Darzalex®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DARAHEX® (DARZALEX®)

Composition:

active substance: daratumumab;

1 ml of concentrate contains 20 mg of daratumumab;

excipients: glacial acetic acid; mannitol (E 421); polysorbate 20; sodium acetate, trihydrate; sodium chloride; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: solution from colorless to yellow.

Pharmacotherapeutic group. Antineoplastic agents. Other antineoplastic agents. Monoclonal antibodies. Daratumumab. ATC code L01X C24.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Daratumumab is a human IgG1-kappa monoclonal antibody that binds to the CD38 protein, which is highly expressed on the surface of multiple myeloma tumor cells, as well as at varying levels on cells and tissues of other types. The CD38 protein performs several functions, such as receptor-mediated adhesion, signaling, and enzymatic activity.

It has been demonstrated that daratumumab strongly inhibits in vivo tumor cell growth expressing CD38. Based on in vitro studies, daratumumab may mediate several effector functions resulting in immune-mediated tumor cell death. These studies suggest that daratumumab may induce tumor cell lysis through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis in malignant tumors expressing CD38. As a result of daratumumab-mediated cell lysis, the numbers of myeloid-derived suppressor cell subsets (CD38+MDSC), regulatory T-cells (CD38+Tregs), and B-cells (CD38+Bregs) are reduced. It is known that T-cells (CD3+, CD4+, and CD8+) express CD38 depending on the stage of development and level of activation. Treatment with daratumumab was associated with a significant increase in the absolute number of CD4+ and CD8+ T-cells, as well as the percentage of lymphocytes in peripheral blood and bone marrow. Furthermore, T-cell receptor DNA sequencing confirmed increased T-cell clonality with daratumumab treatment, indicating its immunomodulatory effect, which may contribute to clinical response.

Daratumumab induced apoptosis in vitro following Fc-mediated cross-linking. In addition, daratumumab altered CD38 enzymatic activity by inhibiting cyclase activity and stimulating hydrolase activity. The clinical relevance of these in vitro effects and their impact on tumor growth are not fully understood.

Natural killer (NK) cells and T-cells.

It is known that NK cells express CD38 and are susceptible to daratumumab-mediated cell lysis. During daratumumab treatment, a reduction in the absolute number and percentage of total NK cells (CD16+ CD56+) and activated (CD16+ CD56dim) NK cells was observed in peripheral blood and bone marrow. However, baseline NK cell levels did not correlate with clinical response.

Immunogenicity.

In patients receiving daratumumab as monotherapy (n = 199) or in combination therapy (n = 412), anti-daratumumab antibody levels were assessed several times during treatment and up to 8 weeks after treatment completion. After initiation of daratumumab treatment, no anti-daratumumab antibodies were detected in the monotherapy group; whereas, in 2 of 412 patients in the combination therapy group, positive results for anti-daratumumab antibodies were recorded. One patient in the combination therapy group developed transient neutralizing antibodies to daratumumab.

However, the assay used has limitations in detecting anti-daratumumab antibodies in the presence of high drug concentrations. Therefore, an accurate assessment of the frequency of antibody development cannot be reliably determined.

Clinical efficacy and safety.

Newly diagnosed multiple myeloma.

Combination therapy with bortezomib, melphalan, and prednisone (VMP) in patients ineligible for autologous stem cell transplantation.

An open-label, randomized, controlled phase III study MMY3007 compared treatment with Darzalex® at a dose of 16 mg/kg in combination with bortezomib, melphalan, and prednisone (D-VMP) versus VMP therapy in patients with newly diagnosed multiple myeloma. Bortezomib was administered subcutaneously at a dose of 1.3 mg/m² body surface area twice weekly during weeks 1, 2, 4, and 5 of the first 6-week cycle (cycle 1; 8 doses), followed by once weekly administration during weeks 1, 2, 4, and 5 of eight additional 6-week cycles (cycles 2–9; 4 doses per cycle). Melphalan at a dose of 9 mg/m² and prednisone at a dose of 60 mg/m² were administered orally on days 1–4 during nine 6-week cycles (cycles 1–9). Darzalex® treatment continued until disease progression or unacceptable toxicity.

A total of 706 patients were randomized: 350 to the D-VMP group and 356 to the VMP group. The median age of patients was 71 years (range: 40–93 years), with 30% of patients aged 75 years or older. The majority were of Caucasian race (85%), 54% were female, 25% had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 50% had a score of 1, and 25% had a score of 2. The myeloma protein was IgG/IgA/light chain in 64%/22%/10% of patients, respectively; 19% of patients had stage I disease according to the International Staging System (ISS), 42% had stage II, and 38% had stage III. Standard cytogenetic risk was observed in 84% of patients. Treatment efficacy was evaluated based on progression-free survival (PFS) data according to the criteria of the International Myeloma Working Group (IMWG).

The primary PFS analysis in study MMY3007 demonstrated improved outcomes in the D-VMP group compared to the VMP group; median PFS was not reached in the D-VMP group and was 18.1 months in the VMP group (hazard ratio [HR] = 0.5; 95% CI: 0.38, 0.65; p < 0.0001), representing a 50% reduction in the risk of disease progression or death for patients receiving D-VMP therapy. Updated PFS analysis approximately 4 months after the end of data collection continued to show improved PFS in the D-VMP group compared to the VMP group. Median PFS was not reached in the D-VMP group and was 19.3 months in the VMP group (HR = 0.46; 95% CI: 0.36, 0.60; p < 0.0001).

