Darzalex (Solution, Concentrate) Instructions for Use

ATC Code

L01FC01 (Daratumumab)

Active Substance

Daratumumab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents, monoclonal antibodies and their drug conjugates; CD38 (clusters of differentiation 38) inhibitors

Pharmacological Action

Mechanism of action

Daratumumab is a human monoclonal IgG1κ antibody that binds to the CD38 protein, which is highly expressed on the surface of cells in various hematological malignancies, including multiple myeloma cells, as well as other cell and tissue types.

The CD38 protein has multiple functions, including receptor-mediated adhesion, signaling, and enzymatic activity.

The ability of daratumumab to potently inhibit the growth of CD38-expressing tumor cells in vivo has been demonstrated. Based on in vitro studies, Daratumumab can cause immune system-mediated tumor cell death through several effector mechanisms.

Data from these studies suggest that Daratumumab is capable of inducing tumor cell lysis via complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis in CD38-expressing malignancies.

Under the action of daratumumab, a reduction in the subpopulation of myeloid-derived suppressor cells (CD38+MDSC), regulatory T cells (CD38+T_reg), and B cells (CD38+B_reg) occurs.

It is known that depending on the stage of development and level of activation, T cells (CD3+, CD4+ and CD8+) can express CD38.

During treatment with Darzalex, a significant increase in the absolute number of CD4+ and CD8+ T cells and the percentage of lymphocytes in whole peripheral blood and red bone marrow was noted.

Using T-cell receptor DNA sequencing, an increase in T-cell clonality was shown during treatment with Darzalex, indicating immunomodulatory effects that may contribute to the clinical response.

Daratumumab induced apoptosis in vitro after Fc-mediated cross-linking. Furthermore, Daratumumab modulated the enzymatic activity of CD38, causing inhibition of cyclase enzymatic activity and stimulation of hydrolase activity.

The significance of these in vitro effects in clinical practice, as well as their impact on tumor growth, is not fully understood.

Number of NK cells and T cells

It is known that NK cells express CD38 in significant quantities, thus they are sensitive to daratumumab-mediated lysis.

During the use of Darzalex, a decrease in the absolute number and percentage of NK cells (CD16+CD56+) and activated NK cells (CD16+CD56^dim) in peripheral blood and bone marrow was observed.

However, no relationship was found between baseline NK cell content and clinical response.

Immunogenicity

Detection of anti-drug antibody formation to daratumumab was conducted among patients receiving daratumumab monotherapy (n=199) and patients receiving combination therapy (n=1384) at multiple time points during treatment and up to 8 weeks after the end of treatment.

From the start of therapy with Darzalex, no antibodies to daratumumab were detected in patients on monotherapy; in the combination therapy group, antibodies to daratumumab were detected in 2 out of 1384 patients; one patient in the combination treatment group had transient formation of neutralizing antibodies to daratumumab.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay methods used.

Furthermore, several factors may influence the observed incidence of positive assay results, including sample handling conditions, timing of sample collection, influence of other drugs, concomitant therapy, and the disease under study.

Thus, comparing the incidence of antibodies to daratumumab with the incidence of antibodies to other drugs may lead to incorrect conclusions.

Pharmacokinetics

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

A population pharmacokinetic model of daratumumab was developed to describe the pharmacokinetic characteristics of this drug, as well as to evaluate the influence of covariates on the distribution of daratumumab in patients with multiple myeloma.

The population pharmacokinetic analysis included 223 patients receiving Darzalex in two clinical studies as monotherapy (150 patients received the drug at a dose of 16 mg/kg).

Absorption and Distribution

In the groups receiving 1-24 mg/kg, the C_max in serum after the first dose increased approximately proportionally to the dose, V_d corresponded to initial distribution in plasma.

The increase in AUC occurred more than proportionally to the dose, and a decrease in clearance was observed as the dose increased.

These data indicate possible saturation of CD38 at higher doses, after which the effect of target-mediated clearance is minimized and the clearance of daratumumab approaches the linear clearance characteristic of endogenous IgG1.

After multiple administrations, a decrease in clearance was also observed, which may be due to a reduction in tumor burden.

At the end of the weekly infusion period using the recommended monotherapy regimen and a dose of 16 mg/kg, the mean (standard deviation) C_max in serum was 915 (410.3) µg/ml, which is approximately 2.9 times higher than after the first infusion.

The mean (standard deviation) serum concentration before the next dose (trough) at the end of the weekly infusion period was 573 (331.5) µg/ml.

Based on population pharmacokinetic analysis, steady state for daratumumab in monotherapy is reached at approximately 5 months upon transitioning to infusions every 4 weeks (by the 21st infusion), the mean (standard deviation) ratio of steady-state C_max to C_max after the first dose was 1.6 (0.5).

The mean (standard deviation) central V_d was 56.98 (18.07) ml/kg.

Elimination

The terminal T_1/2 increases with increasing dose and with multiple administrations of the drug.

