daratumumab (Rx)

>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 with pomalidomide and dexamethasone)

Fatigue (50%)

Infusion-related reaction (50%)

Upper respiratory tract infection (50%)

Cough (43%)

Diarrhea (38%)

Constipation (33%)

Dyspnea (33%)

Nausea (30%)

Muscle spasms (26%)

Back pain (25%)

Pyrexia (25%)

Insomnia (23%)

Arthralgia (21%)

Vomiting (21%)

Chills (20%)

Tremor (19%)

Headache (17%)

Peripheral edema (17%)

Hypokalemia (16%)

Nasal congestion (16%)

Asthenia (15%)

Non-cardiac chest pain (15%)

Pneumonia (15%)

Hyperglycemia (13%)

Anxiety (13%)

Decreased appetite (11%)

Pain (11%)

>10% (Combination therapy with lenalidomide and dexamethasone)

Neutropenia (91%)

Leukopenia (90%)

Lymphopenia (84%)

Thrombocytopenia (67%)

Diarrhea (43-57%)

Upper respiratory tract infection (27-65%)

Infusion-related reactions (35-48%)

Anemia (47%)

Lymphopenia, Grade 3-4 (15-44%)

Constipation (41%)

Peripheral edema (41%)

Fatigue (35-40%)

Back pain (34%)

Asthenia (32%)

Nausea (24-32%)

Dyspnea (21-32%)

Cough (17-30%)

Muscle spasms (26-29%)

Bronchitis (20-29%)

Pneumonia (26%)

Pyrexia (20-26%)

Peripheral sensory neuropathy (24%)

Decreased appetite (22%)

Headache (13-19%)

Neutropenia, Grade 3-4 (14-19%)

Urinary tract infection (18%)

Vomiting (16-17%)

Paresthesia (16%)

Hyperglycemia (14%)

Hypocalcemia (14%)

Leukopenia, Grade 3-4 (10-14%)

Hypertension (13%)

Chills (13%)

>10% (Combination therapy with bortezomib, melphalan, and prednisone)

Thrombocytopenia (88%)

Neutropenia (86%)

Lymphopenia (85%)

Upper respiratory tract infections (48%)

Anemia (47%)

Lymphopenia, Grade 3-4 (12-46%)

Neutropenia, Grade 3-4 (10-34%)

Infusion-related reactions (28%)

Thrombocytopenia, Grade 3-4 (11-27%)

Peripheral edema (21%)

Anemia, Grade 3 (18%)

Pneumonia (16%)

Cough (16%)

Dyspnea (13%)

Anemia, Grade 3 (4-13%)

Pneumonia, Grade 3 (12%)

>10% (Combination therapy with bortezomib, thalidomide, and dexamethasone)

Lymphopenia (95%)

Leukopenia (82%)

Thrombocytopenia (81%)

Neutropenia (63%)

Lymphopenia, Grade 3-4 (15-44%)

Anemia (36%)

Infusion-related reactions (35%)

Nausea (30%)

Upper respiratory tract infection (27%)

Pyrexia (26%)

Bronchitis (20%)

Neutropenia, Grade 3-4 (14-19%)

Cough (17%)

Vomiting (16%)

Leukopenia, Grade 3-4 (10-14%)

1-10% (Combination therapy with pomalidomide and dexamethasone)

Fatigue, Grade 3 (10%)

Pneumonia, Grade 3 (8%)

Back pain, Grade 3 (6%)

Dyspnea, Grade 3-4 (1-6%)

Hyperglycemia, Grade 3 (5%)

Infusion-related reactions, Grade 3 (4%)

Bone pain, Grade 3 (4%)

Diarrhea, Grade 3 (3%)

Tremor, Grade 3 (3%)

Hypokalemia, Grade 3 (3%)

Dizziness, Grade 3 (2%)

Vomiting, Grade 3 (2%)

Insomnia, Grade 3 (2%)

Arthralgia, Grade 3 (2%)

Musculoskeletal chest pain, Grade 3 (2%)

Cough, Grade 3 (1%)

Muscle spasms, Grade 3 (1%)

Pyrexia, Grade 3 (1%)

1-10% (Combination therapy with lenalidomide and dexamethasone)

Hypertension (10%)

Thrombocytopenia, Grade 3-4 (5-9%)

Fatigue, Grade 3-4 (<6%)

Upper respiratory tract infections, Grade 3-4 (<6%)

Diarrhea, Grade 3 (5%)

Nausea, Grade 3 (1-4%)

Dyspnea, Grade 3-4 (<3%)

Infusion-related reactions, Grade 3-4 (<5%)

Pyrexia, Grade 3 (2%)

Vomiting, Grade 3-4 (<2%)

Upper respiratory tract infection, Grade 3 (1%)

