2016年5月27日,美国制药巨头强生的抗癌药Darzalex（daratumumab）在欧盟被批准用于治疗难治性和复发性多发性骨髓瘤成人患者，该药物是一种靶向CD38的人源化单克隆抗体，此次批准是基于之前欧盟委员会提出的加速评估建议。
去年11月份，Darzalex（daratumumab）首度获得FDA批准，用于此前接受过蛋白酶抑制剂（PI）治疗（如武田的Velcade）或免疫调节剂（如Celgene的Revlimid ）治疗却仍发生疾病进展的多发性骨髓瘤患者。
Darzalex（daratumumab）此次获批是基于一项名为SIRIUS的II期临床试验数据，结果表明，daratumumab针对难治性多发性骨髓瘤患者的客观缓解率为30%左右，一年以上整体生存率达到了65%。此外，一项名为GEN501的I/II期临床试验结果也得出了类似的结果。
关于多发性骨髓瘤：
多发性骨髓瘤（multiple myeloma，MM）是一种浆细胞癌，见于骨髓。多发性骨髓瘤中，一组浆细胞（或骨髓瘤细胞）转化为癌细胞并增生，使浆细胞的数目高于正常水平。由于浆细胞在体内广泛游走，有可能累及体内多数骨骼，可能导致压缩性骨折、骨溶解性病灶和相关疼痛。多发性骨髓瘤可导致若干严重健康问题，累及骨骼、免疫系统、肾脏和个体的红细胞计数，部分较常见症状包括骨骼疼痛和疲乏，疲乏是贫血的症状。多发性骨髓瘤属罕见癌症，每年新发病例在美国约为20，000人、全球约为114，000人。

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产地国家：德国
原产地英文商品名:
Darzalex 100mg/5nl(20mg/ml)/Vial 
原产地英文药品名:
daratumumab
中文参考商品译名:
Darzalex注射剂 100毫克/5毫升(20毫克/毫升)/瓶
中文参考药品译名:
达雷木单抗
生产厂家英文名:
Janssen Biotech
--------------------------------------------------
产地国家：德国
原产地英文商品名:
Darzalex 400mg/20nl(20mg/ml)/Vial 
原产地英文药品名:
daratumumab
中文参考商品译名:
Darzalex注射剂 400毫克/20毫升(20毫克/毫升)/瓶 
中文参考药品译名:
达雷木单抗
生产厂家英文名:
Janssen Biotech
DARZALEX 20 mg/mL concentrate for solution for infusion.
1. Name of the medicinal product
DARZALEX 20 mg/mL concentrate for solution for infusion.
2. Qualitative and quantitative composition
Each 5 mL vial contains 100 mg of daratumumab (20 mg daratumumab per mL).
Each 20 mL vial contains 400 mg of daratumumab (20 mg daratumumab per mL).
Daratumumab is a human monoclonal IgG1κ antibody against CD38 antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
Excipients with known effect
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.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Concentrate for solution for infusion.
The solution is colourless to yellow.
4. Clinical particulars
4.1 Therapeutic indications
DARZALEX as monotherapy is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.
4.2 Posology and method of administration
DARZALEX should be administered by a healthcare professional, in an environment where resuscitation facilities are available.
Posology
Pre- and post-infusion medications should be administered to reduce the risk of infusion-related reactions (IRRs) with daratumumab. See below “Recommended concomitant medications”, “Management of infusion-related reactions” and section 4.4.
Dose
The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule:
Table 1: Dosing schedule for DARZALEX

Schedule	Weeks
Weekly	Weeks 1 to 8
Every two weeks	Weeks 9 to 24
Every four weeks	Week 25 onwards until disease progression

Following dilution the DARZALEX infusion should be intravenously administered at the appropriate initial infusion rate, as presented in Table 2 below. Incremental escalation of the infusion rate should be considered only if the previous infusion of daratumumab was well-tolerated as defined in Table 2.
Table 2: Infusion rates for DARZALEX administration