The mean (standard deviation) estimated terminal T_1/2 of daratumumab after the first infusion at a dose of 16 mg/kg was 9 (4.3) days.

Based on population pharmacokinetic analysis, the mean (standard deviation) T_1/2 for non-specific linear elimination was approximately 18 (9) days; this terminal T_1/2 can be expected in the case of complete saturation of target-mediated clearance and with multiple administrations of daratumumab.

Four additional population pharmacokinetic analyses were conducted in patients with multiple myeloma receiving daratumumab therapy as part of various combination therapy regimens (n=1765).

The concentration-time profile of daratumumab was similar in monotherapy and combination therapy.

The mean terminal T_1/2 associated with linear clearance in the combination therapy group was 15-24 days.

Based on population pharmacokinetic analysis, body weight was identified as a statistically significant covariate of daratumumab clearance.

Thus, body weight-based dosing is an appropriate strategy for calculating the dose in patients with multiple myeloma.

Pharmacokinetic modeling of daratumumab was performed for all recommended dosing regimens using individual pharmacokinetic parameters of patients with multiple myeloma (n=1309).

The modeling results confirmed that when the drug is first administered as one or two infusions, the pharmacokinetic parameters are similar, except for those on the first day of therapy.

Pharmacokinetics in Special Patient Groups

Age and sex. Based on population pharmacokinetic analysis in patients receiving monotherapy or various combination therapy regimens, age (range: 31-93 years) does not have a clinically significant effect on the pharmacokinetics of daratumumab; the concentration of daratumumab was similar in younger (aged <65 years, n=706) and elderly (aged ≥65-<75 years, n=913; and ≥75 years, n=369) patients.

Population pharmacokinetic analyses did not reveal a clinically significant effect of sex on daratumumab concentration.

Patients with impaired renal function. No studies of Darzalex have been conducted in patients with impaired renal function.

A population pharmacokinetic analysis was performed based on available data on renal function status in patients receiving daratumumab monotherapy or various combination therapy regimens, including 592 patients with normal renal function (CrCl≥90 ml/min), 757 patients with mild renal impairment (CrCl <90 and ≥60 ml/min), 604 with moderate renal impairment (CrCl<60 and ≥30 ml/min), and 34 with severe renal impairment or end-stage renal disease (CrCl<30 ml/min).

No clinically significant differences in daratumumab concentration were found between patients with impaired renal function and those with normal function.

Patients with impaired hepatic function. No studies of Darzalex have been conducted in patients with impaired hepatic function.

A population pharmacokinetic analysis was conducted in patients receiving Daratumumab as monotherapy or as part of various combination therapy regimens and included 1742 patients with normal hepatic function (total bilirubin and AST levels less than ULN), 224 patients with mild hepatic impairment (total bilirubin level from 1 to 1.5 x ULN or AST level above ULN), and 10 patients with moderate hepatic impairment (total bilirubin >1.5-3.0 x ULN; n=9) or severe hepatic impairment (total bilirubin >3.0 x ULN; n=1).

No clinically significant differences in daratumumab exposure were found in patients with impaired hepatic function compared to patients with normal hepatic function.

Race. According to population pharmacokinetic analysis in patients receiving Daratumumab as monotherapy or as part of various combination therapy regimens, daratumumab exposure was the same in participants of Caucasian race (n=1662) and other races (n=326).

Indications

• In combination with bortezomib, thalidomide and dexamethasone – for the treatment of adult patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplantation;
• In combination with bortezomib, melphalan and prednisone or in combination with lenalidomide and dexamethasone – for the treatment of adult patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplantation;
• In combination with lenalidomide and dexamethasone or in combination with bortezomib and dexamethasone – for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy;
• As monotherapy in adult patients with relapsed and refractory multiple myeloma, who have previously received therapy with proteasome inhibitors and immunomodulatory drugs and who have experienced disease progression on prior therapy;
• In combination with carfilzomib and dexamethasone – for the treatment of adult patients with relapsed or refractory multiple myeloma, who have previously received one to three lines of prior therapy.

ICD codes

Dosage Regimen

Concentrate

Darzalex is administered as an intravenous infusion.

Administration of the drug should be carried out by a healthcare professional in a setting with immediate access to intensive care equipment.

Concomitant medications must be administered before and after the infusion to reduce the risk of infusion reactions (see subsections “Recommended Concomitant Medications” and “Management of Patients with Infusion Reactions”).

Doses

Darzalex dosing regimen in combination with bortezomib, thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplantation (4-week treatment cycles)

The recommended dose of Darzalex is 16 mg/kg body weight as intravenous infusions according to the schedule outlined in Table 1.

Table 1. Dosing regimen of Darzalex in combination with bortezomib, thalidomide and dexamethasone (4-week treatment cycles)

^a The first dose on the once every 2 weeks dosing schedule is administered in week 9.

^b The first dose on the once every 2 weeks dosing schedule is administered in week 1 of therapy resumption after autologous stem cell transplantation.