Additional efficacy results from study MMY3007 are presented in Table 1 below.

Table 1

Additional efficacy results from study MMY3007a

sCR – stringent complete response; CR – complete response; VGPR – very good partial response; PR – partial response; MRD – minimal residual disease.

a Based on the intent-to-treat population.

b p-value based on the Cochran–Mantel–Haenszel chi-square test.

c Based on a threshold value of 10-5.

d The Mantel–Haenszel test was used to estimate the overall risk ratio for stratified tables. A risk ratio > 1 indicates superiority of D-VMP.

e p-value based on Fisher’s exact test.

In patients who achieved a response to treatment, the median time to response was 0.79 months (range: 0.4–15.5 months) in the D-VMP group and 0.82 months (range: 0.7–12.6 months) in the VMP group. The median duration of response had not been reached in the D-VMP group and was 21.3 months (range: 18.4, not estimable) in the VMP group.

An analysis was conducted in a subgroup of patients aged ≥70 years or aged 65–69 years with ECOG performance status of 2, or aged <65 years with significant comorbidities or ECOG performance status of 2 (n = 273 in the D-VMP group, n = 270 in the VMP group). Efficacy results in this subgroup were comparable to those in the overall population. In this subgroup, the median PFS had not been reached in the D-VMP group and was 17.9 months in the VMP group (hazard ratio [HR] = 0.56; 95% CI: 0.42, 0.75; p<0.0001). The overall response rate was 90% in the D-VMP group and 74% in the VMP group (VGPR: 29% in the D-VMP group vs. 26% in the VMP group; CR: 22% in the D-VMP group vs. 18% in the VMP group; sCR: 20% in the D-VMP group vs. 7% in the VMP group). Safety results in this subgroup were comparable to those in the overall population. Furthermore, safety results in patients with ECO游戏副本

1 Primary efficacy endpoint (International Myeloma Working Group criteria)

CI – confidence interval; NR – not reached; MR – minimal response

The overall response rate (ORR) in study MMY2002 was similar regardless of prior myeloma therapy type.

With updated survival data and a median follow-up duration of 14.7 months, the median overall survival (OS) was 17.5 months (95% CI: 13.7, NR).

In study GEN501, 42 patients with relapsed and refractory multiple myeloma received Darzalex® at a dose of 16 mg/kg until disease progression. The median patient age was 64 years (range 44–76 years), 64% were male, and 76% were Caucasian. Patients had received a median of 4 prior lines of therapy. Seventy-four percent of patients had previously undergone autologous stem cell transplantation. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%), and carfilzomib (19%). At baseline, 76% of patients had disease refractory to their last line of treatment, 64% were refractory to both a proteasome inhibitor and an immunomodulatory agent, 60% to alkylating agents, 36% to pomalidomide, and 17% to carfilzomib.

A pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg resulted in a 36% ORR, with 5% CR and 5% VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not reached (95% CI: 5.6 months, NR).

With updated survival data and a median follow-up duration of 15.2 months, the median overall survival had not been reached (95% CI: 19.9 months, NR), and 74% of patients were still alive.

Combination therapy with lenalidomide

An open-label, randomized, active-controlled Phase III study (MMY3003) compared treatment with Darzalex® at a dose of 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) versus lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed or relapsed/refractory multiple myeloma who had received at least one prior line of therapy. Lenalidomide (25 mg once daily orally on days 1–21 of repeated 28-day [4-week] cycles) was administered with low-dose dexamethasone 40 mg weekly (or reduced to 20 mg weekly for patients aged ≥75 years or with body mass index <18.5). On Darzalex® infusion days, dexamethasone 20 mg was administered prior to infusion, and the remainder was given on the day after infusion. Treatment continued in both groups until disease progression or unacceptable toxicity.

A total of 569 patients were randomized: 286 to the DRd group and 283 to the Rd group. The median patient age was 65 years (range: 34 to 89 years), and 11% of patients were aged ≥75 years. The majority of patients (86%) had previously received a proteasome inhibitor, 55% had previously received an immunomodulatory agent (including 18% who had received prior lenalidomide), and 44% had received both a proteasome inhibitor and an immunomodulatory agent. At baseline, 76% of patients had disease refractory to their last line of therapy, 18% were refractory only to a proteasome inhibitor, and 21% were refractory to bortezomib. Patients with lenalidomide-refractory disease were not eligible for inclusion in the study.

Study MMY3003 demonstrated improved PFS in the DRd group compared to the Rd group; median PFS was not reached in the DRd group versus 18.4 months in the Rd group (hazard ratio [HR] = 0.37; 95% CI: 0.27, 0.52; p < 0.0001), representing a 63% reduction in the risk of disease progression or death for patients receiving DRd.

Additional efficacy results from study MMY3003 are presented in Table 3 below.

Table 3

Additional efficacy results from study MMY3003.

