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| {{DrugProjectForm
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| |authorTag={{CMG}};{{AE}}{{AKT}}
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| |genericName=generic name
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| |aOrAn=an
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| |drugClass=[[Antineoplastic agents|antineoplastic agent]]
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| |indicationType=treatment
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| |indication=[[multiple myeloma]]
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| |adverseReactions=[[fatigue]], [[headache]], [[nausea]], [[diarrhea]], [[constipation]], [[decreased appetite]], [[vomiting]], [[lymphocytopenia]], [[neutropenia]], [[thrombocytopenia]], [[anemia]], [[back pain]], [[arthralgia]], [[leg pain]], [[Chest pain|musculoskeletal chest pain]], [[cough]], [[nasal congestion]], [[dyspnea]], [[nasopharyngitis]], [[pneumonia]], and [[infusion-related reaction]]
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| |blackBoxWarningTitle=Warning Title
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| |blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
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| |fdaLIADAdult====Indications===
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| *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.
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| =====Multiple Myeloma=====
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| *Administer post-infusion medication to reduce the risk of delayed [[infusion reactions]] to all patients as follows:
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| ** Administer [[corticosteroids]] ([[monotherapy]]: [[methylprednisolone]] 100 mg, or equivalent, administered [[intravenously]]. Following the second [[infusion]], the dose of [[corticosteroid]] may be reduced (oral or [[intravenous]] [[methylprednisolone]] 60 mg) or [[combination therapy]]: administer 20 mg [[dexamethasone]] prior to every daratumumab [[infusion]]. [[Dexamethasone]] is given [[intravenously]] prior to the first daratumumab [[infusion]] and oral administration may be considered prior to subsequent infusions), [[antipyretics]] (oral [[acetaminophen]] 650 to 1000 mg), and [[antihistamine]] (oral or intravenous [[diphenhydramine]] 25 to 50 mg or equivalent) to reduce the risk of [[infusion reactions]] to all patients 1–3 hours prior to every [[infusion]] of daratumumab.
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| * Administer post-infusion medication to reduce the risk of delayed [[infusion reactions]] to all patients as follows:
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| **[[Monotherapy]]: Administer oral [[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 daratumumab [[infusion|infusions]] (beginning the day after the [[infusion]]).
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| **[[Combination therapy]]: Consider administering low-dose oral [[methylprednisolone]] (≤ 20 mg) or equivalent, the day after the daratumumab [[infusion]]. However, if a background regimen-specific [[corticosteroid]] (e.g. [[dexamethasone]]) is administered the day after the daratumumab [[infusion]], additional post-infusion medications may not be needed.
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| **In addition, for any patients with a history of [[chronic obstructive pulmonary disease]], consider prescribing post-infusion medications such as short and long-acting [[bronchodilators]], and inhaled [[corticosteroids]]. Following the first four [[infusion|infusions]], if the patient experiences no major [[infusion reactions]], these additional inhaled post-infusion medications may be discontinued.
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| *Initiate [[antiviral drug|antiviral]] [[prophylaxis]] to prevent [[herpes zoster]] reactivation within 1 week after starting daratumumab and continue for 3 months following treatment.
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| * Dosing Information
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| **Administer only as an [[intravenous]] [[infusion]] after dilution in 0.9% [[Sodium Chloride]] Injection, USP. Daratumumab should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage [[infusion reactions]] if they occur.
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| **The recommended dose of daratumumab for [[monotherapy]] and [[combination therapy]] with [[lenalidomide]] or [[pomalidomide]] and low-dose [[dexamethasone]] (4-week cycle regimens) is 16 mg/kg actual [[body weight]] administered as an [[intravenous]] [[infusion]] according to the following dosing schedule[[File:Daratumumab T1.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| **The recommended dose of daratumumab for [[combination therapy]] with [[bortezomib]] and [[dexamethasone]] (3-week cycle regimen) is 16 mg/kg actual [[body weight]] administered as an [[intravenous]] [[infusion]] according to the following dosing schedule[[File:Daratumumab T2.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| **If a planned dose of daratumumab is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.