Information on the dosing regimen of drugs used in combination with Darzalex can be found in the respective prescribing information.

Darzalex dosing regimen in combination with bortezomib, melphalan and prednisone (6-week treatment cycles) in patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplantation

The recommended dose of Darzalex is 16 mg/kg body weight as intravenous infusions according to the schedule outlined in Table 2.

Table 2. Dosing regimen of Darzalex in combination with bortezomib, melphalan and prednisone (6-week treatment cycles)

^a The first dose on the once every 3 weeks schedule is administered in week 7.

^b The first dose on the once every 4 weeks schedule is administered in week 55.

Bortezomib is administered by subcutaneous injection at a dose of 1.3 mg/m² body surface area twice weekly in weeks 1, 2, 4, and 5 of the first 6-week cycle (cycle 1, 8 doses), then once weekly in weeks 1, 2, 4, and 5 of the next eight 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 are taken orally on days 1 and 4 of nine 6-week cycles (cycles 1-9).

Dosing regimen as monotherapy and in combination therapy with lenalidomide and dexamethasone or in combination therapy with carfilzomib and dexamethasone in patients with relapsed and refractory multiple myeloma or in combination therapy with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplantation (4-week treatment cycles)

The recommended dose of Darzalex is 16 mg/kg body weight as an intravenous infusion according to the following schedule outlined in Table 3.

Table 3. Dosing regimen of Darzalex as monotherapy and in combination therapy with lenalidomide and dexamethasone or carfilzomib and dexamethasone (4-week treatment cycles)

^a The first dose on the once every 2 weeks dosing schedule is administered in week 9.

^b The first dose on the once every 4 weeks dosing schedule is administered in week 25.

Lenalidomide is taken orally at a dose of 25 mg once daily on days 1-21 of repeated 4-week cycles along with a low dose of dexamethasone (40 mg per week), taken orally or IV (patients over 75 years of age or with a BMI less than 18.5 should take a reduced dose of dexamethasone – 20 mg per week). Patients take dexamethasone at a dose of 20 mg as premedication on days of Darzalex infusion, as well as the day after the infusion. Patients who need to take a reduced dose of dexamethasone take 20 mg only as premedication. Dose adjustment of lenalidomide and dexamethasone is carried out in accordance with the prescribing information for these medicinal products.

Carfilzomib is used as an intravenous infusion twice weekly on days 1, 2, 8, 9, 15, and 16 of repeated 28-day (4-week) therapy cycles (the dose of carfilzomib is 20 mg/m² on days 1 and 2 of cycle 1 and 56 mg/m², starting from day 8 of cycle 1, and thereafter) or as an intravenous infusion once weekly at a dose of 20 mg/m² on day 1 of cycle 1 and with a dose increase to 70 mg/m² on days 8 and 15 of cycle 1, as well as on days 1, 8, and 15 of subsequent cycles.

Dosing regimen in combination therapy with bortezomib and dexamethasone (3-week treatment cycles)

The recommended dose of Darzalex is 16 mg/kg body weight as an intravenous infusion in accordance with the dosing regimen presented below in Table 4.

Table 4. Dosing regimen of Darzalex in combination therapy with bortezomib and dexamethasone (3-week treatment cycles)

^a Administration of the first dose for the once every 3 weeks dosing regimen is performed on week 10.

^b Administration of the first dose for the once every 4 weeks dosing regimen is performed on week 25.

Bortezomib is administered via subcutaneous or intravenous injection at a dose of 1.3 mg/m² of body surface area twice weekly for 2 weeks (days 1, 4, 8, and 11) of repeating 3-week cycles, for 8 cycles. Dexamethasone is taken orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 during the 8 cycles of bortezomib therapy (80 mg per week for 2 weeks of each 3-week cycle) or at a reduced dose of 20 mg per week in patients over 75 years of age, with a BMI less than 18.5, with poorly controlled diabetes mellitus, or with a history of steroid therapy intolerance. On days of Darzalex infusion, patients take dexamethasone at a dose of 20 mg as premedication. Patients who require a reduced dose of dexamethasone take 20 mg only once a week before Darzalex infusion. Bortezomib and dexamethasone are taken for eight 3-week cycles, while Darzalex is used until disease progression. However, administration of dexamethasone at a dose of 20 mg should be continued as premedication. Dose adjustment of bortezomib and dexamethasone is performed in accordance with the prescribing information for these medicinal products.

Infusion Rate

After dilution of Darzalex, the infusion must be performed at the appropriate initial rate (see Table 5). A gradual increase in the infusion rate should only be considered in the absence of infusion reactions.

The first infusion of the drug at a dose of 16 mg/kg in week 1 may be divided into 2 infusions administered over two consecutive days. For example, 2 infusions, each at a dose of 8 mg/kg on day 1 and day 2 (see Table 5).

In patients receiving therapy with Darzalex in combination with carfilzomib and dexamethasone, the daratumumab dose of 16 mg/kg in week 1 should be divided over 2 days to minimize the risk of volume overload (see Option 2 in Table 5).

