Darzalex

Daratumumab.

Each mL contains 20 mg daratumumab.
5 mL vial: Each single-use vial contains 100 mg of daratumumab.
20 mL vial: Each single-use vial contains 400 mg of daratumumab.
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody against CD38 antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
Excipients/Inactive Ingredients: Glacial acetic acid, Mannitol, Polysorbate 20, Sodium acetate trihydrate, Sodium chloride, Water for injection.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC24.
Pharmacology: Pharmacodynamics: Mechanism of action: Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of cells in a variety of hematological malignancies, including multiple myeloma tumor cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signaling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumor cells. Based on in vitro studies, daratumumab may utilize multiple effector functions, resulting in immune mediated tumor cell death. These studies suggest that daratumumab can induce tumor cell lysis through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T_regs) and B cells (CD38+B_regs) are decreased by daratumumab. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with DARZALEX treatment in peripheral whole blood and bone marrow. T-cell receptor DNA sequencing verified that T-cell clonality was increased with DARZALEX treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumor growth, are not well-understood.
Pharmacodynamic effects: Natural killer (NK) cell and T-cell count: NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56^dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment. However, baseline levels of NK cells did not show an association with clinical response.
Immunogenicity: Patients treated with daratumumab monotherapy (n=199) and combination therapy (n=1384) were evaluated for anti-therapeutic antibody (ATA) responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of DARZALEX treatment, none of the monotherapy patients and 2 of the 1384 combination therapy patients tested positive for anti-daratumumab antibodies; 1 of the combination therapy patients developed transient neutralizing antibodies against daratumumab.
Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to daratumumab with the incidence of antibodies to other products may be misleading.
Clinical studies: Newly Diagnosed Multiple Myeloma: Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients ineligible for autologous stem cell transplant: Study MMY3007, an open-label, randomized, active-controlled Phase 3 study, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m² body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2-9; 4 doses per cycle). Melphalan at 9 mg/m², and prednisone at 60 mg/m² were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). DARZALEX treatment was continued until disease progression or unacceptable toxicity.
A total of 706 patients were randomized: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Light chain myeloma in 64%/22%/10% of instances, 19% had ISS Stage I, 42% had ISS Stage II and 38% had ISS Stage III disease. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).
With a median follow-up of 16.5 months, the primary analysis of PFS in study MMY3007 demonstrated an improvement in PFS in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p<0.0001), representing 50% reduction in the risk of disease progression or death in patients treated with D-VMP. Results of an updated PFS analysis after a median follow-up of 40 months continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D-VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51; p<0.0001), representing a 58% reduction in the risk of disease progression or death in patients treated with D-VMP. (See Figure 1.)


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After a median follow-up of 40 months, D-VMP has shown an overall survival (OS) advantage over the VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the D-VMP arm. Median OS was not reached for either arm. (See Figure 2.)


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Additional efficacy results from Study MMY3007 are presented in the table as follows. (See Table 1.)


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In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range: 0.7 to 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.
Relapsed/Refractory Multiple Myeloma: Combination treatment with bortezomib and dexamethasone: Study MMY3004, an open-label, randomized, active-controlled phase 3 trial, compared treatment with darzalex 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had received at least one prior therapy. Bortezomib was administered by SC injection or IV injection at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, 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 the 8 bortezomib cycles (80 mg/week for two out of three weeks of each of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of Darzalex infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a Darzalex pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas Darzalex was given until treatment progression. However, dexamethasone 20 mg was continued as a Darzalex pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information.
A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the Darzalex and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥ 75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior pi (66% received bortezomib) and 76% of patients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Efficacy was evaluated by PFS based on IMWG criteria.
With a median follow-up of 7.4 months, the primary analysis of PFS in study MMY3004 demonstrated an improvement in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (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 for patients treated with DVd versus Vd. Results of an updated PFS analysis after a median follow-up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31 [0.24, 0.39]; p-value < 0.0001), representing a 69% reduction in the risk of disease progression or death in patients treated with DVd versus Vd. (See Figure 3.)


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Additional efficacy results from study MMY3004 are presented in table as follows. (See Table 2.)


