Cyramza

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Cyramza 10 mg/ml concentrate for solution for infusion  
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One ml of concentrate for solution for infusion contains 10 mg ramucirumab. 
 
Each 10 ml vial contains 100 mg of ramucirumab. 
Each 50 ml vial contains 500 mg of ramucirumab.  
 
Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant 
DNA technology. 
 
Excipient with known effect 
 
Each 10 ml vial contains approximately 17 mg sodium. 
Each 50 ml vial contains approximately 85 mg sodium. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
The concentrate is a clear to slightly opalescent and colourless to slightly yellow solution, pH 6.0.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Gastric cancer 
 
Cyramza in combination with paclitaxel is indicated for the treatment of adult patients with advanced 
gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior 
platinum and fluoropyrimidine chemotherapy (see section 5.1).  
 
Cyramza monotherapy is indicated for the treatment of adult patients with advanced gastric cancer or 
gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum or 
fluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate 
(see section 5.1). 
 
Colorectal cancer 
 
Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for 
the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on 
or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine. 
 



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Non-small cell lung cancer 
 
Cyramza in combination with erlotinib is indicated for the first-line treatment of adult patients with 
metastatic non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) 
mutations (see section 5.1). 
 
Cyramza in combination with docetaxel is indicated for the treatment of adult patients with locally 
advanced or metastatic non-small cell lung cancer with disease progression after platinum-based 
chemotherapy. 
 
Hepatocellular carcinoma 
 
Cyramza monotherapy is indicated for the treatment of adult patients with advanced or unresectable 
hepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who have 
been previously treated with sorafenib. 
 
4.2 Posology and method of administration 
 
Ramucirumab therapy must be initiated and supervised by physicians experienced in oncology. 
 
Posology 
 
Gastric cancer and gastro-oesophageal junction (GEJ) adenocarcinoma 
 
Cyramza in combination with paclitaxel 
The recommended dose of ramucirumab is 8 mg/kg on days 1 and 15 of a 28 day cycle, prior to 
paclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m2 administered by intravenous 
infusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxel 
infusion, patients should have a complete blood count and blood chemistry performed to evaluate 
hepatic function. Criteria to be met prior to each paclitaxel infusion are provided in Table 1.  

 
Table 1: Criteria to be met prior to each paclitaxel administration 

 
 Criteria 

Neutrophils Day 1: ≥1.5 x 109/L 

Days 8 and 15: ≥1.0 x 109/L 

Platelets Day 1: ≥100 x 109/L 

Days 8 and 15: ≥75 x 109/L 

Bilirubin <1.5 x upper limit of normal value (ULN) 

Aspartate aminotransferase 
(AST) /Alanine 
aminotransferase (ALT) 

No liver metastases: ALT/AST ≤3 x ULN 

Liver metastases: ALT/AST ≤5 x ULN 

 
Cyramza as a single agent 
The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks. 
 
Colorectal cancer 
 
The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered by intravenous 
infusion, prior to FOLFIRI administration. Prior to chemotherapy, patients should have a complete 
blood count. Criteria to be met prior to FOLFIRI are provided in Table 2. 
 



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Table 2: Criteria to be met prior to FOLFIRI administration 
 

 Criteria 

Neutrophils ≥1.5 x 109/L 

Platelets ≥100 x 109/L 

Chemotherapy-related gastro-
intestinal toxicity 

≤ Grade 1 (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI 
CTCAE]) 

 
Non-small cell lung cancer (NSCLC) 
 
Cyramza in combination with erlotinib for the treatment of NSCLC with activating EGFR mutations 
The recommended dose of ramucirumab in combination with erlotinib is 10 mg/kg every two weeks. 
 
EGFR mutation status should be determined prior to initiation of treatment with ramucirumab and 
erlotinib using a validated test method. See erlotinib prescribing information for the posology and 
method of administration of erlotinib. 
 
Cyramza in combination with docetaxel for the treatment of NSCLC after platinum-based 
chemotherapy 
The recommended dose of ramucirumab is 10 mg/kg on day 1 of a 21 day cycle, prior to docetaxel 
infusion. The recommended dose of docetaxel is 75 mg/m2 administered by intravenous infusion over 
approximately 60 minutes on day 1 of a 21 day cycle. For East Asian patients, a reduced docetaxel 
starting dose of 60 mg/m2 on day 1 of a 21 day cycle should be considered. See docetaxel prescribing 
information for specific dosing advice. 
 
Hepatocellular carcinoma (HCC) 
 
The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks. 
 
Alpha fetoprotein (AFP) testing in HCC 
 
Patients with HCC should be selected based on a serum AFP concentration of ≥ 400 ng/ml with a 
validated AFP test prior to ramucirumab treatment (see section 5.1). 
 
Duration of treatment 
 
It is recommended that treatment be continued until disease progression or until unacceptable toxicity 
has occurred. 
 
Premedication 
 
Premedication is recommended with a histamine H1 antagonist (for example diphenhydramine) prior 
to infusion of ramucirumab. If a patient experiences a Grade 1 or 2 infusion-related reaction 
premedication must be given for all subsequent infusions. If a patient experiences a second Grade 1 or 
2 infusion-related reaction (IRR) administer dexamethasone (or equivalent); then, for subsequent 
infusions, premedicate with the following or equivalent medicinal products: an intravenous histamine 
H1 antagonist (for example diphenhydramine hydrochloride), paracetamol and dexamethasone. 
 
See prescribing information for paclitaxel, for components of FOLFIRI and for docetaxel, as 
applicable, for premedication requirements and additional information. 
 



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Posology adjustments for ramucirumab 
 
Infusion-related reactions 
The infusion rate of ramucirumab should be reduced by 50% for the duration of the infusion and all 
subsequent infusions if the patient experiences a grade 1 or 2 IRR. Ramucirumab should be 
immediately and permanently discontinued in the event of a grade 3 or 4 IRR (see section 4.4). 
 
Hypertension 
The blood pressure of patients should be monitored prior to each ramucirumab administration and 
treated as clinically indicated. Ramucirumab therapy should be temporarily discontinued in the event 
of severe hypertension, until controlled with medical management. If there is medically significant 
hypertension that cannot be controlled safely with antihypertensive therapy, ramucirumab therapy 
should be permanently discontinued (see section 4.4). 
 
Proteinuria 
Patients should be monitored for the development or worsening of proteinuria during ramucirumab 
therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. 
Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. 
Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose 
level (see Table 3). A second dose reduction (see Table 3) is recommended if a urine protein level 
≥2 g/24 hours reoccurs. 
 
Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours 
or in the event of nephrotic syndrome.  
 