Table 5. Infusion Rate of Darzalex (at a dose of 16 mg/kg)

^aA stepwise increase in the infusion rate should only be considered in the absence of infusion reactions.

^b A dilution volume of 500 ml for administration at a dose of 16 mg/kg should only be used if there were no infusion reactions during the previous Week. Otherwise, a dilution volume of 1000 ml must be used.

^c The modified initial rate (100 ml/h) for subsequent infusions (Week 3 and onwards) is applied only if there were no infusion reactions during the previous infusion. Otherwise, the infusion rate instructions for Week 2 specified in the table should be used.

Management of Patients with Infusion Reactions

To reduce the risk of infusion reactions, premedication is required before administration of Darzalex.

In case of infusion reactions of any severity, it is necessary to immediately interrupt the Darzalex infusion and provide appropriate symptomatic therapy.

Management actions in case of infusion reactions may include reducing the infusion rate or discontinuing Darzalex therapy, as described below.

• Grade 1-2 (mild – moderate reactions): after resolution of the infusion reaction symptoms, the infusion should be resumed at a rate no greater than half the rate at which the infusion reaction developed. If the patient does not experience any further infusion reaction symptoms, an increase in the infusion rate is permitted, using appropriate steps and intervals according to the clinical situation until the maximum rate of 200 ml/h is reached (Table 5);
• Grade 3 (severe reactions): after resolution of the infusion reaction symptoms, the issue of resuming the infusion at a rate no greater than half the rate at which the reaction developed should be considered. If the patient does not experience any additional infusion reaction symptoms, an increase in the infusion rate is permitted, using appropriate steps and intervals (Table 5). In case of recurrence of Grade 3 symptoms, the procedure described above must be repeated. If a Grade 3 or higher infusion reaction occurs for the third time, Darzalex must be permanently discontinued;
• Grade 4 (life-threatening reactions): Darzalex must be permanently discontinued.

Missed Dose

If any scheduled dose of Darzalex is missed, this dose should be administered as soon as possible and the therapy schedule should be adjusted appropriately to maintain the interval between infusions.

Dose Adjustment

Dose reduction of Darzalex is not recommended. Delaying the dose administration may be required for recovery of blood cell counts in case of hematological toxicity development (see section “Special Instructions”). Information concerning medicinal products administered concomitantly with Darzalex is presented in the respective prescribing information.

Recommended Concomitant Medications

Medications administered prior to infusion

To reduce the risk of infusion reactions, administration of the following medications 1-3 hours before each Darzalex infusion is recommended for all patients.

• Corticosteroids (long or intermediate-acting)

Monotherapy: methylprednisolone at a dose of 100 mg (or equivalent), intravenously. After the 2nd infusion, the corticosteroid dose may be reduced (oral or IV form of methylprednisolone 60 mg).

Combination therapy: dexamethasone at a dose of 20 mg (or equivalent) before each Darzalex infusion . When dexamethasone is part of the treatment regimen, the therapeutic dose of dexamethasone replaces the premedication on days of Darzalex infusion. Dexamethasone is administered intravenously before the first Darzalex infusion; for subsequent infusions, oral administration may be considered. Additional background regimen-specific corticosteroids (e.g., prednisolone) should not be administered on days of Darzalex infusion when patients receive dexamethasone as premedication.

• Antipyretic (paracetamol orally at a dose from 650 to 1000 mg)
• Antihistamine (diphenhydramine orally or IV at a dose from 25 to 50 mg or an equivalent drug)

Medications administered after infusion

Administration of medications to reduce the risk of delayed infusion reactions is performed after the infusion according to the following scheme.

Monotherapy: corticosteroids orally (20 mg methylprednisolone or an equivalent dose of a long or intermediate-acting corticosteroid according to treatment standards) on the 1st and 2nd day after each Darzalex infusion (starting the day after the infusion day).

Combination therapy: consideration should be given to oral administration of methylprednisolone at a low dose (not more than 20 mg) or an equivalent drug on the day after Darzalex infusion.

However, if a background therapy-specific corticosteroid (e.g., dexamethasone, prednisolone) is administered on the day following Darzalex infusion, administration of additional post-infusion medications may not be required.

Additionally, patients with a history of chronic obstructive pulmonary disease should consider the need for short-acting and long-acting bronchodilators and inhaled corticosteroids after each infusion. If the patient does not experience any significant infusion reactions after the first 4 infusions, the inhaled medications used after infusion may be discontinued at the physician’s discretion.

Prevention of herpes zoster virus reactivation

Antiviral prophylaxis should be considered to prevent herpes zoster virus reactivation.

Special Patient Groups

Patients with renal impairment. Studies of daratumumab in patients with renal impairment have not been conducted. Based on population pharmacokinetic analysis, dose adjustment in patients with renal impairment is not required.

Patients with hepatic impairment. Studies of daratumumab in patients with hepatic impairment have not been conducted. Based on population pharmacokinetic data, dose adjustment in patients with hepatic impairment is not required.