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Median OS was not reached for either treatment group. With an overall median follow-up 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).
Monotherapy: The clinical efficacy and safety of DARZALEX monotherapy for the treatment of patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent, was demonstrated in two open-label studies.
In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg DARZALEX until disease progression. The median patient age was 63.5 years (range, 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a PI and IMiD, 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.
Efficacy results based on Independent Review Committee (IRC) assessment are presented in table as follows. (See Table 3.)


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Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy. With a median duration of follow-up of 9 months, median Overall Survival (OS) was not reached. The 12-month OS rate was 65% (95% CI: 51.2, 75.5).
In Study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg DARZALEX until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to carfilzomib.
Treatment with daratumumab at 16 mg/kg led to a 36% ORR with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median duration of response was not reached (95% CI: 5.6 months, not estimable). With a median duration of follow-up of 10 months, median OS was not reached. The 12-month OS rate was 77% (95% CI: 58.0, 88.2).
Pharmacokinetics: The pharmacokinetics (PK) of daratumumab following intravenous administration of DARZALEX monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg. A population PK model of daratumumab was developed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma. The population PK analysis included 223 patients receiving DARZALEX monotherapy in two clinical trials (150 subjects received 16 mg/kg).
In the 1- to 24 mg/kg cohorts, peak serum concentrations (C_max) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Increases in AUC were more than dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimized and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumor burden decreases.
Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.
At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean (SD) serum C_max value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) plasma concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.
Based on the population pk analysis of Darzalex monotherapy, daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21^st infusion), and the mean (sd) ratio of C_max at steady-state to C_max after the first dose was 1.6 (0.5). The mean (sd) central volume of distribution is 56.98 (18.07) ml/kg.
Three additional population PK analyses were conducted in patients with multiple myeloma that received daratumumab in various combination therapies (N=1390). Daratumumab concentration-time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 15-23 days.
Based on population PK analysis body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.
Simulation of daratumumab pharmacokinetics was conducted for all recommended dosing schedules using individual PK parameters of patients with multiple myeloma (n=1309). The simulation results confirmed that the split and single dosing for the first dose should provide similar PK, with the exception of the PK profile in the first day of the treatment.
Special populations: Age and gender: Based on population PK analyses in patients receiving monotherapy or various combination therapies, age (range: 31-93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n=518) and older (aged ≥65 to <75 years n=761; aged ≥75 years, n=334) patients.
Gender did not affect exposure of daratumumab to a clinically relevant degree in population PK analyses.
Renal impairment: No formal studies of DARZALEX in patients with renal impairment have been conducted. Population PK analysis were performed based on pre-existing renal function data in patients receiving daratumumab monotherapy or various combination therapies, including 441 patients with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 621 with mild renal impairment (CRCL <90 and ≥60 mL/min), 523 with moderate renal impairment (CRCL <60 and ≥30 mL/min), and 27 with severe renal impairment or end stage renal disease (CRCL <30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.
Hepatic impairment: No formal studies of DARZALEX in patients with hepatic impairment have been conducted. Population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies including 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]) 189 with mild hepatic impairment (TB 1.0× to 1.5× ULN or AST>ULN) and 8 patients with moderate (TB >1.5× to 3.0× ULN; n=7) or severe (TB >3.0× ULN; n=1) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.
Race: Based on the population PK analyses in patients receiving either daratumumab monotherapy or various combination therapies, the exposure to daratumumab was similar between white (n=1371) and non-white (n=242) subjects.
Toxicology: Non-Clinical Information: Carcinogenicity and Mutagenicity: No animal studies have been performed to establish the carcinogenic potential of daratumumab. Routine genotoxicity and carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.
Reproductive toxicology: No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development.
Fertility: No animal studies have been performed to determine potential effects on fertility in males or females.

DARZALEX is indicated as monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent.
DARZALEX is indicated in combination with bortezomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
DARZALEX is indicated in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

DARZALEX should be administered by a healthcare professional, in an environment where resuscitation facilities are available.
Pre- and post-infusion medications should be administered to reduce the risk of infusion-related reactions (IRRs) with daratumumab. See Recommended concomitant medications, Management of infusion-related reactions as follows and Precautions.
Posology: Newly diagnosed multiple myeloma: Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens) for patients ineligible for autologous stem cell transplant: The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 4. (See Table 4.)