Table 3: Ramucirumab dose reductions for proteinuria 
 
Initial ramucirumab dose First dose reduction to Second dose reduction to 

8 mg/kg 6 mg/kg 5 mg/kg 

10 mg/kg 8 mg/kg 6 mg/kg 
 
Elective surgery or impaired wound healing 
Ramucirumab therapy should be temporarily discontinued for at least 4 weeks prior to elective 
surgery. Ramucirumab therapy should be temporarily discontinued if there are wound healing 
complications, until the wound is fully healed (see section 4.4). 
 
Permanent discontinuation 
 
Ramucirumab therapy should be permanently discontinued in the event of: 
Severe arterial thromboembolic events (see section 4.4). 
Gastrointestinal perforations (see section 4.4). 
Severe bleeding: NCI CTCAE Grade 3 or 4 bleeding (see section 4.4). 
Spontaneous development of fistula (see section 4.4). 
Hepatic encephalopathy or hepatorenal syndrome (see section 4.4). 
 
Paclitaxel dose adjustments 
 
Paclitaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. 
For NCI CTCAE Grade 4 haematological toxicity or Grade 3 paclitaxel-related non-haematological 
toxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m2 for all following cycles. A 
second reduction of 10 mg/m2 is recommended if these toxicities persist or reoccur.  
 



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FOLFIRI dose adjustments 
 
Dose reductions for individual components of FOLFIRI may be made for specific toxicities. Dose 
modifications of each component of FOLFIRI should be made independently and are provided in 
Table 4. Table 5 provides details of dose delays or dose reductions of components of FOLFIRI at the 
next cycle based on maximum grade of specific adverse drug reactions. 
 
Table 4: FOLFIRI dose reductions 
 

FOLFIRI 
componenta  

Dose level 
Initial dose -1 -2 -3 

Irinotecan 180 mg/m2 150 mg/m2 120 mg/m2 100 mg/m2 
5-FU bolus 400 mg/m2 200 mg/m2 0 mg/m2 0 mg/m2 

5-FU infusion 2,400 mg/m2 
over 46-48 hours 

2,000 mg/m2 
over 46-48 hours 

1,600 mg/m2 
over 46-48 hours 

1,200 mg/m2 
over 46-48 hours 

a 5-FU = 5-fluorouracil. 
 
Table 5: Dose modification of FOLFIRI components due to specific ADRs 
 
ADR NCI 

CTCAE 
grade 

Dose modification at day 1 of cycle subsequent to ADR 

Diarrhoea 2 If diarrhoea has recovered to Grade ≤1, reduce by 1 dose level 
for 5-FU. 
For recurrent Grade 2 diarrhoea, reduce by 1 dose level for 5-FU 
and irinotecan. 

 3 If diarrhoea has recovered to Grade ≤1, reduce by 1 dose level 
for 5-FU and irinotecan. 

 4 If diarrhoea has recovered to Grade ≤1, reduce by 2 dose levels 
for 5-FU and irinotecan. 
If Grade 4 diarrhoea does not resolve to Grade ≤1, withhold 
5-FU and irinotecan for a maximum of 28* days until resolution 
to Grade ≤1. 

Neutropenia or 
Thrombocytopenia 

 Haematological criteria in 
Table 2 are met  

Haematological criteria in 
Table 2 are not met 

 2 No dose modification. Reduce by 1 dose level for  
5-FU and irinotecan. 

 3 Reduce by 1 dose level for 
5-FU and irinotecan. 

Delay 5-FU and irinotecan for 
a maximum of 28* days until 
resolution to Grade ≤1, then 
dose reduce by 1 level for 5-FU 
and irinotecan. 

 4 Reduce by 2 dose levels for 
5-FU and irinotecan. 

Delay 5-FU and irinotecan for 
a maximum of 28* days until 
resolution to Grade ≤1, then 
dose reduce by 2 levels for 
5-FU and irinotecan. 

Stomatitis/Mucositis 2 If stomatitis/mucositis has recovered to Grade ≤1, reduce by 
1 dose level for 5-FU. 
For recurrent Grade 2 stomatitis, reduce by 2 dose levels for 
5-FU. 

 3 If stomatitis/mucositis has recovered to Grade ≤1, reduce by 
1 dose level for 5-FU. 
If Grade 3 mucositis/stomatitis does not resolve to Grade ≤1, 



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delay 5-FU for a maximum of 28* days until resolution to 
Grade ≤1, then dose reduce by 2 levels for 5-FU. 

 4 Withhold 5-FU for a maximum of 28* days until resolution to 
Grade ≤1, then dose reduce by 2 dose levels for 5-FU. 

Febrile neutropenia  Haematological criteria in 
Table 2 are met and fever 
resolved 

Haematological criteria in 
Table 2 are not met and fever 
resolved  

  Reduce by 2 dose levels for 
5-FU and irinotecan. 

Delay 5-FU and irinotecan for 
a maximum of 28* days until 
resolution to Grade ≤1, then 
dose reduce by 2 levels for 
5-FU and irinotecan. 
Consider use of colony-
stimulating factor prior to next 
cycle. 

*The 28 day time period begins on day 1 of the cycle subsequent to the ADR. 
 
Docetaxel dose adjustments 
 
Docetaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. 
Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, 
severe or cumulative cutaneous reactions, or other Grade 3 or 4 non-haematological toxicities during 
docetaxel treatment should have treatment withheld until resolution of the toxicity. It is recommended 
to reduce the docetaxel dose by 10 mg/m2 for all following cycles. A second reduction of 15 mg/m2 is 
recommended if these toxicities persist or reoccur. In this case, East Asian patients with a starting dose 
of 60 mg/m² should have docetaxel treatment discontinued (see Posology). 
 
Special populations 
 
Elderly 
In the pivotal studies there is limited evidence that patients 65 years of age or older are at increased 
risk of adverse events compared to patients younger than 65 years old. No dose reductions are 
recommended (see sections 4.4 and 5.1). 
 
Renal impairment 
There have been no formal studies with Cyramza in patients with renal impairment. Clinical data 
suggest that no dose adjustments are required in patients with mild, moderate or severe renal 
impairment (see sections 4.4 and 5.2). No dose reductions are recommended.   
 
Hepatic impairment 
There have been no formal studies with Cyramza in patients with hepatic impairment. Clinical data 
suggest that no dose adjustments are required in patients with mild or moderate hepatic impairment. 
There are no data regarding ramucirumab administration in patients with severe hepatic impairment 
(see sections 4.4 and 5.2). No dose reductions are recommended. 
 
Paediatric population 
The safety and efficacy of Cyramza in children and adolescents (<18 years) has not been established.  
No data are available.  
 
There is no relevant use of ramucirumab in the paediatric population for the indications of advanced 
gastric cancer or gastro-oesophageal adenocarcinoma, adenocarcinoma of the colon and rectum, lung 
carcinoma, and hepatocellular carcinoma. 
 