Elderly patients. Dose adjustment is not required.

Children. The safety and efficacy of Darzalex in children under 18 years of age have not been established. No data available.

Method of Administration

Darzalex is intended for intravenous administration.

Darzalex is administered as an intravenous infusion after dilution with 0.9% sodium chloride solution.

Instructions for preparation, handling and disposal of the solution

The solution for infusion must be prepared under aseptic conditions as follows.

• Based on body weight, calculate the required dose (mg) and total volume (ml) of Darzalex, as well as the required number of vials of Darzalex.
• Check the color of Darzalex (it should be from colorless to brownish or brownish-yellowish or yellowish). Do not use the solution if there is discoloration, pronounced cloudiness, or presence of foreign particles.
• Under aseptic conditions, withdraw from the infusion bag/container a volume of 0.9% sodium chloride solution equal to the required volume of Darzalex.
• Withdraw the required amount of Darzalex and dilute it to the required volume by adding it to the infusion bag/container with 0.9% sodium chloride solution. Infusion bags/containers should be made of PVC, polypropylene (PP), polyethylene (PE), or a polyolefin mixture (polyethylene with polypropylene). The drug must be diluted under aseptic conditions. The unused portion of the drug from the vial must be discarded.
• Gently invert the bag/container to mix the solution. Shaking or freezing is prohibited.
• Before administration, parenteral drugs should be inspected visually for particulate matter and discoloration (where solution and container permit). Diluted solutions may contain very small transparent or white proteinaceous particles, as Daratumumab is a protein drug. Do not use the solution if there is discoloration, pronounced cloudiness, or presence of foreign particles.
• Since Darzalex does not contain preservatives, the diluted solution must be administered within 15 hours (including infusion time) at room temperature 15-25°C (59-77°F) and under room light.
• If the diluted solution is not used immediately, it can be stored for up to 24 hours at a temperature from 2°C (35.6°F) to 8°C (46.4°F) protected from light. Do not freeze.
• The diluted solution must be administered via intravenous infusion using an infusion set with a flow regulator and a built-in sterile, apyrogenic polyethersulfone filter (pore size 0.22-0.2 µm) with low protein binding. Infusion sets made of polyurethane, polybutadiene, polyvinyl chloride, polypropylene, or polyethylene should be used.
• Do not infuse Darzalex simultaneously with other medicinal products into the same intravenous line.
• Do not store any unused infusion solution for reuse. Any unused product and waste materials should be disposed of in accordance with local requirements.

Solution

Intravenous infusion according to a specific schedule.

Administration of the drug should be performed by a healthcare professional in a setting with immediate access to resuscitation equipment.

Administration of concomitant medications before and after the infusion is necessary to reduce the risk of infusion reactions.

The recommended dose is 16 mg/kg.

Adverse Reactions

This section provides information on adverse reactions (ARs). ARs are adverse events that, based on a comprehensive assessment of available data, were reasonably considered related to the use of daratumumab. In some cases, the relationship of the event to the use of daratumumab could not be definitively established. Furthermore, since the conditions of clinical trials vary significantly, the incidence of adverse reactions in the clinical trials of one drug cannot be directly compared with the incidence in clinical trials of another drug, and these values may not reflect the incidence observed in clinical practice.

The safety data described below reflect the experience with Darzalex (16 mg/kg) in 2066 patients with multiple myeloma, including 1910 patients receiving combination therapy with Darzalex and 156 patients receiving Darzalex as monotherapy.

The most frequent ARs (>20%) were infusion reactions, fatigue, nausea, diarrhea, constipation, pyrexia, dyspnea, cough, neutropenia, thrombocytopenia, anemia, peripheral edema, asthenia, peripheral sensory neuropathy, and upper respiratory tract infections. Serious ARs included sepsis, pneumonia, bronchitis, upper respiratory tract infections, pulmonary edema, influenza, pyrexia, dehydration, diarrhea, and atrial fibrillation.

Table 6 summarizes all ARs that occurred in patients administered Darzalex.

The frequency of ARs is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000) and very rare (<1/10000). Within each frequency group, where appropriate, adverse reactions are presented in order of decreasing severity.

Table 6. ARs in patients with multiple myeloma receiving Darzalex at a dose of 16 mg/kg

⁺ Denotes a grouping of terms.

* No Grade 4.

^# Infusion reactions include terms defined by investigators as infusion-related, see below.

ARs noted in clinical trials of combination therapy with carfilzomib (twice weekly at a dose of 20/56 mg/m²) and dexamethasone

The most frequent (≥ 20%) ARs were infusion reactions, diarrhea, fatigue, upper respiratory tract infections, and pneumonia. Serious ARs with an incidence in the patient group receiving Daratumumab-carfilzomib-dexamethasone combination therapy that was 2% greater than in the patient group receiving carfilzomib-dexamethasone combination therapy were: pneumonia, sepsis, influenza, fever, bronchitis, and diarrhea.

