User:Matt Pijoan

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{{DrugProjectForm |authorTag=Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Allison Tu [2] |genericName=generic name |aOrAn=an |drugClass=antineoplastic agent |indicationType=treatment |indication=multiple myeloma |adverseReactions=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 |blackBoxWarningTitle=Warning Title |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult====Indications===

  • 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.


|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of daratumumab in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non-Guideline-Supported Use of daratumumab in adult patients.

|fdaLIADPed

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

|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of daratumumab in pediatric patients.

|offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non-Guideline-Supported Use of daratumumab in pediatric patients.

|contraindications=*There is limited information regarding contraindications of daratumumab. |warnings=*Infusion Reactions

  • Interference with serological testing
    • Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect 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 serum. The determination of a patient's ABO and Rh blood type are not impacted.
    • Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received daratumumab. Type and screen patients prior to starting daratumumab.
  • Neutropenia
    • Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Daratumumab dose delay may be required to allow recovery of neutrophils. No dose reduction of daratumumab is recommended. Consider supportive care with growth factors.
  • Thrombocytopenia
    • Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Daratumumab dose delay may be required to allow recovery of platelets. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions.

|clinicalTrials=*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 described below reflects exposure to daratumumab (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received daratumumab in combination with either lenalidomide (DRd, n=283; Study 3) or bortezomib (DVd, n=243; Study 4) and five open-label, clinical trials in which patients received daratumumab either in combination with pomalidomide (DPd, n=103; Study 5), in combination with lenalidomide (n=35), or as monotherapy (n=156).

This image is provided by the National Library of Medicine.
  • Laboratory abnormalities worsening during treatment from baseline listed in Table 5.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
  • Laboratory abnormalities worsening during treatment are listed in Table 7.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
  • Laboratory abnormalities worsening during treatment are listed in Table 9.
This image is provided by the National Library of Medicine.
  • Monotherapy: The safety data reflect exposure to daratumumab in 156 adult patients with relapsed and refractory multiple myeloma treated with daratumumab at 16 mg/kg in three open-label, clinical trials. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 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 10. Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
  • Infusion Reactions: In clinical trials (monotherapy and combination treatment; N=820) the incidence of any grade infusion reactions was 46% with the first infusion of daratumumab, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion reaction with second or subsequent infusions. The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion modification due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7.0, 4.3, and 3.5 hours respectively. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any Grade, ≥5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea.
  • Herpes Zoster Virus Reactivation: Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of daratumumab. In monotherapy studies, herpes zoster was reported in 3% of patients. In the randomized controlled combination therapy studies, herpes zoster was reported in 2% each in the DRd and Rd groups respectively (Study 3), in 5% versus 3% in the DVd and Vd groups respectively (Study 4) and in 2% of patients receiving DPd (Study 5).
  • Infections: In patients receiving daratumumab combination therapy, Grade 3 or 4 infections were reported with daratumumab combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 3% versus 2% of patients in the DRd and Rd groups respectively, 4% versus 3% of patients in the DVd and Vd groups respectively and in 5% of patients receiving DPd. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis.
  • Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials of patients with multiple myeloma treated with daratumumab as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 (0.7%) of the 298 combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered daratumumab as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to daratumumab with the incidence of antibodies to other products may be misleading.
Central Nervous System
Fatigue, headache, chills
Cardiovascular
Hypertension
Respiratory
Cough, nasal congestion, dyspnea, nasopharyngitis, pneumonia
Gastrointestinal
Nausea, diarrhea, constipation, decreased appetite, vomiting
Hematologic & oncologic
Lymphocytopenia, neutropenia, thrombocytopenia, anemia
Infection
Herpes zoster
Neuromuscular & skeletal
Back pain, arthralgia, leg pain, musculoskeletal chest pain
Miscellaneous
Infusion-related reaction, fever, physical health deterioration


|postmarketing=There is limited information regarding Postmarketing Experience of daratumumab in the drug label. |drugInteractions=* Indirect Antiglobulin Tests

  • Serum Protein Electrophoresis and Immunofixation Tests
Indirect Antiglobulin Tests

Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.