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Method of administration  
 
Cyramza is for intravenous use. After dilution, Cyramza is administered as an intravenous infusion 
over approximately 60 minutes. It should not be administered as an intravenous bolus or push. To 
achieve the required infusion duration of approximately 60 minutes, the maximum infusion rate of 
25 mg/minute should not be exceeded, instead the infusion duration should be increased. The patient 
should be monitored during infusion for signs of infusion-related reactions (see section 4.4) and the 
availability of appropriate resuscitation equipment should be ensured.  
 
For instructions on dilution of the medicinal product before administration, see section 6.6.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
For patients with NSCLC, ramucirumab is contraindicated where there is tumour cavitation or tumour 
involvement of major vessels (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve traceability of biological medicinal products, the name and the batch number of 
the administered product should be clearly recorded. 
 
Arterial thromboembolic events 
Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, 
cardiac arrest, cerebrovascular accident, and cerebral ischemia have been reported in clinical studies. 
Ramucirumab should be permanently discontinued in patients who experience a severe ATE (see 
section 4.2). 
 
Gastrointestinal perforations 
Ramucirumab is an antiangiogenic therapy and may increase the risk of gastrointestinal perforations. 
Cases of gastrointestinal perforation have been reported in patients treated with ramucirumab. 
Ramucirumab should be permanently discontinued in patients who experience gastrointestinal 
perforations (see section 4.2).  
 
Severe bleeding 
Ramucirumab is an antiangiogenic therapy and may increase the risk of severe bleeding. 
Ramucirumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding 
(see section 4.2). Blood counts and coagulation parameters should be monitored in patients with 
conditions predisposing to bleeding, and in those treated with anticoagulants or other concomitant 
medicinal products that increase the risk of bleeding. For HCC patients with evidence of portal 
hypertension or prior history of oesophageal variceal bleeding, screening for and treatment of 
oesophageal varices should be performed as per standard of care before starting ramucirumab 
treatment. 
 
Severe gastrointestinal haemorrhage, including fatal events, were reported in patients with gastric 
cancer treated with ramucirumab in combination with paclitaxel, and in patients with mCRC treated 
with ramucirumab in combination with FOLFIRI. 
 
Pulmonary haemorrhage in NSCLC 
Patients with squamous histology are at higher risk of developing serious pulmonary bleeding, 
however, no excess of Grade 5 pulmonary haemorrhage was observed in ramucirumab treated patients 
with squamous histology in REVEL. NSCLC patients with recent pulmonary bleeding (>2.5 ml or 
bright red blood) as well as patients with evidence of baseline tumour cavitation, regardless of 
histology, or those with any evidence of tumour invasion or encasement of major blood vessels have 



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been excluded from clinical trials (see section 4.3). Patients receiving any kind of therapeutic 
anticoagulation were excluded from the REVEL NSCLC clinical trial and patients receiving chronic 
therapy with non-steroidal anti-inflammatory drugs or anti-platelet agents were excluded from the 
REVEL and RELAY NSCLC clinical trials. Aspirin use at doses up to 325 mg/day was permitted (see 
section 5.1). 
 
Infusion-related reactions 
Infusion-related reactions were reported in clinical studies with ramucirumab. The majority of events 
occurred during or following a first or second ramucirumab infusion. Patients should be monitored 
during the infusion for signs of hypersensitivity. Symptoms included rigors/tremors, 
back-pain/spasms, chest pain and/or tightness, chills, flushing, dyspnoea, wheezing, hypoxia, and 
paraesthesia. In severe cases symptoms included bronchospasm, supraventricular tachycardia, and 
hypotension. Ramucirumab should be immediately and permanently discontinued in patients who 
experience a Grade 3 or 4 IRR (see section 4.2). 
 
Hypertension 
An increased incidence of severe hypertension was reported in patients receiving ramucirumab as 
compared to placebo. In most cases hypertension was managed using standard antihypertensive 
treatment. Patients with uncontrolled hypertension were excluded from the trials: ramucirumab 
treatment should not be initiated in such patients until and unless their pre-existing hypertension is 
controlled. Patients who are treated with ramucirumab should have their blood pressure monitored. 
Ramucirumab should be temporarily discontinued for severe hypertension until controlled with 
medical management. Ramucirumab should be permanently discontinued if medically significant 
hypertension cannot be controlled with antihypertensive therapy (see section 4.2). 
 
Posterior Reversible Encephalopathy Syndrome 
Cases of posterior reversible encephalopathy syndrome (PRES), including fatal cases, have been rarely 
reported in patients receiving ramucirumab. PRES symptoms may include seizure, headache, 
nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension. A 
diagnosis of PRES can be confirmed by brain imaging (e.g., magnetic resonance imaging). 
Discontinue ramucirumab in patients who experience PRES. The safety of reinitiating ramucirumab in 
patients who develop PRES and recover is not known. 
 
Aneurysms and artery dissections 
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the 
formation of aneurysms and/or artery dissections. Before initiating Cyramza, this risk should be 
carefully considered in patients with risk factors such as hypertension or history of aneurysm. 
 
Impaired wound healing 
The impact of ramucirumab has not been evaluated in patients with serious or non-healing wounds. In 
a study conducted in animals, ramucirumab did not impair wound healing. However, since 
ramucirumab is an antiangiogenic therapy and may have the potential to adversely affect wound 
healing, ramucirumab treatment should be withheld for at least 4 weeks prior to scheduled surgery. 
The decision to resume ramucirumab following surgical intervention should be based on clinical 
judgment of adequate wound healing.  
 
If a patient develops wound healing complications during therapy, ramucirumab should be 
discontinued until the wound is fully healed (see section 4.2). 
 
Hepatic impairment 
Ramucirumab should be used with caution in patients with severe liver cirrhosis (Child-Pugh B or C), 
cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal 
syndrome. There are very limited efficacy and safety data available in these patients. Ramucirumab 
should only be used in these patients if the potential benefits of treatment are judged to outweigh the 
potential risk of progressive hepatic failure. 
 



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In HCC patients, hepatic encephalopathy was reported at a higher rate in the ramucirumab-treated 
patients compared to the placebo-treated patients (see section 4.8). Patients should be monitored for 
clinical signs and symptoms of hepatic encephalopathy. Ramucirumab should be permanently 
discontinued in the event of hepatic encephalopathy or hepatorenal syndrome (see section 4.2). 
 
Fistula 
Patients may be at increased risk for the development of fistula when treated with Cyramza. 
Ramucirumab treatment should be discontinued in patients who develop fistula (see section 4.2).  
 
Proteinuria 
An increased incidence of proteinuria was reported in patients receiving ramucirumab as compared to 
placebo. Patients should be monitored for the development, or worsening of proteinuria during 
ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be 
performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is 
≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a 
reduced dose level. A second dose reduction is recommended if a urine protein level ≥2 g/24 hours 
reoccurs. Ramucirumab therapy should be permanently discontinued if the urine protein level is 
>3 g/24 hours or in the event of nephrotic syndrome (see section 4.2). 
 