Muscle spasms, Grade 3 (1%)

Bronchitis, Grade 3 (1%)

1-10% (Combination therapy with bortezomib, melphalan, and prednisone)

Hypertension (10%)

Upper respiratory tract infection, Grade 3 (5%)

Hypertension, Grade 3 (4%)

Infusion-related reactions, Grade 3 (4%)

Dyspnea, Grade 3 (2%)

Peripheral edema, Grade 3 (1%)

1-10% (Combination therapy with bortezomib, thalidomide, and dexamethasone)

Hypertension (10%)

Hypertension, Grade 3 (4%)

Nausea, Grade 3 (4%)

Infusion-related reactions (<3%)

Vomiting, Grade 3 (2%)

Pyrexia, Grade 3-4 (<2%)

Bronchitis, Grade 3 (1%)

Upper respiratory tract infection, Grade 3 (1%)

Posmarketing Reports

Anaphylactic reaction

Pancreatitis

Infections: Cytomegalovirus, listeriosis

Contraindications

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

Hepatitis B virus reactivation reported in clinical trials; including fatal cases

Severe infusion reactions

• Severe and/or serious reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema and pulmonary edema
• 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
• Signs and symptoms may include respiratory symptoms (eg, cough, wheezing, larynx, throat tightness, and irritation), laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis
• Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, reported; if ocular symptoms occur, interrupt infusion and seek immediate ophthalmologic evaluation prior to restarting therapy
• Premedicate patients with antihistamines, antipyretics, and corticosteroids
• Frequently monitor patients during the entire infusion
• Patients with a history of chronic obstructive pulmonary disease (COPD) may require additional post-infusion medications to manage respiratory complications; consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with COPD

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

The combination of drug and lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because these drugs may cause birth defects and death of unborn child; they are only available through a REMS program; refer to their respective prescribing information on use during pregnancy

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

Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta; based on mechanism of action, drug may cause depletion of fetal CD38 positive immune cells and decreased bone density

Contraception

• 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

Because of potential for serious adverse reactions in breastfed child when therapy is administered with lenalidomide, pomalidomide, or thalidomide, advise women not to breastfeed during treatment

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.

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

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)

IV Compatibilities

0.9% NaCl

IV Incompatibilities

Do not infuse concomitantly in the same IV line with other agents

IV Preparation

Vials are single-use only

Calculate dose (mg), total volume (mL) of solution required

Solution should appear colorless to pale yellow; do not use if opaque particles, discoloration, or other foreign particles are present

Remove a volume of 0.9% NaCl from infusion bag/container equivalent to required volume of daratumumab solution

Withdraw daratumumab dose and dilute to 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

Visually inspect 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

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

Discard any unused product or waste material in accordance with local requirements

Preinfusion medications

• Administer preinfusion medications 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, consider reducing dose (methylprednisolone 60 mg IV)

• Combination therapy

  • PO antipyretics (acetaminophen 650-1000 mg), plus
  • PO or IV antihistamine (diphenhydramine 25-50 mg or equivalent), plus
  • Administer dexamethasone 20 mg (or equivalent) prior to every infusion
  • Dexamethasone is given IV prior to first infusion and consider PO dexamethasone prior to subsequent infusions.

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

  • Administer dexamethasone 20 mg (or equivalent) prior to every infusion
  • Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent, day after infusion
  • If a background regimen-specific corticosteroid (eg, dexamethasone, prednisone) is administered the day after the infusion, additional postinfusion medications may not be needed when patients receive dexamethasone (or equivalent) as a premedication

• 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

Infusion rate

• Consider incremental escalation only in the absence of infusion reactions with the previous infusion

• Week 1 infusion

  • Single-dose infusion (Day 1 [1000 mL dilution]): 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr
  • Split-dose infusion over 2 consecutive days (Days 1 and 2 [500 mL dilution]): 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr

• Week 2 (500 mL dilution)

  • 50 mL/hr for first hour; may increase by 50 mL/hr every hour, not to exceed 200 mL/hr
  • Use the 500 mL dilution only if no infusion reactions occurred during the first 3 hr of the first infusion; otherwise, continue to use the 1000 mL dilution and instructions for the first infusion

• Week 3 and 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
  • Use a modified initial rate (100 mL/hr) for subsequent infusions (ie, Week 3 onwards) only if no infusion reactions occurred during the previous infusion; otherwise, continue to use instructions indicated for Week 2 infusion rate

Infusion rate for infusion-related 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 infusion rate, or treatment discontinuation

• Grade 1-2 (mild-to-moderate)

  • Once 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 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 procedure above in the event of recurrence of additional episodes
  • Permanently discontinue upon third occurrence of Grade ≥3 infusion reaction

• Grade 4 (life threatening)

  • Permanently discontinue treatment

Missed dose

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