Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent adverse reactions of any grade (≥20 % patients) with daratumumab (either intravenous or subcutaneous formulations) when administered either as monotherapy or combination treatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea atrial fibrillation and syncope.

With the exception of IRRs (see Table 5 below), the safety profile of DARZALEX 120MG/ML S.C.
1,800MG subcutaneous formulation (evaluated in 260 and 258 patients treated with the subcutaneous and intravenous formulations respectively) from the phase III study MMY3012 was similar to the known safety profile of the intravenous formulation. Neutropenia is the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation compared to intravenous daratumumab (grade 3 or 4: 13% vs 8%, respectively).


Tabulated list of adverse reactions
Table 5 summarises the adverse reactions that occurred in patients receiving DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation or intravenous formulation of daratumumab.

The data reflects exposure to DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation (1,800 mg) in 490 patients with multiple myeloma (MM) including 260 patients from a phase III active-controlled study (MMY3012) who received DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection as monotherapy and three open-label, clinical studies in which patients received DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection either as monotherapy (N=31, MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection in combination with either bortezomib, melphalan and prednisone (D-VMP, n=67), lenalidomide and dexamethasone (D-Rd, n=65) or bortezomib, lenalidomide and dexamethasone (D-VRd, n=67).

The safety data also reflects exposure to intravenous daratumumab (16 mg/kg) in 2324 patients with multiple myeloma including 1910 patients who received intravenous daratumumab in combination with background regimens and 414 patients who received intravenous daratumumab as monotherapy.
Post-marketing adverse reactions are also included.

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, adverse reactions are presented in the order of decreasing seriousness.


Table 5:     Adverse reactions in multiple myeloma patients treated with intravenous daratumumab or subcutaneous daratumumab
System organ class        Adverse reaction               Frequency         Incidence (%) Any grade     Grade 3-4
Infections and              Upper respiratory tract      Very common       38%           2% infestations               infectiona
Bronchitisa                  Very common       14%           2%
Pneumoniaa                   Very common       14%           9%
Urinary tract infection      Common            7%            1%
Influenza                    Common            4%            1%#
Sepsisa                      Common            4%            3%
Cytomegalovirus infectiona   Common            1%            <1%#
COVID-19d                    Common            7             4
Hepatitis B Virus            Uncommon          <1%           <1% reactivationa
Blood and lymphatic         Neutropeniaa                 Very common       40%           33% system disorders            Thrombocytopeniaa            Very common       30%           18% Anaemiaa                     Very common       27%           12%
Lymphopeniaa                 Very common       13%           11%
Leukopeniaa                  Very common       11%           6%
Immune system               Hypogammaglobulinemiaa       Common            2             <1# disorders                  Anaphylactic reactionb       Rare              -             - Metabolism and              Decreased appetite           Very common       10%           1% nutrition disorders         Hyperglycaemia               Common            6%            3% Hypocalcaemia                Common            5%            1%
Dehydration                  Common            2%            1%#
Psychiatric disorders       Insomnia                     Very common       14%           1%# Nervous system              Peripheral sensory           Very common       26%           3% disorders                    neuropathy
Headache                     Very common       11%           <1%#
Dizziness                    Common            9%            <1%#
Paraesthesia                 Common            9%            <1%
Syncope                      Common            3             2#
Cardiac disorders           Atrial fibrillation          Common            3%            1% Vascular disorders          Hypertensiona                Very common       10%           5% Respiratory, thoracic             Cougha                              Very common               22%              <1%# and mediastinal                   Dyspnoeaa                           Very common               18%              2% disorders                         Pulmonary oedemaa                   Common                    1%               <1% Gastrointestinal                  Diarrhoea                           Very common               29%              3% disorders                         Constipation                        Very common               28%              1% Nausea                              Very common               23%              1%# Vomiting                            Very common               14%              1%# Pancreatitisa                       Common                    1%               <1% Skin and subcutaneous             Rash                                Common                    9%               <1%# tissue disorders                  Pruritus                            Common                    5%               <1%# Musculoskeletal and               Back pain                           Very common               17%              2% connective tissue                 Muscle spasms                       Very common               12%              <1%# disorders                         Arthralgia                          Very common               10%              1%# Musculoskeletal chest pain          Common                    6%               <1%# General disorders and             Fatigue                             Very common               23%              3% administration site               Oedema peripherala                  Very common               22%              1% conditions                        Pyrexia                             Very common               22%              1% Asthenia                            Very common               18%              2% Chills                              Common                    9%               <1%# Injection site erythemae            Common                    4%               0 Injection site reactionsd,e         Common                    8%               0 Injury, poisoning and             Infusion-related reactionsc procedural                          Daratumumab                       Very common               39%              5% complications                        intravenousf
Daratumumab                       Very common               11%              1%# subcutaneouse
#
No grade 4 a
Indicates a grouping of terms.
b
Based on post-marketing adverse reactions.
c
Infusion-related reactions includes terms determined by investigators as related to infusion/injection of daratumumab.
d
Injection site reactions includes terms determined by investigators as related to injection of daratumumab.
e
Frequency based on daratumumab subcutaneous studies only (N=490).
f
Frequency based on daratumumab intravenous studies only (N=2324).
Note: Based on 2814 multiple myeloma patients treated with daratumumab intravenous or daratumumab subcutaneous.
g
Incidence is based on a subset of patients who received at least one dose of study treatment on or after 01 February 2020 (the start of the COVID-19 pandemic) from studies MMY3003, MMY3006, MMY3008 and MMY3013.
Description of selected adverse reactions

Infusion-related reactions (IRRs)
In clinical studies (monotherapy and combination treatments; N=490) with DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation, the incidence of any grade IRRs was 10.2% with the first injection of DARZALEX 120MG/ML S.C. 1,800MG (1,800 mg, week 1), 0.2% with the week 2 injection, and 0.8% with subsequent injections. Grade 3 IRRs were seen in 1.4% of patients. No patients had grade 4 IRRs.

Signs and symptoms of IRR may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, blurred vision and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see section 4.4).

Injection site reactions (ISRs)
In clinical studies (N=490) with 1,800MG daratumumab subcutaneous formulation, the incidence of any grade injection site reaction was 8.2%. There were no grade 3 or 4 ISRs. The most common (≥1%) ISRs were erythema, injection site induration, pruritis.


Infections
In patients receiving DARZALEX 120MG/ML S.C. 1,800MG as monotherapy, the overall incidence of infections was similar between DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation (52.9%) versus intravenous daratumumab groups (50.0%). Grade 3 or 4 infections also occurred at similar frequencies between DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation (11.7%) and intravenous daratumumab (14.3%). Most infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies.

In patients receiving intravenous daratumumab combination therapy, the following were reported: Grade 3 or 4 infections:
Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28% Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.
Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In 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 intravenous daratumumab combination therapy, fatal infections (grade 5) were reported as follows:
Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2% Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.
Key: D=daratumumab; Vd=bortezomib-dexamethasone; Rd=lenalidomide-dexamethasone; Pd=pomalidomide- dexamethasone; VMP=bortezomib-melphalan-prednisone; VTd=bortezomib-thalidomide-dexamethasone.

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.

Other special populations
In the phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was consistent with the overall population (see section 5.1).

Elderly patients
Of the 3207 patients who received daratumumab (n=490 subcutaneous; n=2717 intravenous) at the recommended dose, 38% were 65 to 75 years of age, and 17% were 75 years of age or older. No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1827), 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=777), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form (https://sideeffects.health.gov.il/)