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Bortezomib is given twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at Weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the VMP dose and dosing schedule when administered with DARZALEX see Pharmacology: Pharmacodynamics: Clinical studies under Actions.
Relapsed/Refractory multiple myeloma: Dosing schedule for monotherapy (4-week cycle regimen): The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 5. (See Table 5.)


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For dose and schedule of medicinal products administered with DARZALEX, see Pharmacology: Pharmacodynamics: Clinical studies under Actions and the corresponding Summary of Product Characteristics.
Dosing schedule in combination with bortezomib (3-week cycle regimen): The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 6. (See Table 6.)


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For dose and schedule of medicinal products administered with DARZALEX, see Pharmacology: Pharmacodynamics: Clinical studies under Actions and the corresponding Summary of Product Characteristics.
Infusion rates: Following dilution the DARZALEX infusion should be intravenously administered at the initial infusion rate presented in Table 7 as follows. Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.
To facilitate administration, the first prescribed 16 mg/kg dose at Week 1 may be split over two consecutive days i.e. 8 mg/kg on Day 1 and Day 2 respectively, see Table 7 as follows.


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Management of infusion-related reactions: Pre-infusion medications should be administered to reduce the risk of infusion-related reactions (IRRs) prior to treatment with DARZALEX.
For IRRs of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms.
Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined as follows (see Precautions).
Grade 1-2 (mild to moderate): Once reaction symptoms resolve, the infusion should be resumed at no more than half the rate at which the IRR occurred. If the patient does not experience any further IRR symptoms, infusion rate escalation may be resumed at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 4).
Grade 3 (severe): Once reaction symptoms resolve, restarting of the infusion may be considered at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate (Table 7). The procedure previously should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction.
Grade 4 (life-threatening): Permanently discontinue DARZALEX treatment.
Missed dose (s): If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.
Dose modifications: No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity (see Precautions). For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.
Recommended concomitant medications: Pre-infusion medication: Pre-infusion medications should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every infusion of DARZALEX as follows: Corticosteroid (long-acting or intermediate-acting): Monotherapy: Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).
Combination therapy: Dexamethasone 20 mg, administered prior to every DARZALEX infusion (see Pharmacology: Pharmacodynamics under Actions).
Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions.
Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX infusion days when patients have received dexamethasone as a pre-medication.
Antipyretics (oral paracetamol 650 to 1,000 mg).
Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).
Post-infusion medication: Post-infusion medications should be administered to reduce the risk of delayed infusion-related reactions as follows: Monotherapy: Oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) should be administered on each of the two days following all infusions (beginning the day after the infusion).
Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after the DARZALEX infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed (see Pharmacology: Pharmacodynamics under Actions).
Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-infusion medications including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post-infusion medications may be discontinued at the discretion of the physician.
Prophylaxis for herpes zoster virus reactivation: Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.
Special populations: Renal impairment: No formal studies of daratumumab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses no dosage adjustment is necessary for patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No formal studies of daratumumab in patients with hepatic impairment have been conducted.
Based on population PK analyses, no dosage adjustments are necessary for patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Elderly: No dose adjustments are considered necessary in elderly patients (see Pharmacology: Pharmacokinetics under Actions and Adverse Reactions).
Pediatric population: The safety and efficacy of DARZALEX in children aged below 18 years of age have not been established.
No data are available (see Pharmacology: Pharmacodynamics under Actions).
Method of administration: DARZALEX is for intravenous use. It is administered as an intravenous infusion following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection. For instructions on dilution of the medicinal product before administration, see Instructions for Use and Handling and Disposal under Cautions for Usage.

Symptoms and signs: There has been no experience of overdosage in clinical studies. Doses up to 24 mg/kg have been administered intravenously in a clinical study without reaching the maximum tolerated dose.
Treatment: There is no known specific antidote for DARZALEX overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment be instituted immediately.

Patients with a history of severe hypersensitivity to daratumumab or any of the excipients.