Serum Protein Electrophoresis and Immunofixation Tests

Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, consider other methods to evaluate the depth of response. |useInPregnancyFDA=*Pregnancy Category unassigned There are no human data to inform a risk with use of daratumumab during pregnancy. Animal studies have not been conducted. However, there are clinical considerations. 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect leukocyte populations, infant monkeys had a reversible reduction in leukocytes.

|useInPregnancyAUS=*Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no ADEC guidance on usage of daratumumab in women who are pregnant. |useInLaborDelivery=There is no FDA guidance on use of daratumumab during labor and delivery. |useInNursing=There is no information regarding the presence of daratumumab in human milk, the effects on the breastfed infant,or the effects on milk production. 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. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for daratumumab and any potential adverse effects on the breast-fed child from daratumumab or from the underlying maternal condition. |useInPed=There is no FDA guidance on the use of daratumumab with respect to pediatric patients. |useInGeri=Of the 156 patients that received daratumumab monotherapy at the recommended dose, 45% were 65 years of age or older, and 10% were 75 years of age or older. Of 664 patients that received daratumumab with various combination therapies, 41% were 65 to 75 years of age, and 9% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. |useInGender=There is no FDA guidance on the use of daratumumab with respect to specific gender populations. |useInRace=There is no FDA guidance on the use of daratumumab with respect to specific racial populations. |useInRenalImpair=There is no FDA guidance on the use of daratumumab in patients with renal impairment. |useInHepaticImpair=There is no FDA guidance on the use of daratumumab in patients with hepatic impairment. |useInReproPotential=To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of daratumumab treatment. |useInImmunocomp=There is no FDA guidance on the use of daratumumab in patients who are immunocompromised. |administration=Intravenous |monitoring=Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab 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.

|overdose=The dose of daratumumab at which severe toxicity occurs is not known. In the event of an overdose, monitor patients for any signs or symptoms of adverse effects and provide appropriate supportive treatment.

|drugBox=

Matt Pijoan?
Therapeutic monoclonal antibody
Source u
Target CD38
Identifiers
CAS number 945721-28-8
ATC code L01XC24
PubChem  ?
Chemical data
Formula C6466H9996N1724O2010S42 
Mol. mass  ?
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

?

Legal status

-only(US)

Routes Intravenous

|mechAction=CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab. |structure=There is limited information regarding structure in the drug label. |PD=NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. Daratumumab as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that daratumumab has the potential to delay ventricular repolarization. |PK=Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg of daratumumab in combination with other treatments, increases in area under the concentration-time curve (AUC) were more than dose-proportional. Following the recommended dose of 16 mg/kg when daratumumab was administered as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) value at the end of weekly dosing, was approximately 2.7 to 3-fold higher compared to the mean serum Cmax following the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 ± 332 µg/mL when daratumumab was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when daratumumab was administered as combination therapy. Daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean ± SD ratio of Cmax at steady-state to Cmax after the first dose was 1.6 ± 0.5.

  • Distribution: At the recommended dose of 16 mg/kg, the mean ± SD central volume of distribution was 4.7 ± 1.3 L when daratumumab was administered as monotherapy and 4.4 ± 1.5 L when daratumumab was administered as combination therapy.
  • Elimination: Daratumumab clearance decreased with increasing dose and with multiple dosing. At the recommended dose of 16 mg/kg of daratumumab as monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day. The mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days when daratumumab administered as monotherapy and 23 ± 12 days when daratumumab was administered as combination therapy.
  • Specific populations: The following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered daratumumab as monotherapy or as combination therapy: sex, age (31 to 84 years), mild [total bilirubin 1 to 1.5 times upper limit of normal (ULN) and any alanine transaminase (ALT)] and moderate (total bilirubin 1.5 to 3 times ULN and any ALT) hepatic impairment, or renal impairment [Creatinine clearance] (CLcr) 15 –89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any ALT) hepatic impairment is unknown. Increasing body weight increased the central volume of distribution and clearance of daratumumab, supporting the body weight-based dosing regimen.

|nonClinToxic=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.


|nlmPatientInfo=(Link to patient information page) |brandNames=Darzalex |lookAlike=There is limited information regarding daratumumab Look-Alike Drug Names in the drug label. |drugShortage=Drug Shortage }}


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