Written by: Eric Dallara, RPh, New England Cancer Specialist
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Description:  Diarrhea is the main toxicity of neratinib treatment occurring in 95% of patients in the ExteNET trial on the Neratinib arm in which antidiarrheal prophylaxis was not protocol specified.1  Various prevention and treatment strategies for diarrhea have been studied and will be discussed in this PQI.

Background: Neratinib is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy. The majority (95%) of patients experienced diarrhea in the first month of treatment in ExteNET.  Median time to onset of any grade diarrhea is 2 days (8 days for Grade 3) and median cumulative duration of diarrhea was 59 days (5 days for Grade 3). The Phase 2 CONTROL trial was designed to investigate various approaches to preventing and managing diarrhea in patients on neratinib, including various anti-diarrheal combinations, as well as a dose escalation arm. Mature data is available for budesonide and colestipol; interim data are available for dose escalation in Phase 2 CONTROL trial.4 All preventative strategies from the CONTROL trial reduced the incidence, duration, and severity of diarrhea, and also reduced neratinib discontinuation when compared to the pivotal ExteNET trial.

PQI Process: Upon receipt of neratinib prescription:

  • Consider dose escalation based on data from CONTROL trial (see supplemental information for dosing)
  • Diarrhea Prophylaxis – Diarrhea occurs in 95% of the patients without prophylaxis protocol
    • Begin prophylaxis with the first dose or neratinib and continue for 2 cycles depending on the regimen selected and the patient response
    • Ensure patient has instructions and supply of loperamide and consider colestipol or budesonide (see Supplemental Information for dosing)
    • Refer to Oncolytic Induced Diarrhea PQI
    • Identify drug-drug interactions and side effect profiles of loperamide, colestipol, and budesonide when making clinical recommendations
    • Consider weekly assessment of diarrhea throughout the first 2 cycles
  • Drug-Drug Interactions
    • Avoid concomitant use of PPIs
    • If H2-antagonists must be used, administer neratinib 2 hours before or 10 hours after
    • Other antacids (Tums, Maalox) should be separated by at least 3 hours
  • Verify in EMR that patient is scheduled for CMP to assess liver function
    • Consider monthly CMP for the first 3 months then every 3 months as clinically indicated 

Patient Centered Activities:

  • Neratinib should be taken with food and around the same time each day
    • Dose escalation – Take three tablets (120 mg) daily for 7 day, then four tablets (160 mg) daily for 7 days, then six tablets (240 mg) daily
    • Initiation without escalation – Take six tablets (240 mg daily) with loperamide during the first 56 days, then loperamide as needed to maintain daily bowel movements
  • Maintain adequate oral hydration throughout treatment unless otherwise indicated
  • Counsel on other possible side effects
    • Diarrhea (95%)
      • Voucher for 3-months of anti-diarrheal medication from the manufacturer
      • Advise patients to call office if diarrhea is uncontrolled with anti-diarrheal
    • Nausea (43%)
    • Abdominal pain (36%)
    • Vomiting (26%)
    • Stomatitis (14%)
  • Financial Assistance:
  • 3-month voucher available for anti-diarrheal agents
  • Traditional financial assistance for high medication costs available through PumaPatientLynx

References:

  1. NERLYNX® [Package Insert]. Los Angeles, CA: Puma Biotechnology, Inc.
  2. Hurvitz S, Chan A, Iannotti N, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib- associated diarrhea in patients with HER2+ early-stage breast cancer: CONTROL trial. Presented at: 40th Annual San Antonio Breast Cancer Symposium; Dec 5-9, 2017; San Antonio, TX. Poster P3-14-01.
  3. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. Dec 2017;18(12):1688-1700. https://www.ncbi.nlm.nih.gov/pubmed/29146401.
  4. Barcenas CH, Hurvitz SA, Di Palma J, et al. Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. May 31-June 4, 2019; Chicago, IL. J Clin Oncol. 2019;37:(suppl; abstr 548). https://bit.ly/2Xu86DO.