Stomatitis 
An increased incidence of stomatitis was reported in patients receiving ramucirumab in combination 
with chemotherapy as compared to patients treated with placebo plus chemotherapy. Symptomatic 
treatment should be instituted promptly if stomatitis occurs. 
 
Renal impairment  
There are limited safety data available for patients with severe renal impairment (creatinine clearance 
15 to 29 ml/min) treated with ramucirumab (see sections 4.2 and 5.2). 
 
Elderly patients with NSCLC 
A trend towards less efficacy with increasing age has been observed in patients receiving ramucirumab 
plus docetaxel for the treatment of advanced NSCLC with disease progression after platinum-based 
chemotherapy (see section 5.1). Comorbidities associated with advanced age, performance status and 
the likely tolerability to chemotherapy should therefore be thoroughly evaluated prior to the initiation 
of treatment in the elderly (see sections 4.2 and 5.1). 
 
For ramucirumab used in combination with erlotinib for the first line treatment of NSCLC with 
activating EGFR mutations, patients aged 70 years and older compared to patients under 70 years of 
age, experienced a higher incidence of grade ≥3 adverse events and all grade serious adverse events. 
 
Sodium restricted diet 
Each 10 ml vial contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’. 
Each 50 ml vial contains approximately 85 mg sodium. This is equivalent to approximately 4% of the 
WHO recommended maximum daily intake of 2 g sodium for an adult.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No drug-drug interactions were observed between ramucirumab and paclitaxel. The pharmacokinetics 
of paclitaxel were not affected when co-administered with ramucirumab and the pharmacokinetics of 
ramucirumab were not affected when co-administered with paclitaxel. The pharmacokinetics of 
irinotecan and its active metabolite, SN-38, were not affected when co-administered with 
ramucirumab. The pharmacokinetics of docetaxel or erlotinib were not affected when co-administered 
with ramucirumab. 
 



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4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in females 
Women of childbearing potential should be advised to avoid becoming pregnant while on Cyramza 
and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing 
potential should use effective contraception during and up to 3 months after the last dose of 
ramucirumab treatment.  
 
Pregnancy 
There are no data from the use of ramucirumab in pregnant women. Animal studies are insufficient 
with respect to reproductive toxicity (see section 5.3). As angiogenesis is critical to maintenance of 
pregnancy and to foetal development, the inhibition of angiogenesis following ramucirumab 
administration may result in adverse effects on pregnancy, including the foetus. Cyramza should only 
be used if the potential benefit to the mother justifies the potential risk during pregnancy. If the patient 
becomes pregnant while being treated with ramucirumab, she should be informed of the potential risk 
to the maintenance of pregnancy and the risk to the foetus. Cyramza is not recommended during 
pregnancy and in women of childbearing potential not using contraception. 
 
Breast-feeding 
It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorption 
is expected to be low. As a risk to breast-fed newborns/infants cannot be excluded, breast-feeding 
should be discontinued during treatment with Cyramza and for at least 3 months after the last dose. 
 
Fertility 
There are no data on the effect of ramucirumab on human fertility. Female fertility is likely to be 
compromised during treatment with ramucirumab based on studies in animals (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Cyramza has no or negligible influence on the ability to drive and use machines. If patients experience 
symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or 
use machines until the effect subsides. 
 
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 haemorrhage (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, diarrhoea, 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, diarrhoea, epistaxis and stomatitis. 
 
The most common adverse reactions observed in patients treated with ramucirumab in combination 
with erlotinib are: infections, diarrhoea, hypertension, stomatitis, proteinuria, alopecia and epistaxis. 
 



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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 
Class (MedDRA) 

Very Common  Common  Uncommon  

Blood and 
lymphatic system 
disorders 

Thrombocytopeniaa Neutropeniaa  

Metabolism and 
nutrition disorders 

 Hypokalaemiaa,b 
Hyponatraemiaa 
Hypoalbuminaemiaa 

 

Nervous system 
disorders 

Headache Hepatic encephalopathyc  

Vascular disorders Hypertensiona,d Arterial thromboembolic 
eventsa 

 

Respiratory, 
thoracic, and 
mediastinal 
disorders 

 Epistaxis  

Gastrointestinal 
disorders 

Abdominal paina,e 
Diarrhoea 

Intestinal obstructiona Gastrointestinal 
perforationa 

Skin and 
subcutaneous tissue 
disorders 

 Rasha  

Renal and urinary 
disorders 

Proteinuriaa,f   

General disorders 
and administration 
site disorders 

Peripheral oedema Infusion-related reactionsa  

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 



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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 
(MedDRA) 

Very Common  Common  

Infections and infestations Infectionsj,k Sepsisa,b 
Blood and lymphatic 
system disorders 

Neutropeniaa 
Leukopeniaa,c 
Thrombocytopeniaa 
Anaemiaj 

Febrile neutropeniad 

Metabolism and nutrition 
disorders 

 Hypoalbuminaemiaa 
Hyponatraemiaa 

Nervous system disorders Headachej  
Vascular disorders Hypertensiona,e  
Respiratory, thoracic, and 
mediastinal disorders 

Epistaxis Pulmonary haemorrhagej,l 

Gastrointestinal disorders Stomatitis 
Diarrhoea 

Gastrointestinal haemorrhage eventsa,f 
Gastrointestinal perforationa  
Gingival bleedingj 

Skin and subcutaneous 
tissue disorders 

Alopeciaj Palmar-plantar erthyrodysaesthesia 
syndromeg 

Renal and urinary disorders Proteinuriaa,h  
General disorders and 
administration site disorders 

Fatiguea,i 
Mucosal 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) and study RAISE (ramucirumab plus FOLFIRI). 

Includes: anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, 
haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory-Weiss syndrome, melaena, oesophageal 
haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage. 

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 haemoptysis, laryngeal haemorrhage, haemothorax (a fatal event occurred) and pulmonary 
haemorrhage. 

 
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).  
 



14 

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%), diarrhoea (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: Post-marketing ADRs associated with ramucirumab reported in clinical trials and 
through post-marketing reporting   
 
System Organ Class 

(MedDRA) 
Common  Uncommon Rare  Not known  

Neoplasms benign, 
malignant and 
unspecified 
(including cysts and 
polyps) 

Haemangioma    

Blood and lymphatic 
system disorders 

  Thrombotic 
microangiopathy 

 

Nervous system 
disorders 

  Posterior 
reversible 
encephalopathy 
syndrome 

 

Vascular disorders    Aneurysms and 
artery dissections 

Respiratory, thoracic 
and mediastinal 
disorders 

Dysphonia    

 
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. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no data on overdose in humans. Cyramza has been administered in a Phase 1 study up to 
10 mg/kg every two weeks without reaching a maximum tolerated dose. In case of overdose, 
supportive therapy should be used.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies ATC code: L01XC21. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


15 

Mechanism of action 
 
Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF induced 
angiogenesis. Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF 
Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits 
ligand stimulated activation of VEGF Receptor 2 and its downstream signalling components, 
including p44/p42 mitogen-activated protein kinases, neutralising ligand-induced proliferation and 
migration of human endothelial cells. 
 
