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Daratumumab (interim monograph) DRUG NAME: Daratumumab SYNONYM(S): HuMax CD381 COMMON TRADE NAME(S): Darzalex® CLASSIFICATION: miscellaneous Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Daratumumab is an IgG1ĸ human monoclonal antibody produced in a Chinese hamster ovary cell line. Daratumumab binds to the transmembrane glycoprotein CD38 thus inhibiting the growth of CD38 expressing tumour cells. Mechanism for cell lysis may include direct induction of apoptosis as well as complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. CD38 is 1-4 highly expressed on myeloma cells, but is expressed at low levels on normal lymphoid and myeloid cells. USES: Primary uses: 3 Multiple myeloma Other uses: *Health Canada approved indication SPECIAL PRECAUTIONS: Contraindications: 3 • history of hypersensitivity reaction to daratumumab or Chinese hamster ovary cell proteins Caution: • severe infusion reactions are sometimes reported; pre-medicate with IV corticosteroids, oral antipyretics, and 3 oral/IV antihistamines one hour prior to each infusion. See paragraph following Side Effects table. • antiviral prophylaxis is suggested to prevent herpes zoster reactivation; initiate within 1 week of starting 3 daratumumab and continue for 3 months following treatment 3,5 • daratumumab interferes with antibody screening tests and cross matching; see Interactions SIDE EFFECTS: The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important. ORGAN SITE SIDE EFFECT Clinically important side effects are in bold, italics blood and lymphatic system/ febrile neutropenia anemia (45%, severe 19%) lymphopenia (72%, severe 40%) neutropenia (60%, severe 20%) BC Cancer Agency Cancer Drug Manual Developed: 25 May 2016 Revised: 1 July 2016 © Page 1 of 5 Daratumumab interim monograph Daratumumab (interim monograph) ORGAN SITE SIDE EFFECT Clinically important side effects are in bold, italics gastrointestinal general disorders and administration site conditions immune system infections and infestations metabolism and nutrition musculoskeletal and connective tissue nervous system respiratory, thoracic and mediastinal thrombocytopenia (48%, severe 18%) 6 emetogenic potential: low constipation (15%) diarrhea (16%, severe 1%) nausea (27%) vomiting (14%) 7 extravasation hazard: none chills (10%) fatigue (39%, severe 2%) 3,8 physical health deterioration (3%) pyrexia (21%, severe 1%) infusion reaction; initial infusion (48%, severe 3%); second infusion (5%); subsequent 3,8 infusions (4%) ; see paragraph following Side Effects table 8 herpes zoster (3%) nasopharyngitis (15%) pneumonia; including streptococcal and lobar pneumonia (11%, severe 6%) upper respiratory tract infection (20%, severe 1%) appetite decrease (15%, severe 1%) arthralgia (17%) back pain (23%, severe 2%) musculoskeletal chest pain (12%, severe 1%) pain in extremity (15%, severe 1%) headache (12%, severe 1%) cough (21%) dyspnea (15%, severe 1%) nasal congestion (17%) vascular hypertension (10%, severe 5%) Adapted from standard reference3 unless specified otherwise. Serious adverse reactions are reported in 33% of patients, most frequently pneumonia, general physical health 3 deterioration, and pyrexia. Grade 3-4 laboratory abnormalities are reported in more than 10% of patients. Approximately half of all patients experience an infusion-related reaction. Most reactions occur during the first infusion, however reactions are reported with all infusions. None of the reactions with second or subsequent infusions were rated as Grade 3 or higher severity. Reactions typically occur during the infusion itself or within 4 hours after the infusion is completed. Common symptoms include nasal congestion, cough, chills, allergic rhinitis, larynx or throat tightness/irritation, dyspnea, and nausea. Severe symptoms include bronchospasm, hypoxia, 3,8 dyspnea, and hypertension. Premedicate with intravenous corticosteroid, oral antipyretic, and oral/intravenous antihistamine one hour prior to every infusion of daratumumab. Steroid dose may be decreased following the second infusion. Post-infusion oral corticosteroids are recommended for all patients on days 2 and 3 of each cycle to prevent delayed reactions. Follow incremental infusion rate closely for each cycle and monitor patients during the entire infusion. Interrupt daratumumab for infusion reactions of any grade/severity and manage symptoms. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. When re-challenging, rd permanently discontinue daratumumab following the 3 occurrence of a Grade 3 reaction. Permanently discontinue 3 daratumumab for any life threatening (Grade 4) reaction. BC Cancer Agency Cancer Drug Manual Developed: 25 May 2016 Revised: 1 July 2016 © Page 2 of 5 Daratumumab interim monograph Daratumumab (interim monograph) Patients with a history of obstructive pulmonary disorder may require additional inhaled corticosteroids and bronchodilators post-daratumumab infusion to manage respiratory complications. Post-infusion medications may be 3,5,8 discontinued If no major infusion reactions are reported following the first four infusions. INTERACTIONS: AGENT EFFECT MECHANISM MANAGEMENT Coombs test (Indirect 3,5 Antiglobulin Test) false positive test result for up to 6 months after last infusion; detection of antibodies to minor antigens may also be affected false positive test results for patients with IgGĸ Mprotein which may affect ability to evaluate response to treatment binding of daratumumab to CD38 on red blood cells. • type and screen patients prior to starting daratumumab • notify blood bank as needed for transfusion. detection of daratumumab by SPE or IFE assays • additional tests may be required to evaluate response. Serum protein electrophoresis (SPE) and immunofixation (IFE) 3 assays SUPPLY AND STORAGE: Injection: Janssen Biotech, Inc (USA). supplies daratumumab as single-dose vials (100mg/5mL and 400mg/20mL) 3,8 at a concentration of 20 mg/mL. Refrigerate. Protect from light. Do not shake. For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix. SOLUTION PREPARATION AND COMPATIBILITY: For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix. Additional information: • administer with a low protein binding in-line filter (0.22 or 0.2 micron) 8 • infusion should be completed within 15 hours 8 • do not mix with or infuse with other medications 8 Compatibility: consult detailed reference PARENTERAL ADMINISTRATION: BCCA administration guideline noted in bold, italics Subcutaneous no information found Intramuscular Direct intravenous no information found 8 do NOT use BC Cancer Agency Cancer Drug Manual Developed: 25 May 2016 Revised: 1 July 2016 © Page 3 of 5 Daratumumab interim monograph Daratumumab (interim monograph) BCCA administration guideline noted in bold, italics 3 Continuous infusion over 3.25-15 hours (refer to protocol by which patient is being treated). In the absence of other guidelines, follow incremental infusion rate as below: Dilution Initial rate Rate Maximum volume (first hour) increment rate st 1 infusion 1000 mL 50 mL/h 50 mL/h 200 mL/h every hour nd a 2 infusion 500 mL 50 mL/h 50 mL/h 200 mL/h every hour 500 mL 100 mL/h 50 mL/h subsequent 200 mL/h b infusions every hour no information found Intraperitoneal Intrapleural no information found no information found Intrathecal Intra-arterial no information found no information found Intravesical no information found Intermittent infusion a b Escalate only if there are no Grade 1 or greater infusion reactions during the first 3 hours of the first infusion Escalate only if there are no Grade 1 or greater infusion reactions during a final infusion rate of ≥100mL/hr in the first 2 infusions DOSAGE GUIDELINES: Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities. Adults: BCCA usual dose noted in bold, italics Cycle Length: 4 weeks: 2,3 Intravenous: Cycles 1 and 2: 16 mg/kg IV for one dose on days 1, 8, 15, and 22 Cycles 3 through 6: 16mg/kg IV for one dose on days 1 and 15 Subsequent cycles: 16mg/kg IV for one dose on day 1 3 Dose in renal failure: no starting dose adjustment necessary 3 • no dose adjustment for mild impairment (total bilirubin 11.5X ULN OR AST > ULN); • no information found for moderate or severe impairment Dose in hepatic failure: BC Cancer Agency Cancer Drug Manual Developed: 25 May 2016 Revised: 1 July 2016 © Page 4 of 5 Daratumumab interim monograph Daratumumab (interim monograph) REFERENCES: 1. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N.Engl.J.Med. 2015;373(13):1207-1219. 2. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016. 3. Genentech Inc. DARZALEX® full prescribing information. Horsham, PA, USA; Nov 2015. 4. Laubach JP, Richardson PG. CD38-Targeted Immunochemotherapy in Refractory Multiple Myeloma: A New Horizon. Clin.Cancer Res. 2015;21(12):2660-2662. 5. van de Donk NW, Moreau P, Plesner T, et al. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood 2016;127(6):681-695. 6. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 Mar 2012. 7. BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 November 2014. 8. Lexicomp Online® (database on the Internet). Daratumumab. Lexi-Comp Inc., 17 November 2015. Available at: http://online.lexi.com. Accessed 15 March 2016. BC Cancer Agency Cancer Drug Manual Developed: 25 May 2016 Revised: 1 July 2016 © Page 5 of 5 Daratumumab interim monograph