Infusion-related reactions: DARZALEX can cause serious IRRs, including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported.
Monitor patients throughout the infusion and the post-infusion period.
In clinical trials, IRR were reported in approximately half of all patients treated with DARZALEX.
The majority of IRRs occurred at the first infusion and were Grade 1-2. Four percent of patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension (see Adverse Reactions). Fatal IRRs were not reported in these trials.
Pre-medicate patients with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment with DARZALEX. Interrupt DARZALEX infusion for IRRs of any severity and institute medical management/supportive treatment as needed. For patients with Grade 1, 2, or 3 reactions reduce the infusion rate when re-starting the infusion. If an anaphylactic reaction or life-threatening (Grade 4) IRR occurs, permanently discontinue administration of DARZALEX and institute appropriate emergency care (see Dosage & Administration).
To reduce the risk of delayed IRRs, administer oral corticosteroids to all patients following all DARZALEX infusions. Additionally consider the use of post-infusion medications (e.g. inhaled corticosteroids, short and long acting bronchodilators) for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications should they occur (see Dosage & Administration).
Neutropenia/Thrombocytopenia: DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (see Adverse Reactions).
Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.
Interference with indirect antiglobulin test (indirect Coombs test): Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab infusion. It should be recognized that daratumumab bound to RBCs may mask detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted.
Type and screen patients prior to starting DARZALEX.
In the event of a planned transfusion notify blood transfusion centers of this interference with indirect antiglobulin tests (see Interactions). If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.
Hepatitis B Virus (HBV) reactivation: Hepatitis B virus (HBV) reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening should be performed in all patients before initiation of treatment with DARZALEX.
For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of DARZALEX treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated.
In patients who develop reactivation of HBV while on DARZALEX, suspend treatment with DARZALEX and any concomitant steroids, chemotherapy, and institute appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.
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 (see Interactions). This interference can impact the determination of complete response and of 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) sodium, respectively. This should be taken into consideration by patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machines: DARZALEX has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking daratumumab and this should be taken into account when driving or using machines.

Pregnancy: There are no human or animal data to assess the risk of DARZALEX use during pregnancy. IgG1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore DARZALEX should not be used during pregnancy unless the benefit of treatment to the woman is considered to outweigh the potential risks to the fetus. If the patient becomes pregnant while taking this drug, the patient should be informed of the potential risk to the fetus.
To avoid exposure to the fetus, women of reproductive potential should use effective contraception during and up to 3 months after cessation of DARZALEX treatment.
Breast-feeding: It is not known whether daratumumab is excreted into human or animal milk or affects milk production. There are no studies to assess the effect of daratumumab on the breast-fed infant.
Maternal IgG is excreted in human milk, but does not enter the neonatal and infant circulations in substantial amounts as they are degraded in the gastrointestinal tract and not absorbed. Because the risks of DARZALEX to the infant from oral ingestion are unknown, a decision should be made whether to discontinue breast-feeding, or discontinue DARZALEX therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: No data are available to determine potential effects of daratumumab on fertility in males or females.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of daratumumab based on the comprehensive assessment of the available adverse event information. A causal relationship with daratumumab cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety data described as follows reflect exposure to DARZALEX (16 mg/kg) in 2066 patients with multiple myeloma including 1910 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy.
Newly Diagnosed Multiple Myeloma: Combination treatment with bortezomib, melphalan and prednisone: Adverse reactions described in the table as follows reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for the daratumumab, bortezomib, melphalan and prednisone (D-VMP) group, and median treatment duration of 12 months (range: 0.1 to 14.9 months) for the VMP group in a Phase 3 active-controlled study (Study MMY3007). The most frequent adverse reactions (≥20%) were infusion reactions, upper respiratory tract infection and edema peripheral. Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%). (See Table 8.)


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Laboratory abnormalities worsening during treatment from baseline listed in the table as follows. (See Table 9.)


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Relapsed/Refractory Multiple Myeloma: Combination treatment with bortezomib and dexamethasone: Adverse reactions described in Table 10 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) for the daratumumab-bortezomib-dexamethasone (DVd) group and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib group (Vd) in a Phase 3 active-controlled study (Study MMY3004). The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. Serious adverse reactions included diarrhea, upper respiratory tract infection and atrial fibrillation. Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm. (See Table 10.)


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Laboratory abnormalities worsening during treatment are listed in table as follows. (See Table 11.)


