Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

The most serious adverse reactions associated with ramucirumab treatment (as a single agent or in combination with cytotoxic chemotherapy) were:
Gastrointestinal perforation (see section 4.4)
Severe gastrointestinal hemorrhage (see section 4.4)
Arterial thromboembolic events (see section 4.4)
Posterior reversible encephalopathy syndrome (see section 4.4)

The most common adverse reactions observed in patients treated with ramucirumab as monotherapy are: peripheral oedema, hypertension, diarrhea, abdominal pain, headache, proteinuria and thrombocytopenia.

The most common adverse reactions observed in patients treated with ramucirumab in combination with chemotherapy are: fatigue/asthenia, neutropenia, diarrhea, epistaxis and stomatitis.


The most common adverse reactions observed in patients treated with ramucirumab in combination with erlotinib are: infections, diarrhea, hypertension, stomatitis, proteinuria, alopecia and epistaxis.

Tabulated list of adverse reactions

Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase III clinical trials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCC or in combination with different chemotherapy regimens or erlotinib for the treatment of gastric cancer, mCRC and NSCLC. ADRs are listed below by MedDRA body system organ class.

The following convention has been used for classification of frequency for ADR tables: 
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)
Not known (cannot be estimated from the available data)

Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
Table 6: ADRs reported in patients treated with ramucirumab as monotherapy in phase 3 clinical trials (REGARD, REACH-2 and REACH patients with alpha fetoprotein ≥ 400 ng/ml) 
System Organ            Very Common                          Common                         Uncommon Class (MedDRA)
Blood and               Thrombocytopeniaa        Neutropeniaa lymphatic system disorders
Metabolism and                                   Hypokalaemiaa,b nutrition disorders                              Hyponatraemiaa
Hypoalbuminaemiaa
Nervous system          Headache                 Hepatic encephalopathyc disorders
Vascular disorders      Hypertensiona,d          Arterial thromboembolic eventsa
Respiratory,                                     Epistaxis thoracic, and mediastinal disorders
Gastrointestinal        Abdominal paina,e        Intestinal obstructiona               Gastrointestinal disorders               Diarrhea                                                       perforationa Skin and                                         Rasha subcutaneous tissue disorders
Renal and urinary       Proteinuriaa,f disorders
General disorders       Peripheral oedema        Infusion-related reactionsa and administration site disorders a
Terms represent a group of events that describe a medical concept rather than a single event or preferred term.
b
Includes: hypokalaemia and blood potassium decreased.

c
Based on study REACH-2 and REACH (single-agent ramucirumab in HCC). Includes hepatic encephalopathy and hepatic coma.
d
Includes: blood pressure increased and hypertension.
e
Includes: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain.
f
Includes one case of nephrotic syndrome

Table 7: ADRs reported in patients treated with ramucirumab in combination with chemotherapy or erlotinib in phase 3 clinical trials (RAINBOW, REVEL, RAISE and RELAY) 
System Organ Class           Very Common                         Common                   Uncommon (MedDRA)
Infections and           Infectionsj,k               Sepsisa,b infestations
Blood and lymphatic      Neutropeniaa                Febrile neutropeniad system disorders         Leukopeniaa,c
Thrombocytopeniaa
Anaemiaj
Metabolism and                                       Hypoalbuminaemiaa nutrition disorders                                  Hyponatraemiaa
Nervous system           Headachej disorders
Cardiac disorders                                                                       Cardiac failure Vascular disorders       Hypertensiona,e             Arterial thromboembolic eventsa
Respiratory, thoracic,   Epistaxis                   Pulmonary hemorrhagej,l and mediastinal disorders
Gastrointestinal         Stomatitis                  Gastrointestinal hemorrhage disorders                Diarrhea                    eventsa,f
Gastrointestinal perforationa
Gingival bleedingj
Skin and                 Alopeciaj                   Palmar-plantar subcutaneous tissue                                  erthyrodysaesthesia disorders                                            syndromeg
Renal and urinary        Proteinuriaa,h disorders
General disorders and    Fatiguea,i administration site      Mucosal disorders                inflammationd
Peripheral oedema a
Terms represent a group of events that describe a medical concept rather than a single event or preferred term.
b
Based on study RAINBOW (ramucirumab plus paclitaxel).
c
Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell count decreased.
d
Based on study REVEL (ramucirumab plus docetaxel).
e
Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy.
f
Based on study RAINBOW (ramucirumab plus paclitaxel), study REVEL (ramucirumab plus docetaxel) and study RAISE (ramucirumab plus FOLFIRI). Includes: anal hemorrhage, diarrhea hemorrhage, gastric hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, Mallory-Weiss syndrome, melaena, esophageal hemorrhage, rectal hemorrhage, and upper gastrointestinal hemorrhage.
g
Based on study RAISE (ramucirumab plus FOLFIRI).
h
Includes cases of nephrotic syndrome.
i
Based on study RAINBOW (ramucirumab plus paclitaxel) and study REVEL (ramucirumab plus docetaxel).
Includes: fatigue and asthenia.
j
Based on study RELAY (ramucirumab plus erlotinib).
k
Infections includes all preferred terms that are part of the System Organ Class Infections and infestations.
Most common (≥ 1%) Grade ≥ 3 infections include pneumonia, cellulitis, paronychia, skin infection, and urinary tract infection.
l
Includes hemoptysis, laryngeal hemorrhage, hemothorax (a fatal event occurred) and pulmonary hemorrhage.

Clinically relevant reactions (including Grade ≥ 3) associated with antiangiogenic therapy observed in ramucirumab-treated patients across clinical studies were: gastrointestinal perforations, infusion- related reactions and proteinuria (see sections 4.2 and 4.4).

Colorectal cancer

Ramucirumab in combination with FOLFIRI
In the RAISE study, in mCRC patients treated with ramucirumab plus FOLFIRI, the most frequent (≥ 1%) ADR that led to the discontinuation of ramucirumab was proteinuria (1.5%). The most frequent (≥ 1%) ADRs leading to discontinuation of one or more components of FOLFIRI were: neutropenia (12.5%), thrombocytopenia (4.2%), diarrhea (2.3%) and stomatitis (2.3%). The most frequent component of FOLFIRI to be discontinued was the 5-FU bolus.


Adverse reactions from other sources
Table 8: ADRs associated with ramucirumab reported in clinical trials and through post- marketing reporting

System Organ Class          Common           Uncommon               Rare                Not known (MedDRA)

Neoplasms benign,        Hemangioma malignant and unspecified (including cysts and polyps)
Blood and lymphatic                                           Thrombotic system disorders                                              microangiopathy Endocrine disorders      Hypothyroidism
Nervous system                                                Posterior reversible disorders                                                     encephalopathy syndrome
Cardiac disorders                                                                    Cardiac failurea Vascular disorders                                                                   Aneurysms and artery dissections
Respiratory, thoracic    Dysphonia and mediastinal disorders a In the post-marketing setting, cardiac failure has been observed for ramucirumab mostly in combination with paclitaxel. See section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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