Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions reported in patients treated with sacituzumab govitecan were: neutropenia (67.6%), nausea (62.6%), diarrhoea (62.5%), fatigue (61.5%), alopecia (45.6%), anaemia (40.7%), constipation (36.2%), vomiting (33.6%), decreased appetite (25.7%), dyspnoea (22.1%) and abdominal pain (20.2%).
The most common grade 3 or higher adverse reactions were neutropenia (50.7%), leukopenia (10.5%), diarrhoea (10.3%), anaemia (9.3%), fatigue (6.8%), febrile neutropenia (6.1%), hypophosphataemia (4.2%), dyspnoea (3.1%), lymphopenia (2.9%), abdominal pain (2.8%), nausea (2.8%), vomiting (2.5%), hypokalaemia (2.5%), pneumonia (2.3%) and aspartate aminotransferase increased (2.2%).

The most frequently reported serious adverse reactions in patients treated with sacituzumab govitecan were febrile neutropenia (4.8%), diarrhoea (3.9%), neutropenia (2.6%) and pneumonia (2%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from three clinical studies involving 688 patients who received sacituzumab govitecan 10 mg/kg body weight for the treatment of metastatic TNBC and HR+/HER2- breast cancer. The median exposure to sacituzumab govitecan in this data set was 4.63 months.

The adverse reaction frequencies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than sacituzumab govitecan, such as the disease, other medicinal products or unrelated causes. The severity of adverse drug reactions was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defining grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, and 5 = death.

Adverse reactions are listed by System Organ Class and frequency category. Frequency categories 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); very rare (< 1/10 000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.


Table 2: List of adverse reactions

System organ class (SOC)             Frequency         Adverse reactions Infections and infestations
Very common       Urinary tract infection
Upper respiratory tract infection
Common            Sepsis
Pneumonia
Influenza
Bronchitis
Nasopharyngitis
Sinusitis
Oral herpes
Blood and lymphatic system disorders
Very common          Neutropenia1
Anaemia2
Leukopenia3
Lymphopenia4
Common            Febrile neutropenia
Thrombocytopenia5
Immune system disorders
Very common       Hypersensitivity6
Metabolism and nutrition disorders
Very common       Decreased appetite
Hypokalaemia
Hypomagnesaemia
Common            Dehydration
Hyperglycaemia
Hypophosphataemia
Hypocalcaemia
Hyponatraemia
Psychiatric disorders
Very common       Insomnia
Common            Anxiety
Nervous system disorders
Very common       Headache
Dizziness
Common            Dysgeusia
Vascular disorders
Common              Hypotension
Respiratory, thoracic and mediastinal disorders
Very common         Dyspnoea7
Cough
Common            Epistaxis
Productive cough
Rhinorrhoea
Nasal congestion
Upper airway cough syndrome
Gastrointestinal disorders
Very common       Diarrhoea
Vomiting
Nausea
Constipation
Abdominal Pain
Common            Neutropenic colitis8
Colitis
Stomatitis
Abdominal pain upper
Dyspepsia
Gastrooesophageal reflux disease
Abdominal distension

Uncommon                         Enteritis
Skin and subcutaneous tissue disorders
Very common                      Alopecia
Rash
Pruritus
Common                   Rash maculopapular
Skin hyperpigmentation
Dermatitis acneiform
Dry skin
Musculoskeletal and connective tissue disorders
Very common                     Back pain
Arthralgia
Common                   Musculoskeletal chest pain
Muscle spasms
Renal and urinary disorders
Common                   Haematuria
Proteinuria
Dysuria
General disorders and administration site conditions
Very common                      Fatigue9
Common                           Pain
Chills
Investigations
Common                   Weight decreased
Blood alkaline phosphatase increased
Activated partial thromboplastin time prolonged
Blood lactate dehydrogenase increased
Injury, poisoning and procedural complications
Uncommon                         Infusion related reaction
1: Includes the following preferred terms: neutropenia; neutrophil count decreased.
2: Includes the following preferred terms: anaemia; haemoglobin decreased; red blood cell count decreased.
3: Includes the following preferred terms: leukopenia; white blood cell count decreased.
4: Includes the following preferred terms: lymphopenia; lymphocyte count decreased.
5: Includes the following preferred terms: thrombocytopenia; platelet count decreased.
6: Hypersensitivity events reported up to the end of the day after treatment was administered. Includes events coded to the following preferred terms: dyspnoea; hypotension; flushing; erythema; chest discomfort; rhinitis allergic; wheezing; oedema; urticaria; anaphylactic reaction; mouth ulceration; skin exfoliation; swollen tongue; throat tightness.
7: Includes the following preferred terms: dyspnoea; dyspnoea exertional 8: Includes the preferred term of neutropenic colitis and events reported as typhlitis 9: Includes the following preferred terms: fatigue, asthenia



