapy with bortezomib, melphalan and prednisone

  • Upper respiratory tract infection (48%)
  • Infusion reaction (28%)
  • Peripheral edema (21%)
  • Pneumonia (16%)
  • Cough (16%)
  • Dyspnea (13%)
  • Pneumonia, Grade 3 or 4 (1-12%)

Combination therapy with lenalidomide

  • Upper respiratory tract infection (65%)
  • Infusion reaction (48%)
  • Diarrhea (48%)
  • Fatigue (35%)
  • Cough (30%)
  • Muscle spasms (26%)
  • Nausea/vomiting (17-24%)
  • Dyspnea (21%)
  • Pyrexia (20%)
  • Headache (13%)

Combination therapy with bortezomib

  • Peripheral sensory neuropathy (47%)
  • Infusion reaction (45%)
  • Upper respiratory tract infection (44%)
  • Diarrhea (32%)
  • Dyspnea (21%)
  • Pyrexia (16%)
  • Vomiting (11%)

1-10% (Monotherapy)

Thrombocytopenia, Grade 3 (10%)

Lymphopenia, Grade 4 (10%)

Hypertension (10%)

Chills (10%)

Thrombocytopenia, Grade 4 (8%)

Pneumonia, Grade 3 (6%)

Hypertension, Grade 3 (5%)

Neutropenia, Grade 4 (3%)

Infusion reaction, Grade 3 (3%)

Fatigue, Grade 3 (2%)

Back pain, Grade 3 (2%)

Pyrexia, Grade 3 (1%)

Dyspnea, Grade 3 (1%)

Pain in extremity, Grade 3 (1%)

Musculoskeletal chest pain, Grade 3 (1%)

Upper respiratory tract infection, Grade 3 (1%)

Diarrhea, Grade 3 (1%)

Decreased appetite, Grade 3 (1%)

Headache, Grade 3 (1%)

1-10% (Combination therapy)

Combination therapy with bortezomib, melphalan and prednisone

  • Hypertension (10%)
  • Upper respiratory tract infection, Grade 3 or 4 (0-5%)
  • Infusion reaction, Grade 3 or 4 (1-4%)
  • Dyspnea, Grade 3 or 4 (1-2%)
  • Peripheral edema, Grade 3 or 4 (≤1%)
  • Hypertension, Grade 3 or 4 (1-4%)

Combination therapy with lenalidomide

  • Upper respiratory tract infection, Grade 3 or 4 (1-6%)
  • Fatigue, Grade 3 or 4 (1-6%)
  • Infusion reaction, Grade 3 or 4 (0-5%)
  • Diarrhea, Grade 3 or 4 (0-5%)
  • Dyspnea, Grade 3 or 4 (1-3%)
  • Nausea/vomiting, Grade 3 or 4 (0-1%)

Combination therapy with bortezomib

  • Infusion reaction, Grade 3 or 4 (0-9%)
  • Upper respiratory tract infection, Grade 3 or 4 (0-6%)
  • Peripheral sensory neuropathy, Grade 3 or 4 (0-5%)
  • Dyspnea, Grade 3 or 4 (0-4%)
  • Upper respiratory tract infection, Grade 3 or 4 (0-6%)
  • Diarrhea, Grade 3 or 4 (1-3%)
  • Pyrexia, Grade 3 or 4 (0-1%)
  • Peripheral edema, Grade 3 or 4 (0-1%)

Postmarketing Reports

Anaphylactic reaction

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Warnings

Contraindications

Documented hypersensitivity to drug or components of the formulation

Cautions

May increase neutropenia and/or thrombocytopenia induced by background therapy; monitor CBC counts periodically during treatment; monitor patients with neutropenia for signs of infection; dose delay may be required to allow recovery of neutrophils; no dose reduction is recommended, consider supportive care with growth factors and/or transfusions

Binds to CD38 on RBCs and may result in a positive indirect antiglobulin test (Coombs test)

May cause false-positive results with serum protein electrophoresis (SPE) and immunofixation (IFE) assays

Severe infusion reactions

  • If infusion anaphylactic reaction or life-threatening reaction (Grade 4) occurs, institute appropriate care
  • Severe infusion reactions reported in ~50% of all patients (most during the first infusion); may also occur with subsequent infusions
  • Nearly all reactions occurred during infusion or within 4 hr of completing infusion
  • Prior to the introduction of postinfusion medication in clinical trials, infusion reactions occurred up to 48 hr after infusion
  • Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension
  • Signs and symptoms may include respiratory symptoms (eg, cough, wheezing, larynx, throat tightness and irritation), laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis
  • Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills
  • Premedicate patients with antihistamines, antipyretics, and corticosteroids
  • Frequently monitor patients during the entire infusion
  • Permanently discontinue for life-threatening (grade 4) reactions
  • For grade 1, 2, or 3 reactions, reduce the infusion rate when restarting the infusion
  • To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions
  • Patients with a history of obstructive pulmonary disorders may require additional postinfusion medications to manage respiratory complications
  • Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders
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Pregnancy & Lactation