MRD – minimal residual disease; CI – confidence interval; NR – not reached.

a p-value based on the Cochran-Mantel-Haenszel chi-square test.

b. Based on the population included in the trial with a threshold of 10-4.

c Chi-square test determines the ratio of overall risks. A risk ratio > 1 indicates advantage for DRd.

d p-value based on the likelihood ratio chi-square test.

Median OS has not been reached in either treatment group. With an overall average follow-up duration of 13.5 months, the hazard ratio for OS was 0.64 (95% CI: 0.40, 1.01; p = 0.0534).

Combination therapy with bortezomib.

In an open-label, randomized, controlled Phase III study MMY3004, treatment with Darzalex® at a dose of 16 mg/kg in combination with bortezomib and dexamethasone (DVd) was compared to treatment with bortezomib and dexamethasone (Vd) in patients with newly diagnosed or refractory multiple myeloma who had received at least one line of therapy. Bortezomib was administered via subcutaneous injection or intravenous infusion at a dose of 1.3 mg/m2 body surface area twice weekly for 2 weeks (on days 1, 4, 8, and 11), repeated in 21-day cycles (3 weeks), for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib treatment cycles (80 mg/week during two out of three weeks of the bortezomib cycle), or at a reduced dose of 20 mg weekly for patients aged over 75 years, with body mass index <18.5, poorly controlled diabetes, or steroid intolerance. On days of Darzalex® infusion, dexamethasone at a dose of 20 mg was administered prior to infusion. Darzalex® treatment continued until disease progression or the development of unacceptable toxicity.

A total of 498 patients were randomized: 251 to the DVd group and 247 to the Vd group. Baseline demographic and disease characteristics were comparable between the two groups. The median patient age was 64 years (range 30 to 88 years); 12% of patients were aged ≥75 years. A total of 69% of patients had previously received a proteasome inhibitor (66% had received bortezomib), and 76% had received an immunomodulatory agent (42% had received lenalidomide). At baseline, 32% of patients had disease refractory to their last line of therapy, 33% were refractory only to an immunomodulatory agent, and 28% were refractory to lenalidomide. Patients with bortezomib-refractory disease were not allowed to participate in the study.

Study MMY3004 demonstrated improved PFS in the DVd group compared to the Vd group; median PFS was not reached in the DVd group and was 7.2 months in the Vd group (HR [95% CI]: 0.39 [0.28, 0.53], p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death in patients receiving DVd compared to Vd.

Table 4

Additional efficacy results from study MMY3004.

MRD – minimal residual disease; CI – confidence interval; na – not assessed.

a p-value based on the Cochran-Mantel-Haenszel chi-square test.

b Based on the intent-to-treat population and a boundary value of 10-4.

c Chi-square test determines the risk ratio. A risk ratio > 1 indicates an advantage for DVd.

d p-value based on the likelihood ratio chi-square test.

Median OS was not reached in either treatment group. With an overall median follow-up duration of 7.4 months (95% CI: 0.0, 14.9), the hazard ratio for OS was 0.77 (95% CI: 0.47, 1.26; p = 0.2975).

Cardioelectrophysiology.

Since daratumumab is a human IgG1-kappa monoclonal antibody, there is a low probability of direct interaction with ion channels. The effect of daratumumab on the QTc interval was evaluated in an open-label study involving 83 patients (study GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (at doses of 4–24 mg/kg). Linear mixed pharmacokinetic-pharmacodynamic analyses showed no significant increase in mean QTcF interval (i.e., >20 msec) at the maximum concentration (Cmax) of daratumumab.

Pharmacokinetics.

The pharmacokinetics of daratumumab after intravenous administration at doses ranging from 0.1 mg/kg to 24 mg/kg as monotherapy were evaluated in patients with relapsed and refractory multiple myeloma.

In cohorts receiving doses from 1 to 24 mg/kg, maximum serum concentration (Cmax) after the first dose increased approximately dose-proportionally, and the volume of distribution corresponded to initial distribution within the plasma compartment. After the last weekly infusion, Cmax of daratumumab increased more than dose-proportionally, consistent with target-mediated drug disposition. AUC increased more than dose-proportionally, and clearance decreased with increasing dose. These observations suggest that CD38 saturation may occur at higher doses of daratumumab, after which target-binding-dependent clearance effects are minimized and daratumumab clearance approaches the linear clearance of endogenous IgG1. Clearance also decreases with repeated dosing, which may be related to reduced tumor burden.

With increasing dose and repeated administration, the terminal-phase half-life of daratumumab increases. The mean (standard deviation [SD]) terminal-phase half-life of daratumumab after the first 16 mg/kg dose was 9 (4.3) days. The terminal-phase half-life after the last 16 mg/kg dose increased, but data were insufficient for proper assessment. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days; this represents the terminal-phase half-life expected upon complete saturation of target-mediated clearance and with repeated dosing of daratumumab.

At the end of weekly administration under the recommended monotherapy regimen of 16 mg/kg, the mean (SD) Cmax of daratumumab in serum was 915 (410.3) µg/mL, approximately 2.9 times higher than after the first infusion. The mean (trough) serum concentration of daratumumab prior to administration of the next dose at the end of weekly administration was 573 (331.5) µg/mL.