Clinical efficacy and safety 
 
Gastric cancer 
 
RAINBOW  
RAINBOW, a global, randomised, double-blind, study of Cyramza plus paclitaxel versus placebo plus 
paclitaxel, was conducted in 665 patients with locally recurrent and unresectable or metastatic gastric 
cancer (including GEJ adenocarcinoma) following platinum- and fluoropyrimidine-containing 
chemotherapy, with or without anthracycline. The primary endpoint was overall survival (OS) and the 
secondary endpoints included progression free survival (PFS) and overall response rate (ORR). 
Patients were required to have experienced disease progression during, or within 4 months after the 
last dose of first-line therapy and with ECOG PS 0-1. Patients were randomised in a 1:1 ratio to 
receive Cyramza plus paclitaxel (n=330) or placebo plus paclitaxel (n=335). Randomisation was 
stratified by geographic region, time to progression from the start of first-line therapy (<6 months 
versus ≥6 months) and disease measurability. Cyramza at 8 mg/kg or placebo was administered by 
intravenous infusion every 2 weeks (on days 1 and 15) of a 28-day cycle. Paclitaxel at 80 mg/m2 was 
administered by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. 
 
A majority (75%) of patients randomised in the study received prior platinum and fluoropyrimidine 
combination therapy without anthracycline. The remainder (25%) received prior platinum and 
fluoropyrimidine combination therapy with anthracycline. Two-thirds of the patients experienced 
disease progression while still on first-line therapy (66.8%). Baseline patient demographics and 
disease characteristics were generally balanced between arms: the median age was 61 years; 71% of 
patients were male; 61% were Caucasian, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 
61% of patients; 81% of patients had measurable disease and 79% had gastric cancer; 21% had GEJ 
adenocarcinoma. The majority of patients (76%) had experienced disease progression within 6 months 
from the start of first-line therapy. For patients treated with Cyramza plus paclitaxel the median 
duration of therapy was 19 weeks, and for patients treated with placebo plus paclitaxel the median 
duration of therapy was 12 weeks. The median relative dose intensity of Cyramza was 98.6% and of 
placebo was 99.6%. The median relative dose intensity of paclitaxel was 87.7% for the Cyramza plus 
paclitaxel arm and 93.2% for the placebo plus paclitaxel arm. A similar percentage of patients 
discontinued treatment due to adverse events: 12% of patients treated with Cyramza plus paclitaxel 
compared with 11% of patients treated with placebo plus paclitaxel. Post discontinuation systemic 
anti-cancer therapy was given to 47.9% of patients receiving Cyramza plus paclitaxel and 46.0% of 
patients receiving placebo plus paclitaxel. 
 
Overall survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel 
compared with those receiving placebo plus paclitaxel (HR 0.807; 95% CI: 0.678 to 0.962; p=0.0169). 
There was an increase in median survival of 2.3 months in favour of the Cyramza plus paclitaxel arm: 
9.63 months in the Cyramza plus paclitaxel arm and 7.36 months in the placebo plus paclitaxel arm. 
Progression-free survival was statistically significantly improved in patients receiving Cyramza plus 
paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.635; 95% CI: 0.536 to 0.752; 
p<0.0001). There was an increase in median PFS of 1.5 months in favour of the Cyramza plus 
paclitaxel arm: 4.4 months in the Cyramza plus paclitaxel arm and 2.9 months in the placebo plus 
paclitaxel arm. Objective response rate [ORR(complete response [CR] + partial response [PR])] was 
significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving 
placebo plus paclitaxel (Odds ratio 2.140; 95% CI: 1.499 to 3.160; p=0.0001). The ORR in the 
Cyramza plus paclitaxel arm was 27.9% and in the placebo plus paclitaxel arm was 16.1%. 



16 

Improvements in OS and PFS were consistently observed in pre-specified subgroups based on age, 
sex, race and in most other pre-specified subgroups. Efficacy results are shown in Table 9. 
 
Table 9: Summary of efficacy data – Intent to treat (ITT) population 
 

 Cyramza plus paclitaxel 
N=330 

Placebo plus 
paclitaxel 

N=335 
Overall survival, months   
   Median (95% CI) 9.6 (8.5, 10.8)  7.4 (6.3, 8.4) 
   Hazard ratio (95% CI) 0.807 (0.678, 0.962) 
   Stratified log-rank p-value 0.0169 
Progression free survival, months   
   Median (95% CI) 4.4 (4.2, 5.3)  2.9 (2.8, 3.0) 
   Hazard ratio (95% CI) 0.635 (0.536, 0.752) 
   Stratified log-rank p-value <0.0001 
Objective response rate (CR +PR)   
   Rate- percent (95% CI) 27.9 (23.3, 33.0) 16.1 (12.6, 20.4) 
   Odd ratio 2.140 (1.449, 3.160) 
   Stratified CMH p-value 0.0001 

Abbreviations: CI = confidence interval, CR= complete response, PR= partial response, CMH= 
Cochran-Mantel-Haenszel 
 
Figure 1: Kaplan-Meier curves of overall survival for Cyramza plus paclitaxel versus placebo 
plus paclitaxel in RAINBOW 

 

 
 



17 

Figure 2: Kaplan-Meier curves of progression-free survival for Cyramza plus paclitaxel versus 
placebo plus paclitaxel in RAINBOW 

 

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Cyramza+Paclitaxel

Placebo+Paclitaxel

Number at Risk
Time Since Randomization (Months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

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Cyramza+Paclitaxel
Placebo+Paclitaxel

 
 
REGARD  
REGARD, a multinational, randomised, double-blind study of Cyramza plus BSC versus placebo plus 
BSC, was conducted in 355 patients with locally recurrent and unresectable, or metastatic gastric 
cancer (including GEJ adenocarcinoma) following platinum- or fluoropyrimidine-containing 
chemotherapy. The primary endpoint was OS and secondary endpoints included PFS. Patients were 
required to have experienced disease progression during, or within 4 months after the last dose of, 
first-line therapy for metastatic disease, or during adjuvant treatment or within 6 months after the last 
dose of adjuvant therapy, and had ECOG PS 0-1. To be included in the study, patients were required 
to have total bilirubin of ≤1.5 mg/dl and AST and ALT ≤3 times ULN, or ≤5 times ULN if liver 
metastases were present. 
 
