Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
The most commonly reported adverse reactions related to HALAVEN, are bone marrow suppression manifested as neutropenia, leucopenia, anaemia, thrombocytopenia with associated infections. New onset or worsening of pre-existing peripheral neuropathy has also been reported. Gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, and stomatitis are among reported undesirable effects. Other undesirable effects include fatigue, alopecia, increased liver enzymes, sepsis and musculoskeletal pain syndrome.

Tabulated list of adverse reactions

Unless otherwise noted, the table shows the incidence rates of adverse reactions observed in breast cancer and soft tissue sarcoma patients who received the recommended dose in Phase 2 and Phase 3 studies.

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) and very rare (< 1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.
Where Grade 3 or 4 reactions occurred, the actual total frequency and the frequency of Grade 3 or 4 reactions are given.

System Organ        Adverse Reactions – all Grades
Class
Very Common              Common                 Uncommon                Rare or not (Frequency %)            (Frequency %)          (Frequency %)           known 
Infections and                               Urinary tract          Sepsis (0.5%) infestations                                 infection (8.5%)       (G3/4: 0.5%)a (G3/4: 0.7%)           Neutropenic sepsis
Pneumonia (1.6%)       (0.2%) (G3/4: 0.2%)a
(G3/4: 1.0%)           Septic Shock (0.2%)
Oral candidiasis
Oral herpes            (G3/4:0.2%)a
Upper respiratory tract infection
Nasopharyngitis
Rhinitis
Herpes zoster
*
Blood and           Neutropenia (53.6%)      Lymphopenia (5.7%)                              Disseminated lymphatic system    (G3/4: 46.0%)            (G3/4: 2.1%)                                   intravascular disorders           Leukopenia (27.9%)       Febrile neutropenia                            coagulationb (G3/4: 17.0%)            (4.5%) (G3/4: 4.4%)a
Anaemia (21.8%)          Thrombocytopenia
(G3/4: 3.0%)              (4.2%) (G3/4: 0.7%)

System Organ        Adverse Reactions – all Grades
Class
Very Common              Common                  Uncommon                Rare or not (Frequency %)            (Frequency %)           (Frequency %)           known 
Metabolism and      Decreased appetite       Hypokalaemia (6.8%) nutrition           (22.5%) (G3/4: 0.7%)d    (G3/4: 2.0%) disorders                                    Hypomagnesaemia
(2.8%) (G3/4: 0.3%)
Dehydration (2.8 %)
(G3/4: 0.5%)d
Hyperglycaemia
Hypophosphataemia
Hypocalcaemia
Psychiatric                                  Insomnia disorders                                    Depression
Nervous system      Peripheral neuropathyc   Dysgeusia disorders           (35.9%) (G3/4: 7.3%)     Dizziness (9.0%)
Headache (17.5%)         (G3/4: 0.4%)d
(G3/4: 0.7%)             Hypoaesthesia
Lethargy
Neurotoxicity
Eye disorders                                Lacrimation increased
(5.8%) (G3/4: 0.1%)d
Conjunctivitis
Ear and labyrinth                            Vertigo disorders                                    Tinnitus
Cardiac disorders                            Tachycardia
Vascular                                     Hot flush               Deep vein thrombosis disorders                                    Pulmonary embolism
(1.3%) (G3/4: 1.1%)a
Respiratory,        Dyspnoea (15.2%)a        Oropharyngeal pain      Interstitial lung thoracic and        (G3/4: 3.5%)a            Epistaxis               disease (0.2%) (G3/4: mediastinal         Cough (15.0%)            Rhinorrhoea             0.1%) disorders           (G3/4: 0.5%)d
Gastrointestinal    Nausea (35.7%)           Abdominal pain          Mouth ulceration disorders           (G3/4: 1.1%)d            Stomatitis (11.1%)      Pancreatitis Constipation (22.3%)     (G3/4: 1.0%)d
(G3/4: 0.7%)d            Dry mouth
Diarrhoea (18.7%)        Dyspepsia (6.5%)
(G3/4: 0.8%)             (G3/4: 0.3%)d
Vomiting (18.1%)         Gastrooesophageal
(G3/4: 1.0%)             reflux disease
Abdominal distension

Hepatobiliary                                Aspartate               Hepatotoxicity disorders                                    aminotransferase        (0.8%) (G3/4: 0.6%) increased (7.7%)
(G3/4: 1.4%)d
Alanine aminotransferase increased (7.6%)
(G3/4: 1.9%)d
Gamma glutamyl transferase increased
(1.7%) (G3/4: 0.9%)d
Hyperbilirubinaemia
(1.4%) (G3/4: 0.4%)


System Organ          Adverse Reactions – all Grades
Class
Very Common                Common                   Uncommon               Rare or not (Frequency %)              (Frequency %)            (Frequency %)          known **
Skin and              Alopecia                   Rash (4.9%) (G3/4:       Angioedema              Stevens-Johnson subcutaneous                                     0.1%)                                           syndrome/ Toxic tissue disorders                                 Pruritus (3.9%)                                 epidermal (G3/4: 0.1%)d                                   necrolysisb
Nail disorder
Night sweats
Dry skin
Erythema
Hyperhidrosis
Palmar plantar erythrodysaesthesia
(1.0%) (G3/4: 0.1%)d
Musculoskeletal       Arthralgia and myalgia     Bone pain (6.7%) and connective        (20.4%) (G3/4: 1.0%)       (G3/4: 1.2%) tissue disorders      Back pain (12.8%)          Muscle spasms
(G3/4: 1.5%)               (5.3%) (G3/4: 0.1%)d
Pain in extremity          Musculoskeletal pain
(10.0%) (G3/4: 0.7%)d      Musculoskeletal chest pain
Muscular weakness
Renal and urinary                                Dysuria                  Haematuria disorders                                                                 Proteinuria Renal failure
General disorders     Fatigue/Asthenia           Mucosal and                   (53.2%) (G3/4 : 7.7%)      Inflammation (6.4%) administration site   Pyrexia (21.8%)            (G3/4: 0.9%)d conditions            (G3/4: 0.7%)               Peripheral oedema
Pain
Chills
Chest pain
Influenza like illness
Investigations        Weight decreased
(11.4%) (G3/4: 0.4%)d
 a
Includes Grade 5 events.
b
From spontaneous reporting c
Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating polyneuropathy d
No Grade 4 events
*
Rare
**
Frequency not known

Overall, the safety profiles in the breast cancer and soft tissue sarcoma patient populations were similar.

