DARATUMUMAB Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Effects of Daratumumab on Laboratory Tests Interference with Indirect Antiglobulin Tests (Indirect Coombs Test) 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 <span class="opacity-50 text-xs">[see References (15) ]</span> or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices. Interference with Serum Protein Electrophoresis and Immunofixation Tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO-treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient&apos;s serum, to facilitate determination of a complete response.

DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ]. Patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation. ( 4 )

AND PRECAUTIONS Hypersensitivity and Other Administration Reactions : Permanently discontinue DARZALEX FASPRO for life-threatening reactions. ( 5.1 )

Cardiac

Toxicity in Patients with Light Chain (AL) Amyloidosis : Monitor patients with cardiac involvement more frequently for cardiac adverse reactions and administer supportive care as appropriate. ( 5.2 ) Infections : DARZALEX FASPRO can cause serious and fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.3 ) Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO to allow recovery of neutrophils. ( 5.4 ) Thrombocytopenia : Monitor complete blood cell counts periodically during treatment. Consider withholding DARZALEX FASPRO to allow recovery of platelets. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception. ( 5.6 , 8.1 , 8.3 ) Interference with cross-matching and red blood cell antibody screening : Type and screen patients prior to starting treatment. Inform blood banks that a patient has received DARZALEX FASPRO. ( 5.7 , 7.1 )

5.1 Hypersensitivity and Other Administration Reactions Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

Systemic

Reactions In a pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3%, Grade 3: 0.8%, Grade 4: 0.1%). In patients with high-risk smoldering multiple myeloma (N=193), systemic administration-related reactions occurred in 17% of patients in AQUILA (Grade 2: 7%, Grade 3: 1%). In all patients (N=1639), systemic administration-related reactions occurred in 7% of patients with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 283 systemic administration-related reactions that occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients. Severe reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision. Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.6) ] . Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.6) ] . Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO.

Local

Reactions In this pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193), injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 1.1%. The most frequent (>1%) injection-site reactions were injection site erythema and injection site rash. In patients with high-risk smoldering multiple myeloma (N=193), injection-site reactions occurred in 28% of patients, including Grade 2 reactions in 3%. These local reactions occurred a median of 6 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

5.2 Cardiac Toxicity in Patients with Light Chain (AL)

Amyloidosis

Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions (6.1) ] . Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

5.3 Infections DARZALEX FASPRO can cause serious, life-threatening, or fatal infections. In patients who received DARZALEX FASPRO in a pooled safety population including patients with smoldering multiple myeloma and light chain (AL) amyloidosis (N=1639), serious infections, including opportunistic infections, occurred in 24% of patients, Grade 3 or 4 infections occurred in 22%, and fatal infections occurred in 2.5%. The most common type of serious infection reported was pneumonia (8.5%). Monitor patients for signs and symptoms of infection prior to and during treatment with DARZALEX FASPRO and treat appropriately. Administer prophylactic antimicrobials according to guidelines <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

5.4 Neutropenia Daratumumab may increase neutropenia induced by background therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor complete blood cell counts periodically during treatment according to manufacturer&apos;s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3–4 neutropenia were observed.

5.5 Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor complete blood cell counts periodically during treatment according to manufacturer&apos;s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets.

5.6 Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> . The combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.

5.7 Interference with Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient&apos;s serum <span class="opacity-50 text-xs">[see References (15) ]</span> . The determination of a patient&apos;s ABO and Rh blood type are not impacted <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> . Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> .

5.8 Interference with Determination of Complete Response 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> . This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.