Patients were randomised in a 2:1 ratio to receive an intravenous infusion of Cyramza 8 mg/kg 
(n= 238) or placebo (n= 117) every 2 weeks. Randomisation was stratified by weight loss over the 
prior 3 months (≥ 10% versus < 10%), geographic region, and location of the primary tumour (gastric 
versus GEJ). Baseline demographics and disease characteristics were balanced. The ECOG PS was 1 
for 72% of patients. There were no patients with Child-Pugh B or C liver cirrhosis enrolled in 
REGARD. 11% of patients treated with Cyramza and 6% of patients on placebo discontinued therapy 
due to adverse events. Overall survival was statistically significantly improved in patients receiving 
Cyramza as compared with patients receiving placebo (hazard ratio [HR] 0.776; 95%CI: 0.603 
to 0.998; p= 0.0473), corresponding to a 22% reduction in the risk of death and an increase in median 
survival to 5.2 months for Cyramza from3.8 months for placebo. Progression-free survival was 
statistically significantly improved in patients receiving Cyramza as compared with patients receiving 
placebo (HR 0.483; 95%CI: 0.376 to 0.620; p<0.0001), corresponding to a 52% reduction in the risk 
of progression or death and an increase in median PFS to 2.1 months for Cyramza from 1.3 months for 
placebo. Efficacy results are shown in Table 10. 
 



18 

Table 10: Summary of efficacy data – ITT population 
 

 Cyramza 
N=238 

Placebo 
N=117 

Overall survival, months   
   Median (95% CI) 5.2 (4.4, 5.7)  3.8 (2.8, 4.7) 
   Hazard ratio (95% CI) 0.776 (0.603, 0.998) 
   Stratified log-rank p-value 0.0473 
Progression free survival, months   
   Median (95% CI) 2.1 (1.5, 2.7)  1.3 (1.3, 1.4) 
   Hazard ratio (95% CI) 0.483 (0.376, 0.620) 
   Stratified log-rank p-value <0.0001 
   12-week PFS rate% (95% CI) 40.1 (33.6, 46.4)  15.8 (9.7, 23.3) 

Abbreviations: CI = confidence interval 
 
Figure 3: Kaplan-Meier curves of overall survival for Cyramza versus placebo in REGARD 
 

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Based on limited data from REGARD patients with HER2-positive gastric or GEJ adenocarcinoma 
and patients previously treated with trastuzumab (in RAINBOW), it is considered unlikely that 
Cyramza has a detrimental effect or that it has no effect in patients with HER2-positive gastric cancer. 
Post hoc unstratified subgroup analyses from RAINBOW patients previously treated with trastuzumab 
(n= 39) suggested a survival benefit in such patients (HR 0.679, 95% CI 0.327, 1.419) and 
demonstrated a benefit for progression free survival (PFS) (HR 0.399, 95% CI 0.194, 0.822). 
 
Colorectal cancer 
 
RAISE 
RAISE was a global, randomised, double-blind, study of Cyramza plus FOLFIRI versus placebo plus 
FOLFIRI, in patients with mCRC, who had disease progression on or after first-line therapy with 
bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were required to have ECOG PS 0 or 1 and 
to have disease progression within 6 months of the last dose of first-line therapy. Patients were 
required to have adequate hepatic, renal and coagulation function. Patients with a history of 
uncontrolled hereditary or acquired bleeding or thrombotic disorders, a recent history of severe 
(Grade ≥3) bleeding or who had experienced an arterial thrombotic event (ATE) in the 12 months 
prior to randomisation were excluded. Patients were also excluded if they had experienced any of: an 



19 

ATE, Grade 4 hypertension, Grade 3 proteinuria, a grade 3-4 bleeding event, or bowel perforation 
during first-line bevacizumab therapy. 
 
A total of 1072 patients were randomised (1:1) to receive either Cyramza (n=536) at 8 mg/kg or 
placebo (n=536), in combination with FOLFIRI. All medicinal products were administered 
intravenously. The FOLFIRI regimen was: irinotecan 180 mg/m2 administered over 90 minutes and 
folinic acid 400 mg/m2 administered, simultaneously over 120 minutes; followed by bolus 
5-fluorouracil(5-FU) 400 mg/m2 over 2 to 4 minutes; followed by 5-FU 2400 mg/m2 administered by 
continuous infusion over 46 to 48 hours. Treatment cycles on both arms were repeated every 2 weeks. 
Patients who discontinued one or more components of treatment because of an adverse event were 
permitted to continue therapy with the other treatment component(s) until disease progression or 
unacceptable toxicity. The primary endpoint was OS and the secondary endpoints included PFS, 
objective response rate (ORR) and quality of life (QoL) using the European Organisation for Research 
and Treatment of Cancer (EORTC) QLQ-C30. Randomisation was stratified by geographic region, 
tumour KRAS status (mutant or wild-type), and time to disease progression (TTP) after commencing 
first-line treatment (<6 months versus ≥6 months). 
 
Demographic and baseline characteristics for the ITT population were similar between treatment arms. 
Median age was 62 years and 40% of patients were ≥65 years; 57% of patients were male; 76% were 
White and 20% Asian; 49% had ECOG PS 0; 49% of patients had KRAS mutant tumours; and 24% of 
patients had TTP <6 months after commencing first-line treatment. Post discontinuation systemic anti-
cancer therapy was given to 54% of patients receiving Cyramza plus FOLFIRI and 56% of patients 
receiving placebo plus FOLFIRI. 
 
Overall survival was statistically significantly improved in patients receiving Cyramza plus FOLFIRI 
compared with those receiving placebo plus FOLFIRI (HR 0.844; 95% CI: 0.730 to 0.976; p=0.0219). 
There was an increase in median survival of 1.6 months in favour of the Cyramza plus FOLFIRI arm: 
13.3 months in the Cyramza plus FOLFIRI arm and 11.7  months in the placebo plus FOLFIRI arm. 
Progression-free survival was statistically significantly improved in patients receiving Cyramza plus 
FOLFIRI compared with those receiving placebo plus FOLFIRI (HR 0.793;   95% CI:  0.697 to 0.903; 
p=0.0005). There was an increase in median PFS of 1.2 months in favour of the Cyramza plus 
FOLFIRI arm: 5.7 months in the Cyramza plus FOLFIRI arm and 4.5 months in the placebo plus 
FOLFIRI arm. Efficacy results are shown in Table 11 and Figures 4 and 5. 
 