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| **Administer daratumumab infusion [[intravenously]] at the [[infusion]] rate described below. Consider incremental escalation of the [[infusion]] rate only in the absence of [[infusion reactions]].[[File:Daratumumab T3.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *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:
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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 clinically appropriate up to the maximum rate of 200 mL/hour (Table 3).
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| **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]].
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| **Grade 4 (life threatening): Permanently discontinue daratumumab treatment.
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| *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.
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| *Daratumumab 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 daratumumab solution required and the number of daratumumab vials needed based on patient actual [[body weight]].
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| **Check that the daratumumab solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
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| **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.
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| **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.
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| **Gently invert the bag/container to mix the solution. Do not shake.
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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.
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| **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).
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| **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.
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| *Administer daratumumab as follows:
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| **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), [[polyvinyl chloride|PVC]], [[polypropylene|PP]] or [[polyethylene|PE]].
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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 daratumumab [[Concomitant drugs|concomitantly]] in the same intravenous line with other agents.
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| |offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of daratumumab in adult patients.
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| |offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non-Guideline-Supported Use</i> of daratumumab in adult patients.
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| |fdaLIADPed
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| * There is limited information regarding <i>indications and dosing</i> of daratumumab in pediatric patients.
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| |offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of daratumumab in pediatric patients.
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| |offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non-Guideline-Supported Use</i> of daratumumab in pediatric patients.
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| |contraindications=*There is limited information regarding <i>[[contraindications]]</i> of daratumumab.
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| |warnings=*[[Infusion Reactions]]
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| **Daratumumab 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 daratumumab. Prior to the introduction of post-infusion medication in [[clinical trials]], infusion reactions occurred up to 48 hours after infusion.
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| **Severe reactions have occurred, including [[bronchospasm]], [[hypoxia]], [[dyspnea]], [[hypertension]], [[laryngeal edema]] and [[pulmonary edema]]. Signs and symptoms may include respiratory symptoms, such as [[nasal congestion]], [[cough]], throat irritation, as well as [[chills]], [[vomiting]] and [[nausea]]. Less common symptoms were [[wheezing]], [[allergic rhinitis]], [[pyrexia]], [[chest discomfort]], [[pruritus]], and [[hypotension]].
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| **Pre-medicate patients with [[antihistamines]], [[antipyretics]] and [[corticosteroids]]. 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.
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| **To reduce the risk of delayed [[infusion reactions]], administer oral [[corticosteroids]] to all patients following daratumumab infusions. Patients with a history of [[chronic obstructive pulmonary disease]] may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting [[bronchodilators] and inhaled [[corticosteroids]] for patients with [[chronic obstructive pulmonary disease]].
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| *Interference with [[serological testing]]
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| **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 factor|Rh]] blood type are not impacted.
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| **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.
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| *[[Neutropenia]]
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| **Daratumumab may increase [[neutropenia]] induced by background therapy. Monitor [[complete blood cell count|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.
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| *[[Thrombocytopenia]]
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| **Daratumumab may increase thrombocytopenia induced by background therapy. Monitor [[complete blood cell count|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]].
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| *Interference with determination of complete response
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| **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. This interference can impact the determination of complete response of disease progression in some patients with [[IgG]] kappa [[myeloma protein]].
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| |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).
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| *[[Combination therapy|Combination treatment]] with [[lenalidomide]]: Adverse reactions described in Table 4 reflect exposure to daratumumab (DRd arm) for a median treatment duration of 13.1 months (range: 0 to 20.7 months) and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the [[lenalidomide]] group (Rd) in Study 3. The most frequent adverse reactions (≥20%) were [[infusion reactions]], [[diarrhea]], [[nausea]], [[fatigue]], [[pyrexia]], [[upper respiratory tract infection]], [[muscle spasms]], [[cough]] and [[dyspnea]]. The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were [[pneumonia]] (12% vs Rd 10%), [[upper respiratory tract infection]] (7% vs Rd 4%), [[influenza]] and [[pyrexia]] (DRd 3% vs Rd 1% for each). Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.
