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daratumumab

( DAR a TOOM ue mab )
Funding:
New Drug Funding Program
  • Daratumumab – In Combination with Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma
  • Daratumumab – In Combination with Bortezomib and Dexamethasone for Relapsed Multiple Myeloma
Other Name(s): Darzalex®
Appearance: Clear, colourless to yellow solution, mixed into large bags of fluid
A - Drug Name

daratumumab

COMMON TRADE NAME(S):   Darzalex®

 
B - Mechanism of Action and Pharmacokinetics

Daratumumab is an IgG1Ƙ human monoclonal antibody (mAb) that targets CD38 on the surface of cells in a variety of hematological malignancies. Based on in vitro studies, by binding to CD38, daratumumab induces immune mediated tumour cell death or apoptosis through Fc mediated cross-linking.



Distribution

Time to steady state:  approx. 5 months into the monthly dosing period (by 21st infusion)

Metabolism

Likely via degradation into small peptides and amino acids via catabolic pathways.

Elimination
Clearance

Rate decreases with increasing doses across the dose levels and with repeated dosing

Half-life

Terminal half-life increases with increasing dose and with repeated dosing

Mean estimated terminal half-life following the 1st 16mg/kg dose:  9 Days

Upon complete saturation of target mediated clearance and repeat dosing:  18 days

 

 
C - Indications and Status
Health Canada Approvals:

  • In combination with bortezomib, melphalan and prednisone, for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

  • In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.

  • 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 (IMiD), or who are refractory to both a PI and an IMiD.*

*Approval was based on the primary efficacy endpoint of overall response rate demonstrated in a single-arm study.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   None

Adverse effects described below were reported in ≥ 2% of patients from three pooled open label clinical studies that included patients with relapsed and refractory multiple myeloma treated with 16mg/kg daratumumab monotherapy. Severe adverse events from other studies or post-marketing may also be included.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Hypertension (10%) (may be severe) I  E
Hypotension (5%) I  E
Palpitations (3%) I  E
Dermatological Rash, pruritus (3%) E
Gastrointestinal Abdominal pain (6%) E
Anorexia, weight changes (15%) E
Constipation (15%) E
Diarrhea (18%) E
Dyspepsia (3%) E
Mucositis (3%) E
Nausea, vomiting (28%) I  E
General Edema - limbs (7%) E
Fatigue (40%) E
Fever (22%) E
Hematological Myelosuppression ± infection, bleeding (28%) E  D
Hepatobiliary ↑ LFTs (4%) E  D
Hypersensitivity Infusion related reaction (39%) (for first infusion) (including CRS and anaphylaxis - 6% severe) I  E
Immune Other - Antibody formation (<1%; in combination therapy) D
Infection Infection (59%) (including atypical and viral reactivation - 10% severe) E
Metabolic / Endocrine Abnormal electrolyte(s) (12%) E
Hyperglycemia (9%) E
Hyperuricemia (3%) E
Musculoskeletal Musculoskeletal pain (26%) E
Neoplastic Secondary malignancy (3%) (Basal cell carcinoma) D  L
Nervous System Anxiety (6%) E
Confusion (5%) E
Dizziness (9%) E
Headache (12%) E
Insomnia (6%) E
Neuropathy (5%) E  D
Ophthalmic Blurred vision (6%) E
Renal Renal failure (<2%) E  D
Respiratory Cough, dyspnea (24%) E
Rhinitis (19%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for daratumumab include infection, fatigue, infusion related reaction, myelosuppression ± infection, bleeding, nausea, vomiting, musculoskeletal pain, cough, dyspnea, fever, rhinitis and diarrhea.

The majority of infusion reactions (IRs) (96%) occurred during the first infusion with incidence declining to 4% with subsequent infusions. Most reactions were grade 1 or 2, however, IRRs can be severe and include respiratory symptoms, cytokine release syndrome (CRS), anaphylaxis, nausea, rash and hypotension. Most reactions occurred during infusion or within 4 hours of completion (median onset was 1.5 h).  Without post-infusion medications, infusion reactions can occur up to 48 hours post infusion.

Infections may be severe, including when administered in combination. Opportunistic infections and herpes zoster virus reactivation, some with a fatal outcome were also reported.

Daratumumab may worsen myelosuppression when used in combination with other chemotherapy agents for the treatment of multiple myeloma.

 
E - Dosing

  • HBV screening should be performed in all patients prior to starting daratumumab.

  • Consider antiviral prophylaxis for herpes zoster reactivation.

  • Patient's blood should be typed and screened prior to starting daratumumab given the potential for interference with the indirect Coombs test.

