Dosing and uses of Darzalex (daratumumab)
Adult dosage forms and strengths
solution for injection
- 100mg/5mL vial
- 400mg/20mL vial
- Requires further dilution prior to administration
Multiple Myeloma
Indicated for patients with multiple myeloma who have received at least 3 prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMid
16 mg/kg IV infusion once weekly (weeks 1 to 8); reduce frequency to q2wk (weeks 9-24) and ultimately q4wk (week 25 and thereafter) until disease progression
Preinfusion and postinfusion medications required (see Administration)
Further dilution required (see Administration)
Dosage modifications
Infusion reaction (see Administration)
Renal impairment
- No dosage adjustment required
Hepatic impairment
- Mild (TB <ULN and AST 1-1.5 ULN, or TB 1-1.5 ULN and any AST): No dose adjustment required
- Moderate-to-severe: Not studied
Dosing Considerations
Approved under accelerated approval based on response rate
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Darzalex (daratumumab) adverse (side) effects
Adverse reactions listed below are for any grade unless otherwise noted
>10%
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%)
1-10%
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%)
Warnings
Contraindications
None
Cautions
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
- 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
Pregnancy and 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.
Pharmacology of Darzalex (daratumumab)
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 (predose) concentration: 573 mcg/mL (weekly dose)
Distribution
Vd: 4.7 L (at steady-state)
Elimination
Half-life: 18 days
Clearance: 171.4 mL/day (at steady-state)
Administration
IV Preparation
Each vial is for single use only (does not contain preservatives)
Calculate the dose in mg and total volume in mL of daratumumab solution required and the number vials needed based on patient actual body weight
Check that the 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 that is equal 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)
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
Following dilution, the infusion bag/container may be stored 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
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
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 the 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
Concomitant medications
- Preinfusion medications
- Premedicate patients with antihistamines, antipyretics, and corticosteroids 1 hr before every infusion
- IV corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate-acting or long-acting corticosteroid), plus
- PO antipyretics (acetaminophen 650-1000 mg), plus
- PO or IV antihistamine (diphenhydramine 25-50 mg or equivalent)
- Following the second infusion, the dose of corticosteroid may be reduced (methylprednisolone 60 mg IV)
- Postinfusion medications
- To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions
- PO corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid in accordance with local standards) on the first and second day after all infusions
- History of COPD: Consider prescribing postinfusion medications (eg, short- and long-acting bronchodilators, and inhaled corticosteroids); after the first 4 infusions, if the patient experiences no major infusion reactions, 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
- 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
- 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
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 the infusion at no more than half the rate at which the reaction occurred
- If no further reaction symptoms, infusion rate escalation may resume at increments and intervals as appropriate (see above infusion rate)
- Grade 3 (severe)
- If the intensity of the reaction decreases to ≤grade 2, 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 above (see infusion rate)
- Repeat the procedure above in the event of recurrence of grade 3 symptoms
- 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 2-8ºC (36-46ºF)
- Protect from light
- Do not freeze
- Do not shake
Diluted solution
- May store for up to 24 hr in a refrigerator at 2-8ºC (36-46ºF)
- Protect from light
- Do not freeze