The frequency of ARs assessed as infusion reactions and occurring on the day of any daratumumab infusion or the day after the infusion was 18%, and occurring on the day of the first daratumumab infusion or the day after the first infusion was 12% in the patient group receiving Daratumumab-carfilzomib-dexamethasone combination therapy.

ARs noted in study 20160275* are diarrhea, nausea, fatigue, upper respiratory tract infections^a, pneumonia^b, bronchitis^c, back pain, and insomnia.

^a acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, viral respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, bacterial upper respiratory tract infection, viral upper respiratory tract infection;

^b atypical pneumonia, lung infection, pneumocystis jirovecii pneumonia, pneumonia, bacterial pneumonia, cytomegalovirus pneumonia, mycoplasma pneumonia, syncytial viral pneumonia, viral pneumonia;

^c bronchiolitis, bronchitis, viral bronchitis, tracheobronchitis.

* Note: Listed are ARs that occurred in at least 10% of patients and with a frequency at least 5% higher in the patient group receiving Daratumumab-carfilzomib-dexamethasone combination therapy. Laboratory abnormalities associated with hematological toxicity are excluded and listed separately below.

Laboratory parameters that worsened during therapy compared to baseline values are listed below.

Treatment-emergent hematological laboratory abnormalities in study 20160275 were: anemia, thrombocytopenia, leukopenia, neutropenia, lymphopenia.

Infusion Reactions

In clinical trials (monotherapy and combination therapy, n=2066), the frequency of infusion reactions of any grade was 37% with the first infusion (16 mg/kg, week 1) of Darzalex, 2% with the infusion in week 2, and 6% with subsequent infusions. The occurrence of Grade 3/4 infusion reactions with the second and subsequent infusions was noted in less than 1% of patients.

The median time to onset of reaction was 1.5 hours (range from 0 to 72.8 hours). The frequency of infusion rate modification due to reaction development was 36%. The median duration of infusion at a dose of 16 mg/kg for the 1st, 2nd, and subsequent infusions was 7, 4, and 3 hours, respectively.

Severe infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and arterial hypertension. Other undesirable infusion reactions included nasal congestion, cough, chills, throat irritation, vomiting, and nausea.

In clinical studies, when therapy with Darzalex was interrupted for autologous stem cell transplantation for a median of 3.75 months (range from 2.4 to 6.9 months) and subsequently resumed, the frequency of infusion reactions was 11% during the first infusion. Upon resumption of therapy, the same infusion rate and dilution volume were used as during the last infusion before therapy interruption. Infusion reactions occurring upon resumption of therapy after autologous stem cell transplantation were similar in symptoms and severity (grade 3/4: <1%) to those occurring in other clinical studies at week 2 and subsequent infusions.

In a clinical study in patients receiving combination therapy (n=97), the first administration of daratumumab at a dose of 16 mg/kg at week 1 was divided into 2 infusions on day 1 and day 2 at a dose of 8 mg/kg. The frequency of infusion reactions of any grade was 42%, with such reactions occurring in 36% of patients on day 1, in 4% of patients on day 2, and in 8% of patients during subsequent infusions. The median time to reaction onset was 1.8 hours (range from 0.1 to 5.4 hours). The frequency of infusion rate change due to reaction development was 30%. The median duration of infusions was 4.2 hours for day 1, 4.2 hours for day 2, and 3.4 hours for subsequent infusions.

Infections

Among patients who received Darzalex as part of combination therapy, grade 3 and 4 infections were noted:

• In studies in patients with relapsed and refractory multiple myeloma: daratumumab-bortezomib-dexamethasone (DVd): 21%, bortezomib-dexamethasone (Vd): 19%, daratumumab-lenalidomide-dexamethasone (DRd): 28%, lenalidomide-dexamethasone (Rd): 23%, daratumumab-pomalidomide-dexamethasone (DPd): 28%, daratumumab-carfilzomib-dexamethasone (DKd)^a: 36%, carfilzomib-dexamethasone (Kd)^a: 27%, DKd^b: 21%;
• In studies in patients with newly diagnosed multiple myeloma: daratumumab-bortezomib-melphalan-prednisone (D-VMP): 23%, bortezomib-melphalan-prednisone (VMP): 15%; DRd: 32%, Rd: 23%, daratumumab-bortezomib-thalidomide-dexamethasone (DVTd): 22%, bortezomib-thalidomide-dexamethasone (VTd): 20%.

The most frequently reported severe infection (grade 3 and 4) in the studies was pneumonia. In controlled studies, treatment discontinuation due to infections was noted in 1-4%. Fatal infections primarily included pneumonia and sepsis. Among patients who received Darzalex as part of combination therapy, fatal grade 5 infections were noted:

• In studies in patients with relapsed and refractory multiple myeloma: DVd: 1%, Vd: 2%, DRd: 2%, Rd: 1%, DPd: 2%; DKd^a: 5%, Kd^a: 3%; DKd^b: 0%;
• In studies in patients with newly diagnosed multiple myeloma: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%, DVTd: 0%, VTd: 0%.