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Monotherapy: The data described as follows reflect exposure to DARZALEX in three pooled open-label clinical studies that included 156 patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg. The median duration of DARZALEX treatment was 3.3 months, with the longest duration of treatment being 14.2 months. Adverse reactions occurring at a rate of ≥ 10% are presented in table as follows. The most frequently reported adverse reactions (≥ 20%) were IRRs, fatigue, nausea, back pain, anemia, neutropenia and thrombocytopenia. Four percent of patients discontinued DARZALEX treatment due to adverse reactions, none of which were considered drug related.
Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). (See Table 12.)


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Infusion-related reactions: In clinical trials (monotherapy and combination treatments; N=2066) the incidence of any grade infusion-related reactions was 37% with the first (16 mg/kg, Week 1) infusion of DARZALEX, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion reaction with second or subsequent infusions.
The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 36%. Median durations of 16 mg/kg infusions for the 1^st, 2^nd and subsequent infusions were approximately 7, 4 and 3 hours respectively.
Severe infusion-related reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion-related reactions included nasal congestion, cough, chills, throat irritation, vomiting and nausea.
In study MMY1001, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2 respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.
Infections: In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported as follows: Relapsed/refractory patient studies: DVd: 21%, Vd: 19%.
Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%.
Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (occurred in 1-4% of patients). Fatal infections were primarily due to pneumonia and sepsis.
In patients receiving DARZALEX combination therapy, fatal infections (Grade 5) were reported as follows: Relapsed/refractory patient studies: DVd: 1%, Vd: 2%.
Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%.
Adverse Reactions identified from other clinical trials: Sepsis.
Other Adverse Reactions: Other adverse reactions reported in patients treated with daratumumab in clinical trials are listed in Table 13. (See Table 13).


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Other special population: The incidence of serious adverse reactions was higher in older than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1213), the most common serious adverse reactions that occurred more frequently in elderly (≥65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia.
Postmarketing data: Adverse reactions identified during postmarketing experience with daratumumab are included in Table 14. The frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10000 to <1/1000; Very rare <1/10000, including isolated reports; Not known frequency cannot be estimated from the available data.
In Table 14, adverse reactions are presented by frequency category based on spontaneous reporting rates, as well as frequency category based on precise incidence in a clinical trial, when known. (See Table 14.)


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No drug-drug interaction studies have been performed.
Clinical pharmacokinetic assessments of daratumumab in combination with bortezomib and dexamethasone indicated no clinically-relevant drug-drug interaction between daratumumab and these small molecule medicinal products.
Effects of DARZALEX on laboratory tests: Interference with indirect antiglobulin test (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 or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.
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). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of Complete Responses (CRs) by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response (VGPR), where daratumumab interference is suspected, consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response (see Pharmacology: Pharmacodynamics: Clinical studies under Actions).

Instructions for Use and Handling and Disposal: Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient weight.
Check that the DARZALEX solution is colorless to yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
Using aseptic technique, remove a volume of 0.9% Sodium Chloride from the infusion bag/container that is equal to the required volume of DARZALEX solution.
Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to an infusion bag/container containing 0.9% Sodium Chloride (see Dosage & Administration). Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
Gently invert the bag/container to mix the solution. Do not shake or freeze.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
Since DARZALEX does not contain a preservative, diluted solutions should be administered within 15 hours (including infusion time) at room temperature 15°C-25°C (59°F-77°F) and in room light.
If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C - 8°C (36°F-46°F) and protected from light. Do not freeze.
Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE administration sets must be used.
Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except those previously mentioned in Instructions for Use and Handling and Disposal.

For storage conditions of the diluted medicinal product, see Shelf Life as follows.
Shelf Life: Unopened vials: 24 months.
After dilution: Since daratumumab solutions do not contain a preservative, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the solution may be stored in a refrigerator at 2°C-8°C (36°F-46°F) for up to 24 hours prior to use, followed by 15 hours (including infusion time) at room temperature 15°C-25°C (59°F-77°F) and room light.

Targeted Cancer Therapy

L01FC01 - daratumumab ; Belongs to the class of CD38 (Clusters of Differentiation 38) inhibitors. Used in the treatment of cancer.

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