To describe the pharmacokinetic characteristics of daratumumab and to evaluate the impact of covariates on its pharmacokinetic profile in patients with multiple myeloma, three population pharmacokinetic analyses were conducted: Analysis 1 (n=223) included patients receiving Darzalex® as monotherapy, while Analyses 2 (n=694) and 3 (n=352) included patients with multiple myeloma receiving daratumumab in combination therapy. Analysis 2 included 694 patients (n=326 in the lenalidomide + dexamethasone group, n=246 in the bortezomib + dexamethasone group, n=99 in the pomalidomide + dexamethasone group, n=11 in the bortezomib + melphalan + prednisone group, and n=12 in the bortezomib + thalidomide + dexamethasone group).

Analysis 3 included 352 patients (bortezomib + melphalan + prednisone group).

Based on the pharmacokinetic analysis of daratumumab monotherapy, steady-state concentrations of daratumumab are achieved after approximately 5 months within each 4-week cycle (by the 21st infusion), and the mean (SD) ratio of steady-state Cmax to Cmax after the first dose was 1.6 (0.5). The mean (SD) volume of distribution in the central compartment was 56.98 (18.07) mL/kg.

Two additional pharmacokinetic analyses were conducted in patients with multiple myeloma receiving daratumumab in combination therapy. Concentration-time profiles of daratumumab were similar after monotherapy and combination therapy. The mean estimated terminal-phase half-life associated with linear clearance in combination therapy was approximately 22–23 days.

Based on the results of the three population pharmacokinetic analyses, body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, weight-based dosing is an appropriate strategy for patients with multiple myeloma.

Special patient groups

Effect of age and sex.

Based on results from three population pharmacokinetic analyses in patients receiving daratumumab monotherapy or daratumumab in combination with various agents, age (range 31–93 years) had no clinically significant effect on the pharmacokinetics of daratumumab, and daratumumab exposure was comparable between younger (≤65 years, n=515) and older patients (>65 to ≤75 years, n=562; >75 years, n=181).

Sex had no clinically significant effect on daratumumab exposure.

Patients with renal impairment.

Formal studies of daratumumab in patients with renal impairment have not been conducted. Three population pharmacokinetic analyses were performed based on prior data on renal function in patients receiving daratumumab monotherapy or daratumumab in combination with various agents. These analyses included a total of 381 patients with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 480 patients with mild renal impairment (CRCL <90 and ≥60 mL/min), 376 patients with moderate renal impairment (CRCL <60 and ≥30 mL/min), and 20 patients with severe renal impairment or end-stage renal disease (CRCL <30 mL/min). There were no clinically significant differences in daratumumab exposure between patients with renal impairment and those with normal renal function.

Patients with hepatic impairment.

Formal studies of daratumumab in patients with hepatic impairment have not been conducted. Hepatic function changes are unlikely to affect daratumumab elimination, as IgG1-kappa molecules such as daratumumab are not metabolized via hepatic metabolic pathways.

Three population pharmacokinetic analyses were conducted in patients receiving daratumumab monotherapy or daratumumab in combination with various agents. These analyses included a total of 1081 patients with normal hepatic function (total bilirubin and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 159 patients with mild hepatic impairment (total bilirubin 1.0–1.5 × ULN or AST > ULN), and 7 patients with moderate (total bilirubin >1.5–3.0 × ULN; n=6) or severe hepatic impairment (total bilirubin >3.0 × ULN; n=1). There were no clinically significant differences in daratumumab exposure between patients with hepatic impairment and those with normal hepatic function.

Race.

Results from three population pharmacokinetic analyses in patients receiving daratumumab monotherapy or daratumumab in combination with various agents indicate that daratumumab exposure was comparable in Caucasian patients (n=1046) and patients of other racial groups (n=212).

Clinical characteristics.

Indications.

Darzalex® is indicated:

• in combination with bortezomib, melphalan, and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplantation;
• as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have had disease progression on the last therapy;
• in combination with lenalidomide and dexamethasone, or with bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Since daratumumab is a human IgG1-kappa monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism are unlikely to be major pathways of elimination of the unchanged drug. Therefore, changes in drug-metabolizing enzymes are not expected to affect the elimination of daratumumab. Due to its high specificity for a unique epitope on CD38, daratumumab is not expected to affect drug-metabolizing enzymes.

Clinical pharmacokinetic assessments of pomalidomide, thalidomide, and bortezomib did not demonstrate clinically significant drug interactions between Darzalex® and these medicinal products used in combination therapy.

Effect on indirect antiglobulin test (indirect Coombs test) results

Daratumumab binds to CD38 on red blood cells and interferes with compatibility testing, including antibody screening and cross-matching (see section "Special precautions"). Methods to overcome the interference caused by daratumumab with red blood cells include treatment of reagent red blood cells with dithiothreitol (DTT) to disrupt binding to daratumumab, or other locally validated methods. Since DTT may affect Kell blood group system typing, Kell-negative blood units should be provided after exclusion or identification of alloantibodies using DTT-treated red blood cells. Additionally, consideration should be given to performing phenotyping or genotyping (see section "Special precautions").