^a when using carfilzomib 20/56 mg/m² twice weekly;

^b when using carfilzomib 20/70 mg/m² once weekly.

Special patient groups

Of the 2459 patients who received Darzalex at the recommended dose, 38% were aged 65 to 75 years and 15% were aged 75 years and older. No overall differences in efficacy depending on age were observed. The frequency of serious adverse reactions was higher in elderly patients than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1213), the most frequent serious adverse reactions that occurred more often in the elderly (≥ 65 years) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplantation (n=710), the most frequent serious adverse reaction that occurred more often in the elderly (≥ 75 years) was pneumonia.

Post-marketing experience

Adverse reactions (ARs) received during the post-marketing use of Darzalex are included in Table 7. Frequencies are presented according to the following classification: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000, including isolated reports), frequency unknown (frequency cannot be estimated from the available data).

In Table 7, adverse reactions are listed by frequency categories based on the frequency of spontaneous reports, as well as by frequency categories based on the exact frequency of occurrence in clinical trials, if known.

Table 7. Post-marketing ARs identified with the use of daratumumab

Contraindications

• Hypersensitivity to the components of the drug;
• Moderate and severe hepatic impairment;
• Pregnancy;
• Breastfeeding period;
• Children and adolescents under 18 years of age (due to lack of data on efficacy and safety).

Use in Pregnancy and Lactation

Pregnancy

There are currently no results from studies in humans or animals that have assessed the risk of using Darzalex during pregnancy. IgG1 monoclonal antibodies can cross the placental barrier after the first trimester of pregnancy. Therefore, Darzalex should not be used during pregnancy.

To prevent fetal exposure, women of childbearing potential should use effective methods of contraception during therapy with Darzalex and for 3 months after its discontinuation.

Breastfeeding period

It is currently unknown whether daratumumab is excreted in human or animal breast milk or whether this drug affects milk secretion. To date, no studies have been conducted to evaluate the effect of daratumumab on breastfed infants.

Maternal IgG is excreted in breast milk; however, it does not enter the bloodstream of newborns and infants in significant amounts because these proteins are broken down in the gastrointestinal tract and are not absorbed. Since the risks of the drug for infants associated with its ingestion with milk are unknown, a decision should be made to discontinue breastfeeding or discontinue Darzalex, taking into account the benefits of breastfeeding for the child and the benefits of this drug for the mother’s health.

Fertility

There are currently no data on the potential effects of daratumumab on male and female fertility.

Use in Hepatic Impairment

Contraindicated in moderate and severe hepatic impairment.

Use in Renal Impairment

Dosage adjustment in patients with renal impairment is not required.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Dosage adjustment in elderly patients is not required.

Special Precautions

Infusion reactions

Darzalex can cause serious infusion reactions, including anaphylactic reactions. Infusion reactions can be life-threatening; fatal outcomes have been reported.

Patients should be monitored during and after the infusion.

In clinical trials, infusion reactions were reported in approximately half of the patients who received Darzalex.

In most cases, infusion reactions occurred during the first infusion and were grade 1-2. In 4% of patients, infusion reactions were observed during more than one infusion. Serious reactions also occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema, and pulmonary edema. Clinical manifestations may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common symptoms included wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and arterial hypotension. No fatal infusion reactions were reported in clinical trials.

To reduce the risk of infusion reactions during treatment with Darzalex, patients should be premedicated with antihistamines, antipyretics, and corticosteroids. If infusion reactions of any severity occur, the administration of Darzalex should be interrupted and, if necessary, appropriate medication and supportive care should be initiated. In patients who developed grade 1, 2, or 3 infusion reactions, the infusion rate should be reduced upon resumption of the infusion. If an anaphylactic reaction or life-threatening grade 4 infusion reaction occurs, the administration of the drug should be permanently discontinued and necessary emergency care provided.

To reduce the risk of delayed infusion reactions, oral corticosteroids should be prescribed to all patients receiving Darzalex infusion. Furthermore, for patients with a history of chronic obstructive pulmonary disease, the use of additional post-infusion medications (e.g., inhaled corticosteroids, short- and long-acting bronchodilators) should be considered for the treatment of pulmonary complications should they arise.

Neutropenia/thrombocytopenia

Darzalex may enhance neutropenia and thrombocytopenia caused by background therapy.

Periodically during therapy, a complete blood count should be performed in accordance with the instructions for medical use of the drugs for background therapy. Patients with neutropenia should be monitored for clinical signs of infection. Delaying the next dose of Darzalex may be required to restore blood cell counts. Dose reduction of Darzalex is not recommended. The need for supportive therapy with blood transfusions or growth factors should be considered.

