Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent adverse reactions of any grade (≥ 20% patients) were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, asthenia, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were sepsis, pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

Tabulated list of adverse reactions
Table 6 summarises the adverse reactions that occurred in patients receiving DARZALEX 20MG/ML I.V. The data reflects exposure to DARZALEX 20MG/ML I.V (16 mg/kg) in 2066 patients with multiple myeloma including 1910 patients who received DARZALEX 20MG/ML I.V in combination with background regimens and 156 patients who received DARZALEX 20MG/ML I.V as monotherapy. Post-marketing adverse reactions are also included.

In study MMY3006, the number of CD34+ cell yield was numerically lower in the D-VTd arm compared with the VTd arm (Median: D-VTd: 6.3 x 106/kg; VTd 8.9 x 106/kg) and among those who completed mobilisation, more patients in the D-VTd group received plerixafor compared to those in the VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitution was similar among the transplanted subjects in the D-VTd and VTd arms (D-VTd: 99.8%; VTd: 99.6%; as measured by the recovery of neutrophils > 0.5 x 109/L, leukocytes > 1.0 x 109/L, and platelets > 50 x 109/L without transfusion).
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and very rare (<1/10000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.


Table 6:    Adverse reactions in multiple myeloma patients treated with DARZALEX 20MG/ML I.V 16 mg/kg
System organ class           Adverse reaction        Frequency       Incidence (%) Any grade Grade 3-4
Infections and infestations  Upper respiratory tract Very common infectiona                              41           3
Bronchitis  a
17           2
Pneumoniaa                              16           10
Urinary tract infection Common          8            1
Influenza                               5            1*
Sepsisa                                 4            4
Cytomegalovirus infectiona                              1            <1*
COVID-19      d
7            4
Hepatitis B Virus       Uncommon        -            - reactivationb
Blood and lymphatic system Neutropeniaa              Very common     44           39 disorders                    Thrombocytopenia    a
31           19
Anaemiaa                                27           12
Lymphopeniaa                            14           11
Leukopeniaa                             12           6
Immune system disorders      Hypogammaglobuline Common miaa                                    3            <1*
Anaphylactic reactionb Rare             -            -
Metabolism and nutrition     Decreased appetite      Very common     12           1 disorders                    Hyperglycaemia          Common          7            3 Hypocalcaemia                           6            1
Dehydration                             3            1*
Nervous system disorders     Peripheral sensory      Very common     32           3 neuropathy
Headache                                12           <1*
Paraesthesia                            11           <1
Syncope                 Common          2            2*
Cardiac disorders            Atrial fibrillation     Common          4            1 Vascular disorders           Hypertensiona           Very common     10           5 Respiratory, thoracic and    Cough  a
Very common     25           <1* mediastinal disorders        Dyspnoeaa                               21           3 Pulmonary oedemaa       Common          1            <1
Gastrointestinal disorders   Constipation            Very common     33           1 Diarrhoea                               32           4
Nausea                                  26           2*
Vomiting                                16           1* a
Pancreatitis            Common          1            1
Musculoskeletal and          Back pain               Very common     18           2 connective tissue disorders Muscle spasms                            14           <1* General disorders and        Fatigue                 Very common     26           4 administration site                              a
Oedema peripheral                       26           1 conditions                   Pyrexia                                 23           2 Asthenia                                21           2
Chills                  Common          9            <1*
Injury, poisoning and        Infusion-related        Very common     40           4 procedural complications     reactionc


* No grade 4 a
Indicates grouping of terms b
Post-marketing adverse reaction c
Infusion-related reaction includes terms determined by investigators to be related to infusion, see below d
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=2066) the incidence of any grade IRRs was 37% with the first (16 mg/kg, week 1) infusion of DARZALEX 20MG/ML I.V, 2% with the week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a grade 3/4 IRR with the week 2 or subsequent infusions.

The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 36%. Median durations of 16 mg/kg infusions for the 1st week, 2nd week and subsequent infusions were approximately 7, 4 and 3 hours respectively.
Severe IRRs included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma), hypoxia, and hypertension. Other adverse IRRs included nasal congestion, cough, chills, throat irritation, blurred vision, vomiting and nausea (see section 4.4).

When DARZALEX 20MG/ML I.V dosing was interrupted in the setting of ASCT (study MMY3006) for a median of 3.75 (range: 2.4; 6.9) months, upon re-initiation of DARZALEX 20MG/ML I.V the incidence of IRRs was 11% at first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX 20MG/ML I.V infusion prior to interruption due to ASCT. IRRs occurring at re-initiation of DARZALEX 20MG/ML I.V following ASCT were consistent in terms of symptoms and severity (grade 3/4: <1%) with those reported in previous studies at week 2 or subsequent infusions.

In study MMY1001, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at week 1 split over two days i.e. 8 mg/kg on day 1 and day 2 respectively. The incidence of any grade IRRs was 42%, with 36% of patients experiencing IRRs on day 1 of week 1, 4% on day 2 of week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for week 1-day 1, 4.2 h for week 1- day 2, and 3.4 hours for the subsequent infusions.

Infections
In patients receiving DARZALEX 20MG/ML I.V combination therapy, grade 3 or 4 infections were reported as follows:
Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 28%, 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 DARZALEX 20MG/ML I.V 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 2459 patients who received DARZALEX 20MG/ML I.V at the recommended dose, 38% were 65 to 75 years of age, and 15% 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=1213), the most common serious adverse reactions that occurred more frequently in elderly (≥65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia.


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/