Pre-specified analyses for OS and PFS by stratification factors were performed.  The HR of OS was 
0.82 (95% CI: 0.67 to 1.0) in patients with a KRAS wild type tumour, and 0.89 (95% CI: 0.73 to 1.09) 
in patients with a KRAS mutant tumour. For patients with TTP ≥6 months after commencing first-line 
treatment the HR of OS was 0.86 (95% CI: 0.73 to 1.01), and 0.86 (95% CI: 0.64 to 1.13) in patients 
with TTP <6 months after commencing first-line treatment. Pre-specified subgroup analyses for both 
PFS and OS according to age (<65 and ≥65 years), gender, race, ECOG PS (0 or ≥1), number of 
organs involved, liver metastases only, site of primary tumour (colon or rectum), carcinoembryonic 
antigen levels (<200 μg/L, ≥200 μg/L), all showed a treatment effect favouring Cyramza plus 
FOLFIRI treatment over placebo plus FOLFIRI. In 32 of the 33 pre-specified sub-group analyses for 
OS, the HR was < 1.0. The one sub-group with HR > 1 was for patients with disease progression from 
start of first-line bevacizumab treatment of <3 months (HR 1.02 [95% CI: 0.68 to 1.55]). This one 
sub-group is a group which can be considered to have aggressive disease that is relatively refractory to 
first-line treatment. In both treatment arms, patients who experienced neutropenia had a longer median 
OS compared to patients who did not experience neutropenia. The median OS in patients with any 
grade neutropenia was greater in the ramucirumab arm (16.1 months) than in the placebo arm (12.6 
months). Median OS in patients who did not experience neutropenia was 10.7 months in both arms. 

 



20 

Table 11: Summary of efficacy data – ITT population 
 

 Cyramza plus FOLFIRI 
N=536 

Placebo plus FOLFIRI 
N=536 

Overall survival, months   
   Median (95% CI) 13.3 (12.4, 14.5)  11.7 (10.8, 12.7) 
   Hazard ratio (95% CI) 0.84 (0.73, 0.98) 
   Stratified log-rank p-value 0.022 
Progression free survival, months   
   Median (95% CI) 5.7 (5.5, 6.2)  4.5 (4.2, 5.4) 
   Hazard ratio (95% CI) 0.79 (0.70, 0.90) 
   Stratified log-rank p-value <0.001 

Abbreviations: CI = confidence interval 
 
Figure 4: Kaplan-Meier curves of overall survival for Cyramza plus FOLFIRI versus placebo 
plus FOLFIRI in RAISE 

 
 



21 

Figure 5: Kaplan-Meier curves of progression -free survival for Cyramza plus FOLFIRI versus 
placebo plus FOLFIRI in RAISE 

 
 
The ORR was similar for both treatment arms (13.4% versus 12.5%, ramucirumab plus FOLFIRI 
versus placebo plus FOLFIRI, respectively). The disease control rate (complete response plus partial 
response plus stable disease) was numerically higher in patients on the ramucirumab plus FOLFIRI 
arm as compared to the placebo plus FOLFIRI arm (74.1% versus 68.8%, respectively). For the 
EORTC QLQ-C30, patients in the ramucirumab plus FOLFIRI treatment arm reported a transient 
decrease in QoL compared to the patients in the placebo plus FOLFIRI treatment arm in most of the 
scales. Few between-arm differences were reported after the first month of treatment. 
 
NSCLC 
 
RELAY 
RELAY was a global, randomised, double-blind, phase 3 study of Cyramza plus erlotinib versus 
placebo plus erlotinib that randomised (1:1) 449 previously untreated patients with metastatic non-
small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or 
exon 21 (L858R) activating mutations at study entry. Eligible patients were ECOG PS 0 or 1. Patients 
with CNS metastases or known T790M EGFR mutations at baseline were excluded from the study. 
Patients at a high risk of bleeding, cardiovascular events, including those who had experienced any 
arterial thrombotic event within 6 months of enrolment, were also excluded from the study. 
 
Demographics and baseline characteristics were balanced between arms. 77% of patients were Asian 
and 22% were Caucasian. Patients treated with Cyramza plus erlotinib experienced a statistically 
significant improvement in progression-free survival (PFS) compared to patients treated with placebo 
plus erlotinib (Table 12). Consistent results were observed across subgroups including exon 19 
deletions and exon 21 (L858R) substitution, age, race (Caucasian HR: 0.618, Asian HR: 0.638), 
smokers and never smokers. Overall survival data were immature at the time of the final PFS analysis 
(17.6% maturity). RELAY efficacy results are shown in Table 12 and Figure 6. 
 



22 

Table 12: Summary of efficacy data in RELAY – Intent to treat (ITT) population 
 

 Cyramza plus erlotinib 
N=224 

Placebo plus erlotinib 
N=225 

Progression-free Survival 
Number of events (%) 122 (54.5) 158 (70.2) 
Median – months (95% CI) 19.4 (15.38, 21.55) 12.4 (10.97, 13.50) 
Hazard Ratio (95% CI) 0.591 (0.461, 0.760) 
Stratified Log-rank p-value <0.0001 

Interim Overall Survival 
Number of deaths (%)  37 (16.5) 42 (18.7) 
Median – months (95% CI) NR NR 
Hazard Ratio (95% CI) 0.832 (0.532, 1.303) 
Stratified Log-rank p-value 0.4209 

Objective Response Rate (Complete Response + Partial Response) 
Rate – percent (95% CI) 76 (70.8, 81.9) 75 (69.0, 80.3) 
CR, n (%) 3 (1.3) 2 (0.9) 
PR, n (%) 168 (75.0) 166 (73.8) 

Duration of Response N = 171 N = 168 
Number of events (%)  101 (59.1) 128 (76.2) 
Median – months (95% CI) 18.0 (13.86, 19.78) 11.1 (9.69, 12.29) 
Hazard Ratio (95% CI) 0.619 (0.477, 0.805) 
Unstratified Log-rank p-value 0.0003 

Abbreviations: CI = confidence interval, NR= not reached, CR = complete response, PR = partial 
response. A hierarchal testing procedure was employed to test OS. OS was tested only if PFS was 
significant. Both endpoints were alpha-protected. 
 
Figure 6: Kaplan-Meier curves of progression free survival for Cyramza plus erlotinib versus 
placebo plus erlotinib in RELAY 
 
 

 
REVEL 
REVEL, a randomised, double-blind study of Cyramza plus docetaxel versus placebo plus docetaxel, 
was conducted in 1253 patients with locally advanced or metastatic squamous or non-squamous 
NSCLC with disease progression on or after one platinum-based therapy. The primary endpoint was 



23 

OS. Patients were randomised in a 1:1 ratio to receive Cyramza plus docetaxel (n=628) or placebo 
plus docetaxel (n=625). Randomisation was stratified by geographic region, gender, prior 
maintenance, and ECOG PS. Cyramza at 10 mg/kg or placebo and docetaxel at 75 mg/m2 were each 
administered by intravenous infusion on day 1 of a 21-day cycle. Sites in East Asia administered a 
reduced dose of docetaxel at 60 mg/m2 every 21 days. Patients with recent serious pulmonary, 
gastrointestinal, or postoperative bleeding, evidence of CNS haemorrhage, tumour involvement of 
major airway or blood vessel, intra-tumour cavitation, and history of significant bleeding or 
uncontrolled thrombotic disorders were excluded. Also, patients receiving any kind of therapeutic 
anticoagulation and/or chronic therapy with non-steroidal anti-inflammatory drugs or other anti-
platelets agents or those with untreated, clinically unstable brain/CNS metastases were excluded 
Aspirin use at doses up to 325 mg/day was permitted. (see section 4.4). A limited number of 
non-Caucasian, especially Black patients (2.6%) were included. Therefore there is limited experience 
with the combination of ramucirumab and docetaxel in these patients with advanced NSCLC as well 
as in patients with renal impairment, cardiovascular disease and obesity. 
 