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| [[File:Daratumumab T4.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *Laboratory abnormalities worsening during treatment from baseline listed in Table 5.
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| [[File:Daratumumab T5.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *[[Combination therapy|Combination treatment]] with [[Bortezomib]]: Adverse reactions described in Table 6 reflect exposure to daratumumab (DVd arm) for a median treatment duration of 6.5 months (range: 0 to 14.8 months) and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the [[bortezomib]] group (Vd) in Study 4. The most frequent adverse reactions (>20%) were [[infusion reactions]], [[diarrhea]], [[peripheral edema]], [[upper respiratory tract infection]], [[Peripheral neuropathy|peripheral sensory neuropathy]], [[cough]] and [[dyspnea]]. The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were [[upper respiratory tract infection]] (DVd 5% vs Vd 2%), diarrhea and [[atrial fibrillation]] (DVd 2% vs Vd 0% for each). Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.
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| [[File:Daratumumab T6.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *Laboratory abnormalities worsening during treatment are listed in Table 7.
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| [[File:Daratumumab T7.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *[[Combination therapy|Combination treatment]] with [[Pomalidomide]]: Adverse reactions described in Table 8 reflect exposure to daratumumab, [[pomalidomide]] and [[dexamethasone]] (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study 5. The most frequent adverse reactions (>20%) were [[infusion reactions]], [[diarrhea]], [[constipation]], [[nausea]], [[vomiting]], [[fatigue]], [[pyrexia]], [[upper respiratory tract infection]], [[muscle spasms]], [[back pain]], [[arthralgia]], [[dizziness]], [[insomnia]], [[cough]] and [[dyspnea]]. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included [[pneumonia]] (7%). Adverse reactions resulted in discontinuations for 13% of patients.
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| [[File:Daratumumab T8.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *Laboratory abnormalities worsening during treatment are listed in Table 9.
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| [[File:Daratumumab T9.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *[[Monotherapy]]: The safety data reflect exposure to daratumumab in 156 adult patients with [[relapse|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%.
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| [[File:Daratumumab T10.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| [[File:Daratumumab T11.PNG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *[[infusion reaction|Infusion Reactions]]: In clinical trials ([[monotherapy]] and [[combination therapy|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]].
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| *[[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).
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| *[[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]].
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| *[[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 drugs|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.
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| ======Central Nervous System======
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| : [[Fatigue]], [[headache]], [[chills]]
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| ======Cardiovascular======
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| : [[Hypertension]]
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| ======Respiratory======
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| : [[Cough]], [[nasal congestion]], [[dyspnea]], [[nasopharyngitis]], [[pneumonia]]
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| ======Gastrointestinal======
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| : [[Nausea]], [[diarrhea]], [[constipation]], [[decreased appetite]], [[vomiting]]
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| ======Hematologic & oncologic======
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| : [[Lymphocytopenia]], [[neutropenia]], [[thrombocytopenia]], [[anemia]]
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| ======Infection======
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| : [[Herpes zoster]]
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| ======Neuromuscular & skeletal======
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| : [[Back pain]], [[arthralgia]], [[leg pain]], [[Chest pain|musculoskeletal chest pain]]
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| ======Miscellaneous======
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| : [[Infusion-related reaction]], [[fever]], physical health deterioration
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| |postmarketing=There is limited information regarding Postmarketing Experience of daratumumab in the drug label.
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| |drugInteractions=* Indirect Antiglobulin Tests
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| * Serum Protein Electrophoresis and Immunofixation Tests
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| =====Indirect Antiglobulin Tests=====
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| 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 antigen system|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.