 

Supplemental Information:

Dosing Regimens from CONTROL study:

Loperamide:·      4 mg TID days 1-14, then 4 mg BID days 15-56
Budesonide·      9 mg/day for 1 cycle

·      + loperamide 4 mg TID days 1-14, then 4 mg BID days 15-56

Colestipol·      2 gm BID for 1 cycle + loperamide PRN or

·      + loperamide 4 mg TID days 1-14, then 4 mg BID days 15-28

Neratinib·      120 mg/day on days 1–7, then 160 mg/day on days 8–14,
then 240 mg/day through day 364 or

·      160 mg/day on days 1–14, then 200 mg/day on days 15–28,
then 240 mg/day through day 364

Dose Escalation Regimen:

  • 160 mg (4 tablets) daily days 1-14
  • 200 mg (5 tablets) daily days 15-28
  • 240 mg (6 tablets) daily days 29+

Note: Loperamide was given as needed in this arm of the CONTROL study

 

Dosage Adjustment for Diarrhea:

Grade 1 or 2 (<5 days) or Grade 3 (<2 days)

  • Maximize use of antidiarrheal agents and assess diet and aggravating substances
  • When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose

Grade 2 (>5 days) or Grade 3 (>2 days) or any grade with complicating features of dehydration, fever, hypotension, renal failure, or grade 3/4 neutropenia):

  • Interrupt treatment. Modify diet; maintain fluid intake of ~2 L
  • If diarrhea improves to ≤ grade 1 in 1 week or less, resume neratinib at the same dose
  • If diarrhea improves to ≤ grade 1 in more than 1 week, resume neratinib at the next lower dose
  • When diarrhea has improved to ≤ grade 1 or baseline, initiate

loperamide 4 mg with each subsequent neratinib dose

Recurrent Grade 2 or more occurring at 120 mg once daily dose, or, Grade 4 diarrhea:

  • Permanently discontinue neratinib
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written By: Andrew Kuykendall, MD; Katherine Tobon, PharmD, BCOP; Syeda Saba Kareem PharmD, BCOP
Moffitt Cancer Center

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Description: This PQI will discuss the initiation and management of patients receiving avapritinib for Advanced Systemic Mastocytosis

Background: Avapritinib is a potent tyrosine kinase inhibitor that targets platelet-derived growth factor receptor alpha (PDGFRA) and KIT exon mutants. KIT D816V mutation is expressed in 90-95% of patients with advanced systemic mastocytosis, and results in autophosphorylation and increased survival of neoplastic mast cells. Avapritinib selectively targets and inhibits the autophosphorylation of KIT D816V mutation. Initially approved for the treatment of unresectable and metastatic gastrointestinal stromal tumor (GIST) harboring PDGFRA mutations, avapritinib was approved in June 2021 for adult patients with advanced systemic mastocytosis (AdvSM), a category that includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Avapritinib was approved for AdvSM based on a phase I EXPLORER trial, and a phase 2 PATHFINDER trial which included adult patients with AdvSM (including ASM, SM-AHN, MCL) or relapsed/refractory myeloid malignancies. Fifty-three patients were evaluable for response across the two trials, 47% of patients had prior midostaurin use and 40% had ongoing corticosteroid use.  The overall response rate (ORR) was 57% which included 28% of patients who had complete response (CR) or CR with partial recovery of peripheral blood counts (CRh). The ORR was 72.2% (95% CI 46.5-90.3%) in treatment-naïve patients (n=18) and 48.6% (95%CI 34.1-66^%) in patients with prior antineoplastic therapy including midostaurin (n=35). Median time to response was 2.1 months, and median duration of response was 38.3 months (95% CI: 19 months – not estimable). In the EXPLORER trial, non-traumatic intracranial bleeding (ICB) occurred in 8% of all patients, and in 44% of patients with platelets < 50 x 109/L. Considering this, patients with platelets < 50 x 109/L were excluded from the PATHFINDER trial.

Safety was evaluated in 131 patients in both trials including 80 patients who received the starting dose of 200 mg daily. The most common non-hematological adverse events (incidence >20%) included periorbital edema, peripheral edema, diarrhea, nausea, and fatigue. The most common grade 3 toxicities included anemia, thrombocytopenia, and neutropenia. Dose interruption occurred in 60% of patients and 68% patients required a dose reduction. Among the 749 patients that received avapritinib, intracranial hemorrhage (ICH) occurred in 2.9% of patients; with <1% experiencing a serious ICH. Cognitive effects including memory impairment, cognitive disorder, confusion, delirium, and disorientation occurred in 39% of patients (3% being grade 3 or higher).