Effect on serum protein electrophoresis and immunofixation electrophoresis test results

Daratumumab can be detected by serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) assays used to monitor monoclonal immunoglobulins (M-protein). This may lead to false-positive results in SPE and IFE assays in patients with IgG-kappa myeloma protein, thereby affecting the initial assessment of complete response according to the International Myeloma Working Group (IMWG) criteria. To facilitate determination of complete response in patients with sustained very good partial response in whom daratumumab interference with assay results is suspected, a validated daratumumab-specific IFE assay should be considered to differentiate daratumumab from residual endogenous M-protein in the patient's serum.

Special precautions.

Infusion reactions.

DARZALEX® may cause severe infusion reactions (IRs), including anaphylactic reactions (see section "Side effects").

Patients should be monitored for the occurrence of IRs during administration. Monitoring of patients who experience IRs of any severity should continue until symptoms resolve.

In clinical trials, IRs were reported in approximately half of all patients receiving DARZALEX®.

Most IRs occurred during the first infusion and were of Grade 1–2 severity (see section "Side effects"). IRs occurred in 4% of all patients during more than one infusion. Serious reactions were observed, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema, and pulmonary edema. Symptoms primarily included nasal congestion, cough, throat irritation, chills, vomiting, and nausea. Less common symptoms included wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension (see section "Side effects").

Prior to administration of DARZALEX®, patients should be premedicated with antihistamines, antipyretics, and corticosteroids to reduce the risk of IRs. Infusion of DARZALEX® should be interrupted in the event of an IR of any severity, and appropriate treatment/supportive care for IRs should be initiated as needed. For patients with Grade 1, 2, or 3 IRs, upon resumption of infusion, the infusion rate should be reduced. In the event of an anaphylactic reaction or life-threatening (Grade 4) reaction, appropriate resuscitation measures should be initiated immediately. Treatment with DARZALEX® should be discontinued permanently and immediately (see section "Dosage and administration" and section "Contraindications").

To reduce the risk of delayed-type IRs, all patients should be prescribed oral corticosteroids after DARZALEX® administration. Additionally, post-infusion medications (e.g., inhaled corticosteroids, short- and long-acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications if they occur (see section "Dosage and administration").

Neutropenia/thrombocytopenia.

DARZALEX® may exacerbate neutropenia and thrombocytopenia caused by concomitant therapy (see section "Side effects").

Complete blood counts should be performed periodically during treatment, according to the instructions for use of concomitant medications. Patients with neutropenia should be monitored for signs of infection. Treatment with DARZALEX® may need to be interrupted to allow recovery of white blood cell counts. Dose reduction of DARZALEX® is not recommended. Supportive therapy such as blood transfusions or growth factors should be considered as needed.

Effect on indirect antiglobulin test (indirect Coombs test) results.

Daratumumab binds to CD38 expressed at low levels on red blood cells, which may lead to a positive indirect Coombs test. A daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab infusion. It should be recognized that daratumumab binding to red blood cells may mask the detection of antibodies to minor blood group antigens in patient serum. Administration of the drug does not affect ABO and Rh blood group typing.

Patients should be phenotyped and screened prior to starting daratumumab therapy. Phenotyping should be performed before initiating daratumumab treatment, according to local practice. Daratumumab does not interfere with red blood cell genotyping; therefore, genotyping can be performed at any time.

In case of planned blood transfusion, blood banks should be informed about the potential interference of the drug with the indirect antiglobulin test (see section "Interaction with other medicinal products and other forms of interaction"). In case of emergency transfusion, local blood banks may provide ABO/RhD-compatible red blood cell units without cross-match testing.

Effect on assessment of complete response.

Daratumumab is a human IgG-kappa monoclonal antibody that can be detected by serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE), which are used for clinical monitoring of endogenous M-protein (see section "Interaction with other medicinal products and other forms of interaction"). This interference may affect the determination of complete response and disease progression in some patients with IgG-kappa myeloma protein.

Excipients.

Each 5 ml and 20 ml vial of DARZALEX® contains 0.4 mmol and 1.6 mmol (9.3 mg and 37.3 mg) of sodium, respectively. This corresponds to 0.46% and 1.86% of the WHO recommended maximum daily intake of 2 g of sodium for adults, respectively.

Traceability.

To improve traceability of biological medicinal products, the trade name and batch number of the administered product should be recorded.

Use during pregnancy and breastfeeding.

Women of childbearing potential / contraception.

Women of childbearing potential should use effective contraception during treatment and for 3 months after discontinuation of daratumumab therapy.

Pregnancy.

There are no data from studies evaluating the risk of daratumumab use during pregnancy in humans or animals. It is known that IgG1 monoclonal antibodies cross the placenta after the first trimester of pregnancy. Therefore, daratumumab should not be used during pregnancy unless the expected benefit to the woman outweighs the potential risk to the fetus. If a patient becomes pregnant while receiving this medicinal product, she should be informed of the potential risk to the fetus.

Breastfeeding.

It is unknown whether daratumumab is excreted in human or animal breast milk.

Maternal IgG is excreted in breast milk but is not absorbed in significant amounts into the systemic circulation of newborns and infants, as it is degraded in the gastrointestinal tract.