Description of selected adverse reactions
Neutropenia
The neutropenia observed was reversible and not cumulative; the mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (< 0.5 x 109/l) was 8 days.
Neutrophil counts of < 0.5 x 109/l that lasted for more than 7 days occurred in 13% of breast cancer patients treated with eribulin in the EMBRACE study.
Neutropenia was reported as a Treatment Emergent Adverse Event (TEAE) in 151/404 (37.4% for all grades) in the sarcoma population, compared with 902/1559 (57.9% for all grades) in the breast cancer population. The combined grouped TEAE and neutrophil laboratory abnormality frequencies were 307/404 (76.0%) and 1314/1559 (84.3%), respectively. The median duration of treatment was 12.0 weeks for sarcoma patients and 15.9 weeks for breast cancer patients.
Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported. Out of 1963 breast cancer and soft tissue sarcoma patients who received eribulin at the recommended dose in clinical trials there was one fatal event each of neutropenic sepsis (0.1%) and febrile neutropenia (0.1%). In addition there were 3 fatal events of sepsis (0.2%) and one of septic shock (0.1%).
Severe neutropenia may be managed by the use of G-CSF or equivalent at the physician’s discretion in accordance with relevant guidelines. 18% and 13% of eribulin treated patients received G-CSF in the two phase 3 breast cancer studies (Studies 305 and 301, respectively). In the phase 3 sarcoma study (Study 309), 26% of the eribulin treated patients received G-CSF.
Neutropenia resulted in discontinuation in < 1% of patients receiving eribulin.

Disseminated intravascular coagulation
Cases of disseminated intravascular coagulation have been reported, typically in association with neutropenia and/or sepsis.

Peripheral neuropathy
In the 1559 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with eribulin was peripheral neuropathy (3.4%). The median time to Grade 2 peripheral neuropathy was 12.6 weeks (post 4 cycles). Out of the 404 sarcoma patients, 2 patients discontinued treatment with eribulin due to peripheral neuropathy. The median time to Grade 2 peripheral neuropathy was 18.4 weeks.
Development of Grade 3 or 4 peripheral neuropathy occurred in 7.4% of breast cancer patients and 3.5% of sarcoma patients. In clinical trials, patients with pre-existing neuropathy were as likely to develop new or worsening symptoms as those who entered the study without the condition.
In breast cancer patients with pre-existing Grade 1 or 2 peripheral neuropathy the frequency of treatment-emergent Grade 3 peripheral neuropathy was 14%.

Hepatotoxicity
In some patients with normal/abnormal liver enzymes prior treatment with eribulin, increased levels of liver enzymes have been reported with initiation of eribulin treatment. Such elevations appeared to have occurred early with eribulin treatment in cycle 1 – 2 for the majority of these patients and whilst thought likely to be a phenomenon of adaptation to eribulin treatment by the liver and not a sign of significant liver toxicity in most patients, hepatotoxicity has also been reported.

Special populations

Elderly population
Of the 1559 breast cancer patients treated with the recommended dose of eribulin, 283 patients (18.2%) were ≥ 65 years of age. In the 404 sarcoma patient population, 90 patients (22.3%) treated with eribulin were ≥ 65 years of age. The safety profile of eribulin in elderly patients (≥ 65 years of age) was similar to that of patients <65 years of age except for asthenia/fatigue which showed an increasing trend with age. No dose adjustments are recommended for the elderly population.

Patients with hepatic impairment
Patients with ALT or AST > 3 x ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. Although data are limited, patients with bilirubin > 1.5 x ULN also have a higher incidence of Grade 4 neutropenia and febrile neutropenia (see also sections 4.2 and 5.2).

Paediatric population
Three open-label studies, Studies 113, 213 and 223, were conducted in paediatric patients with refractory or recurrent solid tumours and lymphomas, but excluding central nervous system (CNS) tumours (see section 5.1).

The safety of eribulin monotherapy was evaluated in 43 paediatric patients who received up to 1.58 mg/m2 on Days 1 and 8 of a 21-day cycle (Studies 113 and 223). The safety of eribulin combination with irinotecan was also evaluated in 40 paediatric patients who received eribulin 1.23 mg/m2 on Days 1 and 8 and irinotecan 20 or 40 mg/m2 on Days 1 to 5 of a 21-day cycle, or 100 or 125 mg/m2 on Days 1 and 8 of a 21-day cycle (Study 213).

In Study 113 (Phase 1), the most frequently reported adverse drug reactions were white blood cell count decreased, lymphocyte count decreased, anaemia and neutrophil count decreased.

In Study 213 (Phase 1/2), the most frequently reported adverse drug reactions were neutropenia (Phase 1) and diarrhoea and neutrophil count decreased (Phase 2).

In Study 223 (Phase 2), the most frequently reported adverse drug reactions were neutrophil count decreased, anaemia, and white blood cell count decreased.

The safety profile of eribulin as monotherapy or in combination with irinotecan hydrochloride in this paediatric population was consistent with the known safety profile of either study drug in the adult population.
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/