Description of selected adverse reactions

Neutropenia
The median time to onset of neutropenia (including febrile neutropenia) following the start of the first treatment cycle was 16 days. The median duration of neutropenia was 8 days.

Neutropenia occurred in 67.6% (465/688) of patients treated with sacituzumab govitecan, including Grade 3-4 neutropenia in 50.7% of patients. Neutropenia was the reason for dose reduction in 12.4% of patients. Neutropenic colitis was observed in 1% (7/688) of patients.

Febrile neutropenia occurred in 6.1% (42/688) of patients treated with sacituzumab govitecan. Febrile neutropenia was the reason for dose reduction in 2.9% of patients.

Use in patients with reduced UGT1A1 activity
The incidence of Grade 3-4 neutropenia was 60.6% (43/71) in patients homozygous for the UGT1A1*28 allele, 52.9% (144/272) in patients heterozygous for the UGT1A1*28 allele, and 49.1% (140/285) in patients homozygous for the wild-type allele. The incidence of Grade 3-4 febrile neutropenia was 14.1% (10/71) in patients homozygous for the UGT1A1*28 allele, 5.9% (16/272) in patients heterozygous for the UGT1A1*28 allele, and 4.6% (13/285) in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anaemia was 15.5% (11/71) in patients homozygous for the UGT1A1*28 allele, 7.4% (20/272) in patients heterozygous for the UGT1A1*28 allele, and 8.1% (23/285) in patients homozygous for the wild-type allele.

Compared to patients homozygous for the wild-type allele, earlier median onset of neutropenia and anaemia was observed in patients homozygous for the UGT1A1*28 allele and in patients heterozygous for the UGT1A1*28 allele.

Diarrhoea
The median time to onset of diarrhoea following the start of the first treatment cycle was 13 days. The median duration of diarrhoea was 8 days.

Diarrhoea occurred in 62.5% (430/688) of patients treated with sacituzumab govitecan. Grade 3 events occurred in 10.3% (71/688) of patients. Three of 688 patients (< 1%) discontinued treatment because of diarrhoea.

Hypersensitivity
Hypersensitivity reactions reported up to the end of the day following dosing occurred in 33.0% (227/688) of patients treated with sacituzumab govitecan. Grade 3 and above hypersensitivity occurred in 1.7% (12/688) of patients treated with sacituzumab govitecan. The incidence of hypersensitivity reactions leading to permanent discontinuation of sacituzumab govitecan was 0.1% (1/688).

Immunogenicity
Across clinical studies in patients treated with sacituzumab govitecan, 9 (1.1%) of 785 patients developed antibodies to sacituzumab govitecan; 6 of these patients (0.8% of all patients treated with sacituzumab govitecan) had neutralizing antibodies against sacituzumab govitecan.
Special Populations
There was no difference in discontinuation rate due to adverse events in patients aged 65 years or older compared with younger patients with mTNBC. There was a higher discontinuation rate due to adverse reactions in patients aged 65 years or older (14%) compared with younger patients (3%) with HR+/HER2- metastatic breast cancer. There was a higher incidence rate of serious adverse events in patients aged 75 years or older (67%) compared to patients aged 65 years or older (43%) and patients younger than 65 years (24%) with HR+/HER2- metastatic breast cancer.

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.

You can report any side effects to the Ministry of Health by clicking on the link "Report side effects due to medical treatment" that is located on the Ministry of Health homepage (www.health.gov.il) which redirects to the online form for reporting side effects, or by clicking on the link: https://sideeffects.health.gov.il