Dilution volume	Initial infusion rate (first hour)	Increments of infusion rate	Maximum infusion rate
First infusion	1,000 mL	50 mL/hour	50 mL/hour every hour	200 mL/hour
Second infusiona	500 mL	50 mL/hour	50 mL/hour every hour	200 mL/hour
Subsequent infusionsb	500 mL	100 mL/hour	50 mL/hour every hour	200 mL/hour

a Modified rates should only be used if the first infusion of DARZALEX was well-tolerated as defined by an absence of ≥ Grade 1 IRRs during the first 3 hours.
b Modified rates should only be used if the first 2 infusions of DARZALEX were well-tolerated as defined by an absence of ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr.
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 below (see section 4.4).
• Grade 1-2 (mild to moderate): Once the patient's condition is stable, 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 appropriate (Table 2).
• Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lower, 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 2). The procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX if the patient experiences a ≥ Grade 3 infusion-related symptom at the subsequent infusion.
• 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.
Recommended concomitant medications
Pre-infusion medication
Pre-infusion medications should be administered to reduce the risk of IRRs to all patients approximately 1 hour prior to every infusion of DARZALEX as follows:
• intravenous corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate-acting or long-acting corticosteroid) plus
• oral antipyretics (paracetamol 650 to 1,000 mg), plus
• oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent).
Following the second infusion, the dose of intravenous corticosteroid may be reduced (methylprednisolone 60 mg) at the discretion of the physician.
Post-infusion medication
For the prevention of delayed IRRs, oral corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid in accordance with local standards) should be administered on each of the two days following all infusions (beginning the day after the infusion).
Additionally, for patients with a history of obstructive pulmonary disorder, 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 a population pharmacokinetic (PK) analysis no dosage adjustment is necessary for patients with renal impairment (see section 5.2).
Hepatic impairment
No formal studies of daratumumab in patients with hepatic impairment have been conducted.
Based on a population PK analysis, no dosage adjustments are necessary for patients with mild hepatic impairment (Total Bilirubin [TB] 1.0 x to 1.5 x upper limit of normal [ULN] or aspartate aminotransferase [AST] > ULN). Daratumumab has not been studied in patients with moderate to severe hepatic impairment (TB > 1.5 x ULN and any AST), therefore no dose recommendations can be made in these patient populations (see section 5.2).
Elderly
No dose adjustments are considered necessary (see section 5.2).
Paediatric population
The safety and efficacy of DARZALEX in children aged below 18 years of age have not been established.
No data are available (see section 5.1).
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 section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Infusion-related reactions
Infusion-related reactions (IRRs) were reported in approximately half of all patients treated with DARZALEX. Monitor such patients throughout the infusion and the post-infusion period.
The majority (95%) of IRRs occurred at the first infusion. Five percent of all patients had an IRR at more than one infusion. Symptoms predominantly included (≥ 5%) nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnoea, and nausea, and were mild to moderate in severity. Severe IRRs (3%) including bronchospasm (1.3%), hypertension (0.6%), and hypoxia (0.6%) were also reported (see section 4.8).
Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment with DARZALEX. DARZALEX infusion should be interrupted for IRRs of any severity. Medical management/supportive treatment for IRRs should be instituted as needed. The infusion rate should be reduced when re-starting the infusion (see section 4.2).
For the prevention of delayed IRRs, oral corticosteroids should be administered to all patients the first and second day after all infusions. Additionally the use of post-infusion medications (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of obstructive pulmonary disorder to manage respiratory complications should they occur (see section 4.2).
DARZALEX therapy should be permanently discontinued in the event of life-threatening IRRs.
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 recognised 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.
Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may be considered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping is not impacted by daratumumab and may be performed at any time.
In the event of a planned transfusion blood transfusion centres should be notified of this interference with indirect antiglobulin tests (see section 4.5). If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.
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 section 4.5). 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.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are unlikely to represent major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of daratumumab. Due to the high affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug-metabolising enzymes.
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 (see section 4.4). Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locally validated methods. 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. Alternatively, phenotyping or genotyping may also be considered (see section 4.4).
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 by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, consider other methods to evaluate the depth of response.
4.6 Fertility, pregnancy and lactation
Women of child-bearing potential/Contraception
Women of child-bearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment.
Pregnancy
There are no human or animal data to assess the risk of daratumumab use during pregnancy. IgG1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore daratumumab 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 medicine, the patient should be informed of the potential risk to the fetus.
Breast-feeding
It is not known whether daratumumab is excreted into human or animal milk.
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.
The effect of daratumumab on newborns/infants is unknown. A decision should be made whether to discontinue breast-feeding or to 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 (see section 5.3).
4.7 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.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions were IRRs (48%); see section 4.4. Other frequently reported adverse reactions (≥ 20%) were fatigue (39%), pyrexia (21%), cough (21%), nausea (27%), back pain (23%), upper respiratory tract infection (20%), anaemia (27%), neutropenia (22%) and thrombocytopenia (20%).
Tabulated list of adverse reactions
Table 3 summarizes the adverse drug reactions that occurred in patients receiving DARZALEX. The data 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 20 months.
Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.
Table 3: Adverse reactions in multiple myeloma patients treated with DARZALEX 16 mg/kg