Effect on indirect antiglobulin test (indirect Coombs test) results

Daratumumab binds to the CD38 protein, which is present in small amounts on red blood cells, which may lead to a positive indirect Coombs test result. The daratumumab-associated positive indirect Coombs test result may persist for up to 6 months after the final infusion of this drug. It should be taken into account that the binding of daratumumab to red blood cells may interfere with the detection of antibodies to minor antigens in the patient’s serum. This does not affect the determination of AB0 and Rh blood groups.

Extended phenotyping and antibody screening should be performed before prescribing Darzalex.

Methods to reduce the influence of daratumumab include treating red blood cells with dithiothreitol (DTT) to disrupt binding with daratumumab or using other validated methods. Because the Kell antigen system is also sensitive to DTT treatment, Kell-negative units should be used after excluding or detecting the presence of alloantibodies using DTT-treated red blood cells. As alternative measures, phenotyping or genotyping can be performed.

In case of a planned blood transfusion, the blood transfusion department should be informed about this effect on the indirect antiglobulin test results (see the “Drug Interactions” section). If an emergency blood transfusion is necessary, ABO/RhD-compatible red blood cells can be administered without cross-matching, in accordance with local blood transfusion station rules.

Hepatitis B virus (HBV) reactivation

Cases of hepatitis B virus reactivation (some of which were fatal) have been reported in patients receiving Darzalex therapy. Screening for hepatitis B virus is recommended for all patients before starting Darzalex therapy.

Patients who are seropositive for HBV should be monitored for clinical and laboratory signs of hepatitis B virus reactivation during therapy and for at least 6 months after its completion. Measures should be taken according to current clinical guidelines. The need for consultation with a hepatitis specialist should also be assessed if indicated.

In patients with hepatitis B virus reactivation during Darzalex therapy, Darzalex therapy, as well as any concomitant corticosteroids and chemotherapeutic drugs, should be suspended, and appropriate therapy should be initiated. In patients with well-controlled hepatitis B virus reactivation, resumption of Darzalex therapy should be discussed with a physician experienced in HBV therapy.

Excipients

Each 5 ml or 20 ml vial of concentrate contains 0.4 mmol or 1.6 mmol (9.3 mg or 37.3 mg) of sodium, respectively. This information should be taken into account by patients on a controlled sodium diet.

Effect on ability to drive vehicles and operate machinery

Darzalex does not affect, or has a negligible effect on, the ability to drive vehicles and operate machinery. However, fatigue has been reported in patients treated with daratumumab, which should be taken into account when driving vehicles and operating machinery.

Overdose

Symptoms: no cases of overdose were registered in clinical trials. In studies, patients received doses up to 24 mg/kg, and the maximum tolerated dose was not reached.

Treatment: there is currently no known specific antidote for Darzalex. In case of overdose, the patient should be monitored for any complaints or symptoms. If they are detected, appropriate symptomatic therapy should be initiated immediately.

Drug Interactions

No studies on the interaction of daratumumab with other drugs have been conducted.

Based on a clinical pharmacokinetic assessment of daratumumab in combination with lenalidomide, thalidomide, bortezomib, carfilzomib, and dexamethasone, no clinically significant drug interaction was identified between daratumumab and these low molecular weight drugs.

Effect of Darzalex on laboratory test results

Effect on the indirect antiglobulin test (indirect Coombs test)

Daratumumab binds to the CD38 protein, which is present in small amounts on red blood cells, which may lead to a positive indirect Coombs test result. The daratumumab-associated positive indirect Coombs test result may persist for up to 6 months after the final infusion of this drug. It should be taken into account that the binding of daratumumab to red blood cells may interfere with the detection of antibodies to minor antigens in the patient’s serum. This does not affect the determination of AB0 and Rh blood groups.

Extended phenotyping and antibody screening should be performed before prescribing Darzalex.

The possibility of performing phenotyping before starting daratumumab therapy should be considered in accordance with local practice. Daratumumab does not affect red blood cell genotyping, and it can be performed at any time.

In case of a planned blood transfusion, the blood transfusion department should be informed about this effect on the indirect antiglobulin test results. If an emergency blood transfusion is necessary, ABO/RhD-compatible red blood cells can be administered without cross-matching, in accordance with local blood transfusion station rules.

Effect on immunofixation and serum protein electrophoresis

Daratumumab may be detected by serum protein electrophoresis and immunofixation methods used to detect pathogenic monoclonal immunoglobulins (M-protein). This may lead to false-positive results of serum protein electrophoresis and immunofixation in patients with IgG kappa myeloma protein, which affects the initial assessment of complete response to therapy according to the International Myeloma Working Group (IMWG) criteria. In patients with a persistent very good partial response to therapy, if an influence of daratumumab on the assessment result is suspected, a validated daratumumab-specific immunofixation test should be considered to distinguish between daratumumab and remaining M-proteins in the patient’s plasma and determine the complete response to therapy.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature from 2°C (35.6°F) to 8°C (46.4°F). Do not freeze. Do not shake.

Shelf Life

Shelf life – 24 months. Do not use after the expiration date.

After preparation, the solution can be stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F) protected from light for no more than 24 hours.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.