The effect of daratumumab on newborns/infants is unknown. The decision to discontinue breastfeeding or discontinue DARZALEX® therapy should be made considering the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

There are no data available on the potential effect of daratumumab on fertility in men and women.

Ability to affect reaction speed when driving and operating machinery.

DARZALEX® has no or negligible effect on the ability to drive and use machinery. However, fatigue has been reported in patients receiving daratumumab, and this should be taken into account when driving or operating machinery.

Method of Administration and Dosage

Darzalex® must be administered by a physician in a setting where resuscitation equipment is available.

To reduce the risk of infusion reactions (IR), appropriate concomitant medications should be administered before and after daratumumab infusion. See below "Recommended Concomitant Therapy," "Management of Infusion Reactions," and section "Special Precautions."

Dosage

Newly Diagnosed Multiple Myeloma

Darzalex® regimen in combination with bortezomib, melphalan, and prednisone (treatment schedule consisting of 6-week cycles) for patients who are not candidates for autologous stem cell transplantation: the recommended dose of Darzalex® is 16 mg/kg body weight. The drug is administered as intravenous infusions according to the schedule outlined in Table 5.

Table 5

Dosage schedule for Darzalex® in combination with bortezomib, melphalan, and prednisone ([VMP regimen (bortezomib [Velcade], melphalan, and prednisone)]; treatment schedule consisting of 6-week cycles).

a The first dose of the regimen in each 3-week cycle is administered in week 7.

b The first dose of the regimen in each 4-week cycle is administered in week 55.

Bortezomib is administered twice weekly in weeks 1, 2, 4, and 5 during the first 6-week cycle, followed by once weekly in weeks 1, 2, 4, and 5 for an additional eight 6-week cycles. For information on drug dosing within the VMP regimen and its administration schedule in combination with Darzalex®, see section "Pharmacodynamics".

Recurrent/Refractory Multiple Myeloma.

Darzalex® administration schedule as monotherapy and in combination with lenalidomide (treatment schedule consisting of 4-week cycles): the recommended dose of Darzalex® is 16 mg/kg body weight. The medicinal product is administered by intravenous infusion according to the schedule presented in Table 6.

Table 6

Administration schedule of Darzalex® as monotherapy and in combination with lenalidomide (treatment schedule consisting of 4-week cycles).

a The first dose of the regimen in each 2-week cycle is administered in week 9.

b The first dose of the regimen in each 4-week cycle is administered in week 25.

For information on dosing and administration schedule of drugs used in combination with DARZALEX®, see section "Pharmacodynamics" and the respective Summary of Product Characteristics of those medicinal products.

Dosing regimen in combination with bortezomib (3-week cycle regimen):

the recommended dose of DARZALEX® is 16 mg/kg body weight. The medicinal product is administered by intravenous infusion according to the schedule outlined in Table 7.

Table 7

Dosing schedule of DARZALEX® in combination with bortezomib (3-week cycle regimen).

a The first dose of the regimen in each 3-week cycle is administered at week 10.

b The first dose of the regimen in each 4-week cycle is administered at week 25.

For information on doses and administration schedules of medicinal products used in combination with DARZALEX®, see the "Pharmacodynamics" section and the respective instructions for medical use of the medicinal products.

Infusion rate.

After dilution, DARZALEX® solution should be administered intravenously at the initial infusion rate indicated in Table 8 below. Gradual increases in infusion rate should only be considered in the absence of infusion-related reactions.

Table 8

Infusion rate of the medicinal product DARZALEX®.

a Gradual increase in the infusion rate should only be considered in the absence of infusion reactions.

b A dilution volume of 500 ml should only be used if no infusion reactions have been observed during the first 3 hours after the first infusion. Otherwise, continue using a dilution volume of 1000 ml and follow the instructions for the first infusion.

c An adjusted initial infusion rate for subsequent infusions (e.g., third infusion) should only be applied if no infusion reactions have occurred during the first two infusions at a final infusion rate of ≥ 100 ml/h. Otherwise, use the instructions for the second infusion.

Management of infusion reactions.

To reduce the risk of infusion reactions, appropriate premedications should be administered prior to Darzalex® infusion.

If infusion reactions of any severity occur, Darzalex® infusion should be immediately stopped and symptoms managed accordingly.

Management of infusion reactions may also require slowing the infusion rate or discontinuing Darzalex® treatment as outlined below (see section "Dosage and Administration").

• Grade 1–2 (mild to moderate): After resolution of reaction symptoms, resume infusion at a rate no greater than half of the rate at which the reaction occurred. If symptoms do not recur, the infusion rate may be increased in clinically appropriate increments and intervals up to a maximum rate of 200 ml/h (Table 8).
• Grade 3 (severe): After resolution of reaction symptoms, resume infusion at a rate no greater than half of the rate at which the reaction occurred. If symptoms do not recur, the infusion rate may be increased in clinically appropriate increments and intervals (Table 8). If grade 3 symptoms recur, repeat the procedure outlined above. If grade 3 or higher infusion reactions occur for the third time, discontinue Darzalex® treatment completely.
• Grade 4 (life-threatening): Discontinue Darzalex® treatment.

Missed dose(s).