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| =====Serum Protein Electrophoresis and Immunofixation Tests=====
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| Daratumumab may be detected on [[serum protein electrophoresis]] (SPE) and [[immunofixation]] (IFE) assays used for monitoring disease [[monoclonal antibodies|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.
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| |useInPregnancyFDA=*<b>Pregnancy Category unassigned</b>
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| 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]].
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| |useInPregnancyAUS=*<b>Australian Drug Evaluation Committee (ADEC) Pregnancy Category</b>
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| There is no ADEC guidance on usage of daratumumab in women who are pregnant.
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| |useInLaborDelivery=There is no FDA guidance on use of daratumumab during labor and delivery.
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| |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. [[Immunoglobulin G|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.
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| |useInPed=There is no FDA guidance on the use of daratumumab with respect to pediatric patients.
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| |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.
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| |useInGender=There is no FDA guidance on the use of daratumumab with respect to specific gender populations.
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| |useInRace=There is no FDA guidance on the use of daratumumab with respect to specific racial populations.
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| |useInRenalImpair=There is no FDA guidance on the use of daratumumab in patients with renal impairment.
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| |useInHepaticImpair=There is no FDA guidance on the use of daratumumab in patients with hepatic impairment.
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| |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.
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| |useInImmunocomp=There is no FDA guidance on the use of daratumumab in patients who are [[immunocompromised]].
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| |administration=Intravenous
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| |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.
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| |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.
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| |drugBox={{Drugbox2
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| | Verifiedfields = changed
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| | Watchedfields = changed
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| | verifiedrevid = 458638612
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| | type = mab
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| | image =
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| | alt =
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| | mab_type = mab
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| | source = u
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| | target = [[CD38]]
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| <!--Clinical data -->
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| | tradename = daratumumab
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| | Drugs.com = {{Drugs.com|MTM|daratumumab}}
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| | MedlinePlus =
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| | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
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| | pregnancy_US = <!-- A / B / C / D / X -->
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| | pregnancy_category=
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| | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
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| | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
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| | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
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| | legal_US = Rx-only
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| | legal_status =
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| | routes_of_administration = [[Intravenous]]
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| | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
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| | ChemSpiderID = none
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| <!-- Pharmacokinetic data -->
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| | bioavailability =
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| | protein_bound =
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| | metabolism =
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| | elimination_half-life =
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| | excretion =
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| <!-- Identifiers -->
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| | CAS_number_Ref = {{cascite|changed|??}}
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| | CAS_number = 945721-28-8
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| | ATC_prefix = L01
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| | ATC_suffix = XC24
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| | UNII_Ref = {{fdacite|correct|FDA}}
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| | UNII = 4Z63YK6E0E
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| | PubChem =
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| | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| | DrugBank =
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| | KEGG_Ref = {{keggcite|changed|kegg}}
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| | KEGG = D10777
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| <!-- Chemical data -->
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| | C=6466 | H=9996 | N=1724 | O=2010 | S=42
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| | molecular_weight =
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| }}
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| |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|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.
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| |structure=There is limited information regarding structure in the drug label.
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| |PD=NK cells express [[CD38]] and are susceptible to daratumumab mediated cell [[lysis]]. Decreases in absolute counts and percentages of total [[NK-cells|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]].
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| |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.
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| 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.
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| *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]].
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| *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]].
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| *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.
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| *Drug interactions: The coadministration of [[lenalidomide]], [[pomalidomide]] or [[bortezomib]] with daratumumab did not affect the [[pharmacokinetics]] of daratumumab. The coadministration of daratumumab with [[bortezomib]] did not affect the [[pharmacokinetics]] of [[bortezomib]].
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| |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.
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| |nlmPatientInfo=(Link to patient information page)
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| |brandNames=Darzalex
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| |lookAlike=There is limited information regarding daratumumab Look-Alike Drug Names in the drug label.
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| |drugShortage=Drug Shortage
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| }}
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