 

Pre-medications (prophylaxis for infusion reaction) for daratumumab monotherapy:

To be given at least 1 hour prior to infusion:

  • Corticosteroid IV (e.g. methylprednisolone 100 mg or equivalent)*†
  • Oral antipyretic (e.g. acetaminophen 650-1000 mg)
  • H1-receptor antagonist IV/PO (e.g. diphenhydramine 25-50 mg or equivalent)
  • Famotidine 20 mg IV (or equivalent)
  • Montelukast 10 mg PO**

*This dose may be reduced following the second infusion (i.e. IV methylprednisolone 60 mg or equivalent).

For daratumumab combination therapy, corticosteroid IV/PO (e.g. dexamethasone 20 mg) is recommended.

**The addition of montelukast given prior to the first infusion numerically reduced the incidence of respiratory IRs in the study by Nooka et al.

 

Post-infusion Medications for daratumumab monotherapy:

  • Oral corticosteroid (e.g. methylprednisolone 20 mg or equivalent) for 2 days post-infusion
  • Consider bronchodilators (e.g. short and long acting) and inhaled corticosteroids if chronic obstructive pulmonary disorder&***

For daratumumab combination therapy, corticosteroid PO (e.g. dexamethasone 20 mg) on the day after infusion is recommended.

&For daratumumab combination therapy, consider adding an H1-receptor antagonist if the patient is at higher risk of respiratory complications.

***These may be discontinued after the 4th infusion if no major IRs occurred.

 

For daratumumab pre/post-infusion medication in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone, see the respective regimen monographs.

 



Adults:

​​​​​​Dosing Schedule:

Daratumumab 16mg/kg* IV (monotherapy):

Weeks Schedule
Weeks 1 to 8 Weekly
Weeks 9 to 24 Every 2 weeks
Week 25 onwards until disease progression Every 4 weeks

*Splitting the first dose over 2 days has been described (8 mg/kg days 1 and 2) and may be considered. The same premedications listed above should be administered prior to both treatment days (Reece et al 2018).

For daratumumab dosing in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone, see the respective regimen monographs. 

 


Dosage with Toxicity:

No dose reductions of daratumumab are recommended. A dose delay may be required in case of myelosuppression. Consider supportive care with transfusions or growth factors, as needed.

Hepatitis B virus (HBV) reactivation: Hold daratumumab, concomitant steroids and chemotherapy. Consult with a HBV expert and manage appropriately. Restart of daratumumab treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

 

Table 1: Management of Infusion Reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Grade Management Re-challenge
1 or 2
  • Stop or slow the infusion rate.
  • Manage the symptoms.
     

Restart:

  • Once symptoms have resolved, the infusion may be restarted at a rate of no more than 50% of the rate at which the reaction occurred.
  • If no reaction occurs, escalate the rate at no more than 50 mL/hour every hour.
  • Re-challenge with pre-medications and with infusion rate modification (eg. Table 2 below).
3
  • Stop treatment.
  • Aggressively manage symptoms.
     

Restart:

  • Once symptoms have resolved, the infusion may be restarted at a rate of no more than 50% of the rate at which the reaction occurred.
  • If no reaction occurs, escalate the rate at no more than 50 mL/hour every hour.
  • Re-challenge with pre-medications and with infusion rate modification (eg. Table 2 below).
  • If a grade 3 IR recurs for the 3rd time, discontinue permanently (do not re-challenge).
4
  • Stop treatment.
  • Aggressively manage symptoms.
  • Discontinue permanently (do not re-challenge).


Dosage with Hepatic Impairment:

Hepatic Impairment Daratumumab Dose
Mild (total bilirubin 1 to 1.5 times ULN or AST > ULN) No dose adjustment necessary
Moderate (total bilirubin 1.5 to 3 times ULN and any AST) No data
Severe impairment (total bilirubin >3 times ULN and any AST)

 



Dosage with Renal Impairment:

No dose adjustment is necessary.  Formal studies have not been conducted; daratumumab is not renally cleared.



Dosage in the elderly:

No dose adjustments necessary.  No overall differences in safety or effectiveness were observed.



Dosage based on gender:

Based on population PK analysis, there are no significant differences between genders.



Dosage based on ethnicity:

No significant differences were seen between white and non-white patients in the population PK analysis.



Children:

Safety and efficacy have not been established.



 
F - Administration Guidelines

  • Daratumumab infusion should be administered at the appropriate initial infusion rate with incremental escalation. Subsequent infusion rate escalation or dilution reduction should only be considered if the previous infusion was well-tolerated (Table 2).