If a scheduled dose of Darzalex® is missed, administer it as soon as possible and adjust the dosing schedule accordingly, maintaining the dosing interval.

Dose adjustment.

Dose reduction of Darzalex® is not recommended. In cases of hematologic toxicity, treatment interruption may be required to allow recovery of blood cell counts (see section "Dosage and Administration"). For information on concomitant medications used with Darzalex®, refer to the respective product information for those drugs.

Recommended concomitant therapy.

Premedication.

Premedication should be administered to all patients 1–3 hours before each Darzalex® infusion to reduce the risk of infusion reactions, as follows:

• Corticosteroids (intermediate- or long-acting).

Monotherapy:

Methylprednisolone 100 mg or equivalent intravenously. After the second infusion, the corticosteroid dose may be reduced (methylprednisolone 60 mg orally or intravenously).

Combination therapy:

Dexamethasone 20 mg or equivalent administered before each Darzalex® infusion (see section "Pharmacodynamics").

Dexamethasone should be administered intravenously before the first Darzalex® infusion, and oral administration may be considered before subsequent infusions. Additional concomitant corticosteroids depending on the treatment regimen (e.g., prednisolone) should not be administered on Darzalex® infusion days when patients have received dexamethasone as premedication.

• Antipyretics (acetaminophen 650–1000 mg orally).
• Antihistamines (diphenhydramine 25–50 mg orally or intravenously or equivalent).

Post-infusion medication.

Post-infusion medications should be administered to reduce the risk of delayed infusion reactions as follows:

Monotherapy:

Oral corticosteroids (20 mg methylprednisolone or equivalent intermediate- or long-acting corticosteroid according to local standards) should be administered every other day after all infusions (starting the day after infusion).

Combination therapy:

Consider using low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after Darzalex® administration. However, if concomitant corticosteroids depending on the treatment regimen (e.g., dexamethasone, prednisolone) are administered the day after Darzalex® infusion, additional post-infusion medications may not be required (see "Pharmacodynamics").

Additionally, in patients with a history of chronic obstructive pulmonary disease (COPD), consider post-infusion medications including short- and long-acting bronchodilators and inhaled corticosteroids. If no major infusion reactions occur after the first four infusions, the use of these inhaled medications after infusion may be discontinued at the physician’s discretion.

Prophylaxis of herpes zoster reactivation.

Antiviral prophylaxis should be considered to prevent herpes zoster reactivation.

Special patient populations

Patients with renal impairment.

Formal studies of daratumumab in patients with renal impairment have not been conducted. Based on population pharmacokinetic analysis, dose adjustment is not required in patients with renal impairment (see section "Pharmacokinetics").

Patients with hepatic impairment.

Formal studies of daratumumab in patients with hepatic impairment have not been conducted. Based on population pharmacokinetic analysis, dose adjustment is not required in patients with hepatic impairment (see section "Pharmacokinetics").

Elderly patients.

Dose adjustment is not considered necessary (see section "Pharmacokinetics").

Route of administration

Darzalex® is intended for intravenous infusion. It should be administered as an intravenous infusion after dilution with 9 mg/ml (0.9%) sodium chloride injection solution.

The vial is intended for single use only.

Prepare the infusion solution under aseptic conditions as follows:

• Determine the required dose (mg), total volume (ml) of Darzalex® solution, and number of Darzalex® vials based on the patient’s body weight.
• Check that the Darzalex® solution is colorless to yellow. Do not use if particulate matter, foreign particles, or discoloration are present.
• Under aseptic conditions, withdraw from the infusion bag/container a volume of 0.9% sodium chloride solution equal to the required volume of Darzalex® solution.
• Withdraw the required volume of Darzalex® solution and transfer it into the infusion bag/container containing 0.9% sodium chloride solution to achieve the final volume. Infusion bags/containers should be made of polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP + PE). Dilute under appropriate aseptic conditions. Discard any unused portion remaining in the vial.
• Gently invert the bag/container to mix the solution. Do not shake.
• Prior to administration, inspect the solution for mechanical particulates and discoloration. The diluted solution may contain very small, translucent to white protein particles, as daratumumab is a protein. Do not use if particulate matter, foreign particles, or discoloration are present.
• Since Darzalex® contains no preservatives, the diluted solution should be administered within 15 hours (including infusion time) at room temperature (15–25 °C) and under normal room light.
• If not used immediately, the solution may be stored for up to 24 hours at 2–8 °C in a light-protected container. Do not freeze.
• Administer the solution via intravenous infusion using an infusion set equipped with a flow regulator and an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 µm). Use polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE intravenous administration sets.
• Do not administer Darzalex® simultaneously with other medicinal products using the same intravenous administration system.
• Do not store any unused portion of the infusion solution for later use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of Darzalex® in children (under 18 years of age) have not been established. Data are lacking (see section "Pharmacodynamics").

Overdose.

Symptoms. There is no clinical experience with overdose. In a clinical study, the drug was administered intravenously at doses up to 24 mg/kg.

Treatment. There is no known specific antidote for daratumumab. In case of overdose, monitor the patient for any adverse event symptoms and initiate appropriate symptomatic treatment immediately.

