HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DARZALEX™ safely and effectively. See full prescribing information for DARZALEX.
DARZALEX (daratumumab) injection, for intravenous use
Initial U.S. Approval – 2015
INDICATIONS AND USAGE
DARZALEX is a human CD38-directed monoclonal antibody indicated 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. (1)
This indication is approved under accelerated approval based on response rate (14). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
DOSAGE AND ADMINISTRATION
Pre-medicate with corticosteroids, antipyretics and antihistamines. (2.2)
Dilute and administer as an intravenous infusion. (2.3, 2.4)
Recommended dose is 16 mg/kg body weight:
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Weekly |
Weeks 1 to 8 |
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Every two weeks |
Weeks 9 to 24 |
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Every four weeks |
Week 25 onwards until disease progression |
Administer post-infusion medications. (2.2)
DOSAGE FORMS AND STRENGTHS
Injection:
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100 mg/5 mL solution in a single-dose vial (3)
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400 mg/20 mL solution in a single-dose vial (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
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Infusion reactions: Interrupt DARZALEX infusion for infusion reactions of any severity. Permanently discontinue the infusion in case of life-threatening infusion reactions. (2.1, 5.1)
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Interference with cross-matching and red blood cell antibody screening: Type and screen patients prior to starting treatment. Inform blood banks that a patient has received DARZALEX. (5.2, 7.1)
ADVERSE REACTIONS
The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions, fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
DARZALEX is indicated 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.
This indication is approved under accelerated approval based on response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose and Schedule
The recommended dose of DARZALEX is 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule.
If a planned dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.
Administer DARZALEX infusion intravenously at the appropriate infusion rate. Consider incremental escalation of the infusion rate only in the absence of infusion reactions with the previous infusion of DARZALEX as defined in Table 2.
For infusion reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below [see Warnings and Precautions (5.1)].
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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 appropriate (Table 2).
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Grade 3 (severe): If the intensity of the reaction decreases to Grade 2 or lower, 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 2. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction.
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Grade 4 (life threatening): Permanently discontinue DARZALEX treatment.
2.2 Recommended Concomitant Medications
Pre-infusion Medication
Administer pre-infusion medications to reduce the risk of infusion reactions to all patients approximately 1 hour prior to every infusion of DARZALEX as follows:
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intravenous corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate-acting or long-acting corticosteroid), plus
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oral antipyretics (acetaminophen 650 to 1000 mg), plus
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oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent).
Following the second infusion, the dose of corticosteroid may be reduced (methylprednisolone 60 mg intravenously).
Post-infusion Medication
Administer post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows:
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oral corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid in accordance with local standards) on the first and second day after all infusions.
For patients with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued.
Prophylaxis for Herpes Zoster Reactivation
Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment [see Adverse Reactions (6.1)].
2.3 Preparation for Administration
DARZALEX is for single use only.
Prepare the solution for infusion using aseptic technique as follows:
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Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.
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Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
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Using aseptic technique, remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of DARZALEX solution.
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Withdraw the necessary amount of DARZALEX 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 2 [see Dosage and Administration (2.1)]. 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.
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Gently invert the bag/container to mix the solution. Do not shake.
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Following dilution the infusion bag/container may be stored for up to 24 hours in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF), protected from light. Do not freeze. After allowing the bag/container to come to room temperature, use immediately since DARZALEX solutions do not contain a preservative.
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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.
2.4 Administration
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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). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE administration sets must be used.
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Infusion should be completed within 15 hours.
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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.
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Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
3 DOSAGE FORMS AND STRENGTHS
DARZALEX is a colorless to pale yellow, preservative-free solution available as:
Injection:
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100 mg/5 mL (20 mg/mL) in a single-dose vial.
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400 mg/20 mL (20 mg/mL) in a single-dose vial.
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Infusion Reactions
DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion.
Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion.
Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and 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 [see Adverse Reactions (6.1)].
Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.1)].
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 post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.
5.2 Interference with Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum1 [see References (15)]. The determination of a patient's ABO and Rh blood type are not impacted [see Drug Interactions (7.1)].
Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.
5.3 Interference with Determination of Complete Response
Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.1)]. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.
6 ADVERSE REACTIONS
The following serious adverse reactions are also described elsewhere in the labeling:
6.1 Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data reflect exposure to DARZALEX in 156 adult patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg in three open-label, clinical trials. The median duration of exposure was 3.3 months (range: 0.03 to 20.4 months).
Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).
Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients.
Adverse reactions occurring in at least 10% of patients are presented in Table 3. Table 4 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.
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