    Table 2: Standard infusion rates
     
      Dilution volume Initial Infusion Rate (1st hr) Increments of infusion rate Max infusion rate Approximate infusion time
    Week 1 (single dose infusion) 1000 mL 50 mL/hr 50 mL/hr every hour 200 mL/hr 6.5 hr
    Week 1 (split dose infusion; applicable to days 1 and 2) 500 mL 50 mL/hr 50 mL/hr every hour 200 mL/hr 4 hr
    Week 2a 500 mL 50 mL/hr 50 mL/hr every hour 200 mL/hr 4 hr
    Subsequent Infusionsb, c 500 mL 100 mL/hr 50 mL/hr every hour 200 mL/hr 3.25 hr

    a If single dose infusion is used for week 1, the 500 mL dilution volume for the 16 mg/kg dose should be used only if there were no IRRs in the previous week.

    b Initial infusion rate should only be modified if treatment in Weeks 1 and 2 were well-tolerated (no ≥ grade 1 IRRs during ≥100 mL/hr).

    If the patient did not experience an IR in the first 2 infusions of daratumumab, consideration can be given to administer daratumumab as a rapid infusion starting with the 3rd dose (20% of the dose over 30 minutes at 200 mL/hour, then the remaining 80% of the dose over 60 minutes at 450 mL/hour).
     

  • Missed doses should be administered as soon as possible and the dosing schedule adjusted accordingly. The treatment interval should be maintained.

  • Daratumumab should be diluted in 0.9% Sodium Chloride; remove a volume from the IV bag that is equal to the required volume of daratumumab solution.

  • Daratumumab solution is colourless to yellow.

  • The diluted solution may develop very small, translucent to white proteinaceous particles. Do not use if opaque particles, discolouration, or other foreign particles.

  • Administer by IV infusion using an infusion set with a flow regulator and an in-line, low protein-binding filter (0.22 or 0.2 µm). Polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE administration sets must be used.

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

  • Store vials at 2oC - 8oC

  • Do not shake or freeze, protect from light.


​​​​​Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
 



 
G - Special Precautions
Contraindications:

  • Patients with a history of severe hypersensitivity to daratumumab or who have hypersensitivity to any ingredient in the formulation or component of the container.

Other Warnings/Precautions:

  • Daratumumab can cause severe infusion-related reactions (IRRs), including anaphylaxis.  It should only be administered by healthcare professionals with appropriate medical support to manage these reactions.  Pre and post infusion medications should be administered (see Dosing section).

 


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Crosses placental barrier: Likely

    Has not been studied in pregnant women.  IgG1 monoclonal antibodies are known to transfer across the placenta. 

     

  • Fetotoxicity: Likely

    Based on its mechanism of action, it may cause fetal myeloid or lymphoid-cell depletion and decreased bone density.  Daratumumab should not be used during pregnancy unless the benefit of treatment outweighs potential risks to the fetus.  If exposure to daratumumab occurred in utero, live vaccines should not be administered to the infant until a hematology evaluation has been completed.
     

    Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.

     

  • Breastfeeding: Not recommended

    Human IgG is excreted in breast milk. 

  • Fertility effects: No information available
 
H - Interactions

  • No formal drug interaction studies have been conducted.  IgG1 molecules are biotransformed by degradation into small peptides and amino acids via catabolic pathways.
     
  • Daratumumab interferes with the indirect antiglobulin (Coombs) test by binding to CD38 on RBCs.  Daratumumab-mediated positive Coombs test may persist for up to 6 months after treatment completion. Patient's blood should be typed and screened prior to initiating treatment.  Notify blood transfusion centres of this in the event of a planned transfusion and educate patients. 
     
  • Daratumumab may interfere with the serum protein electrophoreses (SPE) and immunofixation (IFE) assays used to monitor M-protein.  This can impact the monitoring of response and disease progression in some patients with IgG kappa myeloma protein.

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and before each dose

Blood

Type and screen prior to starting daratumumab. In the event of a planned transfusion, notify blood transfusion centres.

Electrolytes, renal function tests

Baseline and as clinically indicated

Liver function tests

Baseline and as clinically indicated

HBV serology

Baseline for all patients and as clinically indicated. For patients with evidence of HBV serology at baseline, monitor during treatment and for at least 6 months post treatment. Consult with an expert in HBV

Clinical toxicity assessment for infusion-related reactions, hypersensitivity, infection, anemia, bleeding, respiratory problems, musculoskeletal pain, skin changes, GI and cardiac effects

Baseline and at each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Daratumumab – In Combination with Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma
  • Daratumumab – In Combination with Bortezomib and Dexamethasone for Relapsed Multiple Myeloma

 
K - References

Product Monograph. Darzalex (daratumumab). Janssen Inc. May 2019.

Lonial A, Weiss BW, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Jan; 387: 1551-60.

Nooka AK, Gleason C, Sargeant MO, et al. Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab. J Oncol Pract. 2018 Jul;14(7):414-422

Reece DE, Phillips MJ. Infusion Reactions with Monoclonal Antibody Therapy in Myeloma: Learning from Experience. J Oncol Pract. 2018 Jul;14(7):425-426


September 2019 Updated infusion reaction information in Dosing and Administration sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.