 

PQI Process: Upon receiving a prescription for avapritinib:

  • Confirm diagnosis for AdvSM
  • Avapritinib is not recommended for in patients with platelet counts of < 50,000/mm3
  • Verify dose – usual dose for AdvSM is 200 mg orally once daily which differs from usual dose for GIST which is 300 mg orally once daily
    • Dose should be taken on an empty stomach (1-hr prior or 2-hr after a meal)
  • Dose modifications for toxicity (AdvSM patients):
First Dose Reduction100 mg once daily
Second Dose Reduction50 mg once daily
Third Dose Reduction25 mg once daily
Fourth Dose ReductionPermanently discontinue
  • Assess drug-drug interactions
    • Avoid avapritinib administration with moderate or strong CYP3A4 inhibitors or inducers
    • If concomitant use of avapritinib with a moderate CYP3A4 inhibitor is unavoidable, reduce starting dose to avapritinib 50 mg once daily
  • Monitor Platelet Counts
    • Obtain platelet count every 2 weeks for the first 8 weeks
    • After 8 weeks, frequency of platelet count monitoring is dependent on the platelet count at that time:
      • Platelets < 75,000/mm3: monitor every 2 weeks
      • Platelets 75,000 – 100,000/mm3: monitor every 4 weeks
      • Platelets >100,000/mm3: monitor as clinically indicated
    • Dose modification for renal impairment:
      • No dose adjustment is recommended for patients with mild to moderate renal impairment
      • Not studied in patients with creatinine clearance < 30mL/min
    • Dose modification for hepatic impairment:
      • No dose adjustment is recommended for patients with mild to moderate hepatic impairment
      • Not studied in patients with total bilirubin > 3 times ULN
    • Dose modifications for specific adverse reactions

 

 Adverse EffectRecommendation
Intracranial HemorrhageAny Grade

·       Permanently discontinue

Central Nervous System Effects (memory impairment, cognitive disorder, confusion, disturbances in attention, amnesia, mental impairment, mental status changes, dementia, abnormal thinking, mental disorder, and retrograde amnesia)Grade 1

·       Continue avapritinib, reduce dose or withhold treatment until improvement to baseline or resolution of symptoms

·       Resume at same or reduced dose

Grade 2

·       Hold avapritinib until improvement to   baseline, Grade 1 or resolution of symptoms

·       Resume at same or reduced dose

Grade 2 or 3

·       Hold avapritinib until improvement to baseline, Grade 1 or resolution of symptoms

·       Resume at same or reduced dose

Grade 4

·       Permanently discontinue

Thrombocytopenia (platelet < 50,000/mm3)·       Hold avapritinib until resolution (platelet > 50,000/mm3)

·       Resume avapritinib at reduced dose

·       Consider platelet support if platelet counts do not recover (platelet > 50,000/mm3)

Other Grade 3 or 4 Reactions·       Hold until improvement to > Grade 2

·       Resume at same or reduced dose as clinically appropriate

 

Patient Centered Activities:

  • Provide Oral Chemotherapy Education Sheet
  • Counsel patient on proper medication administration
    • Avapritinib should be taken on an empty stomach, at least 1-hr prior to 2-hr after a meal
    • Missed dose can be taken within 8-hours of next scheduled dose
  • Do not repeat dose if vomiting occurs after avapritinib administration
  • Counsel patients on potential drug-drug and drug-food interactions including herbals and grapefruit juice
  • Monitor patient for most common adverse effects
    • Central nervous side effects such as dizziness, trouble sleeping, changes in mood or behavior or any neurological sign or symptom related to intracranial hemorrhage
      • Patient and caregiver should be alert for cognitive changes such as memory loss, forgetfulness, and confusion
    • Other common side effects include edema, fatigue, diarrhea, nausea, vomiting 

Supplemental Information:

  • Patient Support Program: YourBlueprint
    • Dedicated case manager available at 1-888-258-7768 (1-888-BLUPRNT)
    • Monday – Friday 8AM – 8PM ET
  • Co-Pay Assistance Program
    • Eligible, commercially insured patients may reduce their out-of-pocket costs ($0 per month)

 

References:

  1. AYVAKIT® (avapritinib) [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation; June 2021.
  2. Gotlib J, Radia D, George T. Pure Pathologic Response Is Associated with Improved Overall Survival in Patients with Advanced Systemic Mastocytosis Receiving Avapritinib in the Phase I EXPLORER Study Blood (2020) 136 (Supplement 1): 37–38.
  3. DeAngelo DJ, Reiter A, Radia D, et al. CT023 – PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM). Abstract #CT023. Presented at the 2021 American Association for Cancer Research Annual Meeting, April 11, 2021.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written by: Yonatan Resnick, PharmD, New England Cancer Specialists
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Description: This PQI will discuss the development and rationale of the oral DNMT/CDA inhibitor for the management of intermediate-1, intermediate-2, and high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Background: Decitabine/cedazuridine is a fixed-dose combination of the hypomethylating agent decitabine and the cytidine deaminase inhibitor cedazuridine, which prevents degradation of decitabine in the gastrointestinal tract and liver and enables its absorption via oral dosing. The therapy was approved in July 2020.6 It is indicated for the treatment of adult patients with MDS, including previously treated and untreated, de novo and secondary MDS with the following French American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and CMML and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups).  It has long been noted that the development of an oral DNMT inhibitor would alleviate much of the burden associated with the treatment of MDS/CMML for those patients on IV DNMT inhibitors.  Specifically, an oral option would decrease clinic visits, reduce travel time associated with treatment, reduce the need for IV access and the associated infection risks, and decrease exposures to the health care system.  Published data of the phase 1/2 trial as well as preliminary data of the phase 3 trial demonstrates the safety and efficacy of the administration of decitabine plus cedazuridine, administered orally.1,3 It is important to educate the providers in your practice on the rationale behind the approval of decitabine/cedazuridine using the following data. In the phase 3 Study (ASCERTAIN study), presented at ASH 2019 – Compared oral IV decitabine to decitabine/cedazuridine (DEC-C): 138 MDS intermediate or MDS high risk or CMML patients randomized to receive sequence A (DEC-C35/100mg daily x 5 days or IV decitabine 20mg/m2 daily x 5 days) or sequence B (IV decitabine 20mg/m2 daily x 5 days or DEC-C- (35/100mg) daily x 5 days).  All patients then received DEC-C on cycles 3 and onward. The 5 day oral: IV AUC ratio was 99% demonstrating equivalent systemic exposure of the two formulations. LINE 1 demethylation is a PD marker and the difference between IV and PO was < 1%, confirming the PK findings. Overall response rate of 65% (complete response + partial response + marrow CR + hematologic improvement) is in line with what is seen with conventionally dosed IV decitabine. Transfusion independence noted in 50% of patients in phase 2 trial and 32.7% of patients in phase 3 trial. No differences were noted in any common side effects between the IV and PO formulations.

PQI Process:

  • Utilize the reporting tools available in your EMR to identify patients who are receiving IV decitabine for MDS or CMML and discuss the option of converting to oral decitabine/cedazuridine with their physician
    • Do NOT substitute decitabine/cedazuridine for an intravenous decitabine product within a cycle
    • Confirm diagnosis and dosing strategy
  • Educate providers on the availability of a new formulation of decitabine to administer to patients as an alternative to traveling to the clinic for 5 consecutive days for IV infusion
    • Note feasibility and change of clinic visits
  • Upon receiving a prescription for decitabine/cedazuridine:
  • Recommended dosage of is 1 tablet (35 mg decitabine and 100 mg cedazuridine) orally once daily on days 1 through 5 of each 28-day cycle (MIN 4 cycles) until disease progression/unacceptable toxicity
    • A complete or partial response may take longer than 4 cycles
  • Obtain complete blood cell counts and comprehensive metabolic panel prior to initiating therapy and before each cycle
    • Delay the next cycle if absolute neutrophil count (ANC) ≤ 1,000/µL and platelets ≤ 50,000/µL in the absence of active disease. Monitor complete blood cell counts until ANC is ≥ 1,000/µL and platelets ≥ 50,000/µL
    • If hematologic recovery occurs (ANC ≥ 1,000/µL and platelets ≥ 50,000/µL) within 2 weeks of achieving remission, continue at the same dose
    • If hematologic recovery does not occur (ANC ≥ 1,000/µL and platelets ≥ 50,000/µL) within 2 weeks of achieving remission
      • Delay therapy for up to 2 additional weeks AND resume at a reduced dose by administering on Days 1 through 4. Consider further dose reductions if myelosuppression persists after a dose reduction
      • Maintain or increase dose in subsequent cycles as clinically indicated
      • Recommended dose reductions for myelosuppression
        • First dose reduction: 1 tablet orally once daily on Days 1 through 4
        • Second dose reduction: 1 tablet orally once daily on Days 1 through 3
        • Third dose reduction: 1 tablet orally once daily on Days 1, 3 and 5
      • Serum bilirubin or AST/ALT ≥ 2x ULN
        • Delay next cycle and resume at same or reduced dose upon resolution

Patient Centered Activities:

  • Provide Oral Chemotherapy Education Sheet
  • Educate patient on schedule of administration: 5 consecutive days every 4 weeks
    • Consider Monday-Friday (Days 1-5) when defining proper schedule
  • Educate patient not to consume food 2 hours before and 2 hours after each dose
  • Discuss with patient the infectious risks associated with bone marrow suppression and how to mitigate
    • avoiding sick contacts, prompt recognition and reporting of fever, signs and symptoms of bleeding/bruising, feelings of excessive fatigue
  • Educate the patient on when to contact the care team
    • Fever of 100.4 degrees Fahrenheit (38 degrees Celsius)
    • Nausea/vomiting: ensure that patient has adequate anti-nausea medication at home including at least two different medications with different mechanisms of action which can be alternated
    • Unusual bleeding
    • Black/tarry stools
    • Bloody urine
    • Painful mouth sores
  • Discuss the management (dietary/lifestyle/pharmacologic management) of both constipation and diarrhea
  • Monitor lab values before each cycle, focusing on neutropenia
  • Educate patient to avoid taking over the counter medication that can excessively thin blood (acetylsalicylic acid[Aspirin], NSAIDS)

References:

  1. Savona, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol 2019; 6: e194-203
  2. Garcia-Manero, et al. Oral Cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML. Blood April 2013. Epub ahead of print.
  3. Garcia-Manero, et al. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross-Over Phase 3 Study (ASCERTAIN) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine. 61st ASH Annual Meeting, Orlando, FL. Dec 7-10, 2019. Abstract #846.
  4. Aster et al. UpToDate. Clinical manifestations and diagnosis of myelodysplastic syndrome (MDS). Apr, 2020.
  5. Decitabine drug monograph.
  6. Inqovi® (decitabine and cedazuridine) [prescribing information]. Princeton, NJ: Taiho Oncology.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written by: Lauren Trisler, PharmD, BCOP – Carle Cancer Center
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Description: Daratumumab injection is an anti-CD38 monoclonal antibody (mAb) FDA approved for use in a range of multiple myeloma patients including first line, transplant ineligible and relapse/refractory.1 The subcutaneous formulation (DARZALEX FASPRO®) is not indicated for front-line transplant eligible patients but is indicated for varied multiple myeloma indications (review supplemental information for reference)6. This PQI will provide guidance for optimal administration and management of both daratumumab infusions and subcutaneous formulation.