System Organ Class	Adverse reaction	Frequency (All grades)	Incidence (%)
			All grades	Grade 3-4
Infections and infestations	Pneumonia**	Very common	11	6
	Upper respiratory tract infection		20	1
	Nasopharyngitis		15	0
Blood and lymphatic system disorders	Anaemia	Very common	27	17
	Neutropenia		22	12
	Thrombocytopenia		20	14
	Lymphopenia	Common	6	6
Metabolism and nutrition disorders	Decreased appetite	Very common	15	1
Nervous system disorders	Headache	Very common	12	1
Vascular disorders	Hypertension	Very common	10	4
Respiratory, thoracic and mediastinal disorders	Cough	Very common	21	0
	Nasal Congestion		17	0
	Dyspnoea		15	1
Gastrointestinal disorders	Nausea	Very common	27	0
	Diarrhoea		16	1
	Constipation		15	0
	Vomiting		13	0
Musculoskeletal and connective tissue disorders	Back pain	Very common	23	2
	Arthralgia		17	0
	Pain in extremity		15	1
	Musculoskeletal chest pain		12	1
General disorders and administration site conditions	Fatigue	Very common	39	2
	Pyrexia		21	1
	Chills		10	0
Injury, poisoning and procedural complications	Infusion-related reactiona	Very common	48	3
No grade 4 Pneumonia also includes the terms pneumonia streptococcal and lobar pneumonia a Infusion-related reaction includes terms determined by investigators to be related to infusion, see below

Infusion-related reactions
Infusion-related reactions include but are not limited to the following multiple adverse reaction terms: nasal congestion, cough, chills, allergic rhinitis, throat irritation, dyspnoea, nausea (all ≥ 5%), bronchospasm (2.6%), hypertension (1.3%) and hypoxia (1.3%).
The median time to onset of a reaction was 1.5 hours (range: 0.02 to 9.3 hours). Median durations of infusion for the first, second and subsequent infusions were 7.0, 4.6 and 3.4 hours respectively.
Haemolysis
There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed in clinical studies and post-marketing safety data.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard.
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
E-mail: medsafety@hpra.ie
4.9 Overdose
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
Treatment
There is no known specific antidote for daratumumab overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment should be instituted immediately.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC24
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 multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilize multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are susceptible to daratumumab mediated cell lysis.
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 tumour 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+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. However, baseline levels of NK cells or kinetics of NK cell decrease did not show an association with clinical response.
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 daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.
Immunogenicity
Patients (n = 199) were evaluated for anti-therapeutic antibody responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab treatment, none of the patients tested positive for anti-daratumumab antibodies.
However, the employed assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab. Therefore, the incidence of antibody development might not have been reliably determined.
Clinical efficacy and safety
The clinical efficacy and safety of DARZALEX for the treatment of patients with relapsed and refractory multiple myeloma 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), 11% of patients were ≥ 75 years of age, 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 proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.
Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC) assessment are presented in Table 4 below.
Table 4: IRC assessed efficacy results for study MMY2002

Efficacy endpoint	DARZALEX 16 mg/kg N = 106
Overall response rate1 (ORR: sCR+CR+VGPR+PR) [n (%)] 95% CI (%)	31 (29.2) (20.8, 38.9)
Stringent complete response (sCR) [n (%)]	3 (2.8)
Complete response (CR) [n]	0
Very good partial response (VGPR) [n (%)]	10 (9.4)
Partial response (PR) [n (%)]	18 (17.0)
Clinical Benefit Rate (ORR+MR) [n(%)]	36 (34.0)
Median Duration of Response [months (95% CI)]	7.4 (5.5, NE)
Median Time to Response [months (range)]	1 (0.9; 5.6)
1 Primary efficacy endpoint (International Myeloma Working Group criteria) CI = confidence interval; NE = not estimable; MR = minimal response

Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy.
At a survival update with a median duration of follow-up of 14.7 months, median Overall Survival (OS) was 17.5 months (95% CI:13.7, not estimable ).
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.
Pre-planned interim analysis showed that 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).
At a survival update with a median duration of follow-up of 15.2 months, median OS was not reached (95% CI: 19.9 months, not estimable), with 74% of subjects still alive.
Cardiac electrophysiology
Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect of daratumumab on the QTc interval was evaluated in an open-label study for 83 patients (Study GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (4 to 24 mg/kg). Linear mixed PK-PD analyses indicated no large increase in mean QTcF interval (i.e., greater than 20ms) at daratumumab Cmax.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with DARZALEX in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme.
This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The pharmacokinetics (PK) of daratumumab following intravenous administration 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 in two clinical trials (150 subjects received 16 mg/kg).
In the 1- to 24 mg/kg cohorts, peak serum concentrations (Cmax) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Following the last weekly infusion, Cmax increased in a greater than dose-proportional manner, consistent with target mediated drug disposition. 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 minimised and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumour 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. The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are insufficient data for a reliable estimation. 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 schedule and dose of 16 mg/kg, the mean (SD) serum Cmax value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.
Based on the population PK analysis, daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The mean (SD) central volume of distribution is 56.98 (18.07) mL/kg.
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.
Special populations
Age and gender
Based on population PK analysis, age (range: 31-84 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged < 65 years, n = 127) and older (aged ≥ 65 years, n = 96; aged ≥ 75years, n = 18; aged ≥85 years, n = 0) patients.
Gender [female (n = 91), male (n = 132)] did not affect exposure of daratumumab to a clinically relevant degree.
Renal impairment
No formal studies of daratumumab in patients with renal impairment have been conducted. A population PK analysis was performed based on pre-existing renal function data in patients receiving daratumumab, including 71 with normal renal function (creatinine clearance [CRCL] ≥ 90 mL/min), 78 with mild renal impairment (CRCL < 90 and ≥ 60 mL/min), 68 with moderate renal impairment (CRCL < 60 and ≥ 30 mL/min), and 6 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 daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.
A population PK analysis was performed to evaluate the effect of hepatic impairment as defined using the National Cancer Institute (NCI) criteria of hepatic dysfunction on the clearance of daratumumab based on pre-existing hepatic function data in 223 patients. No clinically important differences in the exposure to daratumumab were observed between patients with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST > ULN; n = 34) and those with normal hepatic function (TB and AST ≤ ULN; n = 189). Daratumumab has not been studied in patients with moderate (TB > 1.5 x to 3 x ULN and any AST) or severe (TB > 3 x ULN and any AST) hepatic impairment.
Race
Based on the population PK analysis the exposure to daratumumab was similar between white (n = 197) and non-white (n = 26) subjects.
5.3 Preclinical safety data
Toxicology data have been derived from studies with daratumumab in chimpanzees and with a surrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has been conducted.
Carcinogenicity and mutagenicity
No animal studies have been performed to establish the carcinogenic potential of daratumumab.
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.
6. Pharmaceutical particulars
6.1 List of excipients
Glacial acetic acid
Mannitol (E421)
Polysorbate 20
Sodium acetate trihydrate
Sodium chloride
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened vials
18 months
After dilution
From a microbiological point of view, unless the method of opening/ dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should be no more than 24 hours at refrigerated conditions (2 °C-8 °C) protected from light, followed by 15 hours (including infusion time) at room temperature (15°C - 25°C) and room light.
6.4 Special precautions for storage
Store in a refrigerator (2 °C-8 °C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
5 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off button containing 100 mg of daratumumab. Pack size of 1 vial.
20 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off button containing 400 mg of daratumumab. Pack size of 1 vial.
6.6 Special precautions for disposal and other handling
This medicinal product is for single-use only.
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 colourless to yellow. Do not use if opaque particles, discolouration 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 section 4.2). 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.
• Visually inspect parenteral medicinal products for particulate matter and discolouration prior to administration. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discolouration 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) 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) 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 micrometre). 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.
7. Marketing authorisation holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
8. Marketing authorisation number(s)
EU/1/16/1101/001
EU/1/16/1101/002
9. Date of first authorisation/renewal of the authorisation
20 May 2016
10. Date of revision of the text
20 May 2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.