Summary of safety profile
The most commonly reported undesirable effects related to Eribulin mesylate (HALAVEN), are bone marrow suppression manifested as neutropenia, leucopenia, anemia, thrombocytopenia with associated infections. New onset or worsening of pre-existing peripheral neuropathy has also been reported.
Gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhea, 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 events 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 Class | Adverse Reactions – all Grades | |||
| Very Common (Frequency %) |
Common (Frequency %) |
Uncommon (Frequency %) |
Rare or not known | |
| Infections and infestations | Urinary tract infection (8.5%) (G3/4: 0.7%) Pneumonia (1.6%) (G3/4: 1.0%) Oral candidiasis, Oral herpes Upper respiratory tract infection Nasopharyngitis, Rhinitis Herpes zoster |
Sepsis (0.5%) (G3/4: 0.5)a Neutropenic sepsis (0.2%) (G3/4: 0.2%)a Septic Shock (0.2%) (G3/4:0.2%)a |
||
| Blood and lymphatic system disorders |
Neutropenia (53.6%) (G3/4: 46.0%) Leukopenia (27.9%) (G3/4: 17.0%) Anaemia (21.8%) (G3/4: 3.0%) |
Lymphopenia (5.7%) (G3/4: 2.1%) Febrile neutropenia (4.5%) (G3/4: 4.4%)a Thrombocytopenia (4.2%) (G3/4: 0.7%) |
*Disseminated intravascular coagulationb |
|
| Metabolism and nutrition disorders | Decreased appetite (22.5%) (G3/4: 0.7%)d |
Hypokalaemia (6.8%) (G3/4: 2.0%) Hypomagnesaemia (2.8%) (G3/4: 0.3%) Hypocalcemia (2.0%) (G3/4: 0.4%) Dehydration (2.8 %) (G3/4: 0.5%) Hyperglycaemia Hypophosphataemia |
||
| Psychiatric disorders | Insomnia, Depression | |||
| Nervous system disorders |
Peripheral neuropathyc (35.9%) (G3/4: 7.3%) Headache (17.5%) (G3/4: 0.7%) |
Dysgeusia Dizziness (9.0%) (G3/4: 0.4%)d Hypoaesthesia Lethargy Neurotoxicity |
||
| Eye disorders | Lacrimation increased (5.8%) (G3/4: 0.1%)d Conjunctivitis |
|||
| Ear and labyrinth disorders |
Vertigo Tinnitus |
|||
| Cardiac disorders | Tachycardia | |||
| Vascular disorders | Hot flush Pulmonary embolism (1.3%) (G3/4: 1.1%)a |
Deep vein thrombosis | ||
| Respiratory, thoracic and mediastinal disorders |
Dyspnoea (15.2%)a (G3/4: 3.5%) Cough (15.0%) (G3/4: 0.5%)d |
Oropharyngeal pain Epistaxis Rhinorrhoea |
Interstitial lung disease (0.2%) (G3/4: 0.1%) |
|
| Gastrointestinal disorders | Nausea (35.7%) (G3/4: 1.1%)d Constipation (22.3%) (G3/4: 0.7%) Diarrhoea (18.7%) (G3/4: 0.8%) Vomiting (18.1%) (G3/4: 1.0%) |
Abdominal pain Stomatitis (11.1%) (G3/4: 1.0%)d Dry mouth Dyspepsia (6.5%) (G3/4: 0.3%)d Gastrooesophageal reflux disease Abdominal distension |
Mouth ulceration Pancreatitis | |
| Hepatobiliary disorders | Alanine aminotransferase increased (7.6%) (G3/4: 1.9%)d Aspartate aminotransferase increased (7.7%) (G3/4: 1.4%)d Gamma glutamyl transferase increased (1.7%) (G3/4: 0.9%)d Hyperbilirubinaemia (1.4%) (G3/4: 0.4%) |
Hepatotoxicity (0.8%) (G3/4: 0.6%) |
||
| Skin and subcutaneous tissue disorders |
Alopecia | Rash (4.9%) (G3/4: 0.1%) Pruritus (3.9%) (G3/4: 0.1%)d Nail disorder, Night sweats Dry skin, Erythema Hyperhidrosis, Palmar plantar erythrodysaesthesia (1.0%) (G3/4: 0.1%)d |
Angioedema | ** Stevens-Johnson syndrome/ Toxic epidermal necrolysis b |
| Musculoskeletal and connective tissue disorders |
Arthralgia and myalgia (20.4%) (G3/4: 1.0%) Back pain (12.8%) (G3/4:1.5%) Pain in extremity (10.0%) (G3/4: 0.7%)d |
Bone pain ( 6.7%) (G3/4: 1.2%) Muscle spasms (5.3%) (G3/4: 0.1%)d Musculoskeletal pain and musculoskeletal chest pain Muscular weakness |
||
| Renal and urinary disorders |
Dysuria | Haematuria Proteinuria Renal failure |
||
| General disorders and administration site conditions |
Fatigue/Asthenia (53.2%) (G3/4 : 7.7%) Pyrexia (21.8%) (G3/4: 0.7%) |
Mucosal Inflammation (6.4%) (G3/4: 0.9%)d 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. |
||||
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. 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 preexisting 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%.
Hepatoxicity
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 mesilate (HALAVEN) 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.
| Reporting of suspected adverse drug reactions |
| Please contact: |
| HI-Eisai Pharmaceutical, Inc. |
| +63 2 88875837 / +63 2 88875160 / +63 9088672236 |