Background: Daratumumab is administered as single agent or in combination with other multiple myeloma treatment options including proteasome inhibitors and immunomodulating agents and is dosed at 16mg/kg.1 One of the most common adverse reactions of daratumumab is infusion reactions of any grade.  The occurrence rate is observed at 37% with the first (16mg/kg, week 1) infusion1 and one study observed occurrence rate rising to 58% in patients did not receive montelukast prior to their first infusion5.The median time to onset of an infusion reaction is 1.5 hours (range 0-73 hours).1  Infusion related reactions often present with symptoms similar to allergic rhinitis such as cough, wheezing and rhinorrhea due to CD-38 expression on airway smooth muscle cells.2 In the CASSIOPEIA trial, when daratumumab was reinitiated post ASCT (at the rate/dilution volume used for the last dose), infusion reaction rates and severity were reported at rates consistent with week 2 (all 11%, Grade 3 or 4 <1%).1 An option to manage infusion reactions is to split the first dose over 2 days.  Daratumumab is administered at a dose of 8mg/kg on days 1 and 2.1 DARZALEX FASPRO® utilizes flat dosing for subcutaneous injection at (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to recommended schedule.6 For monotherapy, the corticosteroid may include methylprednisolone 100 mg or equivalent, with the option to reduce to 60mg after the second infusion.  For combination therapy consider administering 20 mg dexamethasone or equivalent prior to every infusion.  When dexamethasone is the background regimen corticosteroid, this will serve as the daratumumab premedication. Delayed infusion reactions have been noted with daratumumab, and it is recommended to administer corticosteroids the day or two after each daratumumab infusion, unless the background regimen-specific corticosteroid is administered the day after daratumumab.  Consider prescribing post-infusion medications such as short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.1  Due to the low incidence of infusion reactions after the first infusion, a 90-minute infusion of daratumumab has been shown to be safe in patients who have received at least 2 infusions of daratumumab.2 Additional adverse events reported with daratumumab infusions include neutropenia and thrombocytopenia.  These can be managed by dose delays.  Dose reductions are not recommended.  Supportive care with growth factors and transfusions can be considered. Herpes Zoster Virus and Hepatitis B Virus reactivation have both been reported in patients receiving daratumumab in 2-5% and 1% of patients respectively.

 

PQI Process: Prior to the first infusion:

  • Verify concomitant medications to be given with daratumumab and determine the dosing frequency
    • Review Infusion rates, duration and dilution volumes (see Supplemental Information)1,2
  • Ensure orders are placed for premedications – administer 1-3 hours before start of infusion1
    • Corticosteroid-intermediate or long acting such as methylprednisolone 100mg IV
    • Acetaminophen 650 -1000 mg PO
    • Diphenhydramine 25-50 mg IV or PO
  • Consider adding an H2RA and LRA for the first 2-3 infusions3
    • Montelukast (Singular®) 10 mg PO x 1
    • Famotidine 20 mg IV
  • Determine duration and dose of post-infusion corticosteroids
  • Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease
    • Discontinue after 4 infusions if the patient does not experience any major infusion reactions
  • To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is correct between either DARZALEX FASPRO® for subcutaneous injection or DARZALEX® for intravenous infusion
  • Determine if day 1 will be administered as a single dose or a split dose
    • Split doses can be considered for clinics with shorter hours of operation and may result in cost savings if full infusion is not able to be completed due to time constraints or reaction
  • Patients experiencing grades 1-3 infusion reactions can be rechallenged
    • Permanently discontinue for the 3rd occurrence of a grade 3 or any grade 4 infusion reaction1
  • Verify with immunohematology and laboratories/transfusion medicine departments that patient will be receiving CD38 mAbs and provide patient with a wallet card that specifies the blood profile (ABO, Rh and IST) * This should be determined before the first infusion of daratumumab
  • Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting and continue for 3 months following completion of treatment
  • Check hepatitis B status and advise that daratumumab administration could reactivate the virus
  • Infusion set fitted with a flow regulator and an in-line sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (0.22 or 0.2 micrometer) is required
  • Monitor patient for infusion reactions and manage infusion reactions per institutional standards
    • Infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions1

Prior to the second infusion (week 2)

  • Determine if patient experienced an infusion reaction during the previous infusion
    • If no reaction, prepare daratumumab in the week 2 volume of 500mL and administer via the rate titrations listed below for week 2
    • If an infusion reaction occurred during the first infusion, use the dilution volume of 1,000 mL
  • Check CBC for neutropenia and thrombocytopenia regularly during treatment

Prior to the third and subsequent infusions (week 3 and beyond)