Adverse Reactions

The most common adverse reactions (≥ 20%) were infusion-related reactions, fatigue, nausea, diarrhea, muscle spasms, pyrexia, cough, neutropenia, thrombocytopenia, anemia, peripheral sensory neuropathy, and upper respiratory tract infection. Serious adverse reactions included pneumonia, upper respiratory tract infections, pulmonary edema, influenza, pyrexia, diarrhea, and atrial fibrillation.

Table 9 summarizes adverse reactions observed in patients receiving DARZALEX®. The data reflect exposure to DARZALEX® (16 mg/kg) in 1166 patients with multiple myeloma, including 872 patients from three phase 3 controlled studies who received DARZALEX® in combination with lenalidomide and dexamethasone (DRd; n = 283; study MMY3003); bortezomib and dexamethasone (DVd; n = 243; study MMY3004); or bortezomib, melphalan, and prednisone (D-VMP; n = 346; study MMY3007), and from five open-label clinical trials in which patients received DARZALEX® in combination with pomalidomide and dexamethasone (DPd; n = 103), in combination with lenalidomide and dexamethasone (n = 35), or as monotherapy (n = 156).

Adverse reactions occurring during the post-marketing period are also included in the listing.

Frequency is defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000). Within each frequency category, adverse reactions are listed in order of decreasing severity when appropriate.

Table 9
Adverse reactions in patients with multiple myeloma who received DARZALEX® at a dose of 16 mg/kg.

* No Grade 4 reactions.

a Denotes grouped terms.

b Adverse reaction occurring in the post-marketing period.

c "Infusion reaction" includes events considered by investigators to be infusion-related; see below.

Infusion reactions.

In clinical studies (monotherapy and combination therapy; N = 1166), the incidence of infusion reactions of any grade was 40% during the first infusion of Darzalex®, 2% during the second infusion, and 4% during subsequent infusions. Grade 3 infusion reactions during the second or subsequent infusions occurred in less than 1% of patients. Grade 4 infusion reactions were reported in 2 of 1166 (0.2%) patients.

The median time to onset of reaction was 1.4 hours (range: 0 to 72.8 hours). The rate of infusion interruptions due to reactions was 37%. The mean duration of the first, second, and subsequent infusions was 7 hours, 4.3 hours, and 3.4 hours, respectively.

Severe infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions included nasal congestion, cough, chills, throat irritation, vomiting, and nausea (see section "Special warnings and precautions for use").

In study MMY1001, patients receiving combination therapy with daratumumab (n=97) were initially administered a daratumumab dose of 16 mg/kg during week 1, split over 2 days, i.e., 8 mg/kg on day 1 and day 2.

The incidence of infusion reactions of any grade was 42%, with 36% of patients experiencing a reaction on day 1 of week 1, 4% on day 2 of week 1, and 8% during all subsequent infusions. The median time to onset of reaction was 1.8 hours (range: 0.1 to 5.4 hours). The rate of infusion interruptions due to reactions was 30%. The mean duration of infusions was: 4.2 hours on day 1 of week 1; 4.2 hours on day 2 of week 1; and 3.4 hours for subsequent infusions.

Infections.

In patients receiving Darzalex® as part of combination therapy, the incidence of Grade 3 and 4 infections when Darzalex® was used in combination with background therapy was as follows: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; D-VMP: 23%, VMP: 15%; DPd: 28%. Pneumonia was the most common severe (Grade 3 or 4) infection observed during the study. Treatment was discontinued due to infection in 1–5% of patients. The number of fatal infections in controlled studies was generally similar between treatment arms including Darzalex® and the active control group (< 2%); these were primarily pneumonia and sepsis.

Hemolysis.

There is a theoretical risk of hemolysis. Continuous monitoring of this safety signal will occur in clinical studies and post-marketing safety data.

Other special populations.

In the Phase III study MMY3007, which compared D-VMP treatment with VMP treatment in patients with newly diagnosed multiple myeloma who were not candidates for autologous stem cell transplantation, the safety profile in the subgroup of patients with an ECOG performance status score of 2 (D-VMP: n = 89, VMP: n = 84) was consistent with the overall population (see section "Pharmacodynamics").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions through the national reporting system.

Shelf life.

2 years.

Due to the potential for microbial contamination, unless the method of opening and dilution excludes the risk of microbial contamination, the medicinal product should be used immediately. If not used immediately, the duration and conditions of storage of the diluted solution are the responsibility of the user; the diluted solution should be stored at 2–8 °C for no more than 24 hours in a light-protected container, followed by no more than 15 hours (including infusion time) at 15–25 °C under room lighting conditions.

Storage conditions.

Store in the original packaging to protect from light at 2–8 °C. Do not freeze. Keep out of the reach of children.

Storage conditions for the diluted solution are described in the section "Shelf life".

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

5 ml or 20 ml of concentrate in a glass vial with an elastomeric stopper, aluminum seal, and flip-off cap; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Manufacturers responsible for batch release.

Janssen Biologics B.V. or Celegene AG.

Manufacturer's address and place of business.

Janssen Biologics B.V., Einsteinweg 101, 2333 SB Leiden, The Netherlands or

Celegene AG, Hochstrasse 201, 8200 Schaffhausen, Switzerland