Pregnancy

There are no human data to inform a risk with use of daratumumab during pregnancy and animal studies have not been conducted

Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta

Based on its mechanism of action, daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone density

Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed

Contraception

  • To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after discontinuing treatment

Lactation

Unknown if distributed in human breast milk

Human IgG is known to be present in human milk; published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

more...
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Pharmacology

Mechanism of Action

Monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells

The binding to CD38 is believed to induce rapid tumor cell death through programmed cell death, or apoptosis, and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity

Absorption

Peak plasma concentration: 915 mcg/mL (weekly dosing)

Trough concentration: 573 mcg/mL (monotherapy); 502 mcg/mL (combination therapy)

Steady-state, monotherapy: 5 months

Distribution

Vd, steady-state: 4.7 L (monotherapy); 4.4 L (combination therapy)

Elimination

Half-life: 18 days (monotherapy); 22-23 days (combination therapy)

Clearance: 171.4 mL/day (at steady-state)

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Administration

IV Preparation

Vials are single-use only

Calculate the dose (mg), total volume (mL) of solution required and the number of vials needed

Check solution is colorless to pale yellow; do not use if opaque particles, discoloration, or other foreign particles are present

Using aseptic technique, remove a volume of 0.9% NaCl from the infusion bag/container equivalent to the required volume of daratumumab solution

Withdraw the daratumumab dose from the vial(s) and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% NaCl (first infusion 1000 mL; second and subsequent infusions 500 mL)

Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE)

Discard any unused portion left in the vial

Gently invert the bag/container to mix the solution

Do not shake

Following dilution, store infusion bag/container for up to 24 hr in a refrigerator at 2-8ºC (36-46ºF); protect from light and do not freeze

After allowing the bag/container to come to room temperature, use immediately since the solution does not contain a preservative

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit

Do not use if visibly opaque particles, discoloration, or foreign particles are observed

IV Administration

Should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur

Administer diluted solution by IV infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, nonpyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer)

Polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE administration sets must be used

Infusion should be completed within 15 hr

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 concomitantly in the same IV line with other agents

Infusion rate

  • Consider incremental escalation only in the absence of infusion reactions with the previous infusion
  • First infusion (1000 mL dilution)
    • 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr
  • Second infusion (500 mL dilution)
    • 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr
    • Use a dilution volume of 500 mL only if there were no infusion reactions during the first 3 hr of the first infusion; otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion
  • Subsequent infusions (500 mL dilution)
    • 100 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr
    • If there were no infusion reactions during a final infusion rate of ≥100 mL/hr in the first 2 infusions, then use a modified initial rate for subsequent infusions (eg, third infusion onward); otherwise to follow rate for the second infusion

Infusion reactions

  • For infusion reactions of any grade/severity, immediately interrupt the infusion, and manage symptoms
  • Management of infusion reactions may further require reduction in the rate of infusion, or treatment discontinuation
  • Grade 1-2 (mild-to-moderate)
    • Once reaction symptoms resolve, resume infusion at no more than half the rate at which the reaction occurred
    • If no further reaction symptoms experienced, resume infusion rate escalation at increments and intervals as clinically appropriate up to 200 mL/hr
  • Grade 3 (severe)
    • Once reaction symptoms resolve, resume infusion at no more than half the rate at which the reaction occurred
    • If no further reaction symptoms experienced, resume infusion rate escalation may resume at increments and intervals outlined in infusion rate
    • Repeat the procedure above in the event of recurrence of additional episodes
    • Permanently discontinue upon the third occurrence of Grade ≥3 infusion reaction
  • Grade 4 (life threatening)
    • Permanently discontinue treatment

Missed dose

  • If a planned dose is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval

Storage

Unopened vials

  • Does not contain a preservative
  • Refrigerate at 2-8°C (36-46°F)
  • Protect from light
  • Do not freeze
  • Do not shake

Diluted solution

  • Use immediately at room temperature 15-25°C (59-77°F) and in room light
  • Diluted solution may be kept at room temperature for up to15 hr (including infusion time)
  • If not used immediately
    • Refrigerate at 2-8°C (36-46°F)
    • Protect from light
    • Do not freeze
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Images

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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
  • Manage and view all your plans together – even plans in different states.
  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.