  • Determine if patient experienced an infusion reaction during the previous infusion and repeat prior infusion if reaction occurred
  • If no infusion reaction during the second week infusion, rapid administration can be considered
    • Monitor vital signs prior to infusion, every 15 minutes for the first hour, and at the end of the infusion
    • Observe patient for signs and symptoms of an infusion reaction for 30 minutes following rapid infusion

Patient Centered Activities:

  • Counsel patient on disease state, treatment regimen, adverse reactions, and verify understanding
  • Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting and continue for 3 months following completion of treatment
  • Check hepatitis B status and advise that daratumumab administration could cause reactivation
  • Provide patient with treatment calendar outlining planned treatment schedule
  • Provide patient with wallet card detailing blood profile
    • This card should be carried throughout treatment and at least 6 months after treatment ends

 

References:

  1. Darzalex® (daratumumab) [prescribing information]. Horsham, PA: Janssen Biotech; August 2020.
  2. Barr, H., Dempsey, J., Waller, A. et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. Leukemia 32, 2495–2518 (2018). https://doi.org/10.1038/s41375-018-0120-2
  3. Moreau, P., van de Donk, N.W.C.J., Miguel, J.S. et al. Practical Considerations for the Use of Daratumumab, a Novel CD38 Monoclonal Antibody, in Myeloma. Drugs 76, 853–867 (2016). https://doi.org/10.1007/s40265-016-0573-4
  4. Mateos MV, Nahi H, Legiec W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA. Abstract #8005. Presented at the 2019 ASCO Annual Meeting, June 2, 2019; Chicago, IL.
  5. Ajai Chari, Tomer M Mark, Amrita Krishnan, Keith Stockerl-Goldstein, Saad Z Usmani, Anil Londhe, Delores Etheredge, Hollee Parros, Sarah Fleming, Baolian Liu, Scott Freeman, Jon Ukropec, Thomas Lin, Ajay K Nooka; Use of Montelukast to Reduce Infusion Reactions in an Early Access Treatment Protocol of Daratumumab in United States Patients with Relapsed or Refractory Multiple Myeloma. Blood 2016; 128 (22): 2142.
  6. Darzalex Faspro® (daratumumab and hyaluronidase-fihj) [prescribing information]. Horsham, PA: Janssen Biotech; May 2020.

 

Supplemental Information:

Infusion rates, duration and dilution volumes for daratumumab administrations1,2

 Dilution VolumeInitial Rate (1st hour)Rate Increment (absence of reaction)Maximum rateAverage Infusion Duration
Week 1 
Option 1

Single Dose

(16 mg/kg)

1,000 mL50 mL/hour50 mL/hour every hour200 mL/hour7 hours
Option 2

Split Dose

 
Week 1 Day 1

(8 mg/kg)

500 mL50 mL/hour50 mL/hour every hour200 mL/hour4.2 hours
Week 1 Day 2

(8 mg/kg)

500 mL50 mL/hour50 mL/hour every hour200 mL/hour4.2 hours
Week 2 (16mg/kg)500 mL50 mL/hour50 mL/hour every hour200 mL/hour4 hours
Week 3 & Beyond (16mg/kg) 
Option 1, Standard Infusion500 mL100 mL/hour50 mL/hour every hour200 mL/hour3 hours
Option 2,

90 Minute Infusion

500 mL200 mL/hour for 30 minutes (20% of dose) 450 mL/hour over 60 minutes (80% of dose)90 minutes

Indications1,6

Darzalex® (daratumumab) injection, for intravenous useDarzalex Faspro® (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use
For the treatment of adult patients with multiple myeloma:

 

• in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy

 

• in combination with bortezomib, melphalan and prednisone in newly

diagnosed patients who are ineligible for autologous stem cell transplant

 

• in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant

 

• in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy

 

• in combination with carfilzomib and dexamethasone in patients who have received one to three prior lines of therapy

 

• in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor

 

• as monotherapy, in patients 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

For the treatment of adult patients with multiple myeloma:

 

• in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant

 

• in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy

 

• in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy

 

• in combination with pomalidomide and dexamethasone in patients who have received at least one prior therapy including lenalidomide and a proteasome inhibitor

 

• as monotherapy, in patients 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

Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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