Baseline patient demographics and disease characteristics were generally balanced between arms: the 
median age was 62 years; 67% of patients were male; 82% were Caucasian, 13% Asian; the ECOG PS 
was 0 for 32% of patients, 1 for 67% of patients; 73% of patients had non-squamous histology and 
26% had squamous histology. The most common prior therapies included pemetrexed (38%), 
gemcitabine (25%), taxane (24%), and bevacizumab (14%); 22% of patients received prior 
maintenance therapy. The median duration of docetaxel therapy was 14.1 weeks for the ramucirumab 
plus docetaxel arm (with a median of 4.0 infusions received) and 12.0 weeks for the placebo plus 
docetaxel arm (with a median of 4.0 infusions received). 
 
OS was statistically significantly improved in patients receiving Cyramza plus docetaxel compared 
with those receiving placebo plus docetaxel (HR 0.857; 95% CI: 0.751 to 0.979; p=0.024). There was 
an increase in median survival of 1.4 months in favour of the Cyramza plus docetaxel arm: 
10.5 months in the Cyramza plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm. 
PFS was statistically significantly improved in patients receiving Cyramza plus docetaxel compared 
with those receiving placebo plus docetaxel (HR 0.762; 95% CI: 0.677 to 0.859; p<0.001). There was 
an increase in median PFS of 1.5 months in favour of the Cyramza plus docetaxel arm: 4.5 months in 
the Cyramza plus docetaxel arm and 3 months in the placebo plus docetaxel arm. ORR  was 
significantly improved in patients receiving Cyramza plus docetaxel compared with those receiving 
placebo plus docetaxel (22.9% vs. 13.6%, p<0.001). The primary QoL analysis showed similar time to 
deterioration for all Lung Cancer Symptom Scale (LCSS) scores between treatment arms. 
 
A consistent improvement (ramucirumab plus docetaxel vs placebo plus docetaxel) was observed in 
important subgroups for PFS and OS. OS subgroup results included the following: non-squamous 
histology (HR 0.83; 95% CI: 0.71 to 0.97; median OS [mOS]: 11.1 vs 9.7 months) and squamous 
histology (HR 0.88; 95% CI: 0.69 to 1.13; mOS: 9.5 vs 8.2 months); patients with prior maintenance 
(HR 0.69; 95% CI: 0.51 to 0.93; mOS: 14.4 vs 10.4 months); time since start of prior therapy 
<9 months (HR 0.75; 95% CI: 0.64 to 0.88; mOS: 9.3 vs 7.0 months); patients <65 years old 
(HR 0.74, 95% CI: 0.62, 0.87; mOS: 11.3 vs 8.9 months). A trend towards less efficacy with 
increasing age has been observed in patients receiving ramucirumab plus docetaxel for the treatment 
of advanced NSCLC with disease progression after platinum-based chemotherapy (see section 5.1). 
No differences in efficacy between treatment arms have been observed in the subgroups of patients 
≥65 years old (OS HR 1.10, 95% CI: 0.89, 1.36; median OS [mOS]: 9.2 vs 9.3 months, see section 
4.4), patients pre-treated with taxanes (HR 0.81; 95% CI:0.62 to 1.07; mOS 10.8 vs 10.4 months) and 
those with time since start of prior therapy ≥9 months (HR 0.95; 95% CI: 0.75 to 1.2; mOS: 13.7 vs 
13.3 months). Efficacy results are shown in Table 13. 
 



24 

Table 13: Summary of efficacy data – ITT population 
 

 Cyramza plus docetaxel 
N=628 

Placebo plus docetaxel 
N=625 

Overall survival, months 
Median – months (95% CI) 10.5 (9.5, 11.2) 9.1 (8.4, 10.0) 
Hazard ratio (95% CI) 0.857 (0.751, 0.979) 
Stratified log-rank p-value 0.024 

Progression free survival, months  
Median (95% CI) 4.5 (4.2, 5.4) 3.0 (2.8, 3.9) 
Hazard Ratio (95% CI) 0.762 (0.677, 0.859) 
Stratified log-rank p-value <0.001 

Objective response rate (CR + PR)  
Rate – percent (95% CI) 22.9 (19.7, 26.4) 13.6 (11.0, 16.5) 
Stratified CMH p-value <0.001 

Abbreviations: CI = confidence interval, CR= complete response, PR= partial response, CMH = 
Cochran-Mantel-Haenszel 
 
Figure 7: Kaplan-Meier curves of overall survival for Cyramza plus docetaxel versus placebo 
plus docetaxel in REVEL 

 
 



25 

Figure 8: Kaplan-Meier curves of progression-free survival for Cyramza plus docetaxel versus 
placebo plus docetaxel in REVEL 

 
 
Hepatocellular carcinoma 
 
REACH-2  
REACH-2 was a global, randomised, double-blind study of Cyramza plus BSC versus placebo plus 
BSC that randomised (2:1) 292 patients with HCC who had a serum AFP ≥ 400 ng/ml at study entry. 
Patients enrolled into the study had disease progression on or after prior sorafenib therapy or were 
intolerant to sorafenib. Eligible patients were Child Pugh A (score < 7), had creatinine clearance 
≥ 60 ml/min, and ECOG PS of 0 or 1. In addition, patients were either Barcelona Clinic Liver Cancer 
(BCLC) stage B and no longer amenable to locoregional therapy, or were BCLC stage C. Patients with 
brain metastases, leptomeningeal disease, uncontrolled spinal cord compression, a history of or current 
hepatic encephalopathy or clinically meaningful ascites, severe variceal bleeding in the 3 months prior 
to treatment, or gastric or oesophageal varices at high risk of bleeding were excluded from the study. 
The primary endpoint was overall survival. The threshold for the elevated AFP study entry 
requirement for REACH-2 was determined based on the survival results from a pre-specified 
subgroup, exploratory analysis from REACH, a previously completed, supportive phase 3 clinical 
study in 565 HCC patients randomised (1:1) to either Cyramza plus BSC or placebo plus BSC that had 
disease progression on or after prior sorafenib therapy.  
 
In REACH-2, baseline patient demographics and disease characteristics were generally balanced 
between arms, except for AFP, which was lower in the placebo arm. Patients treated with Cyramza 
experienced a statistically significant improvement in OS, compared to placebo (Table 14). The major 
efficacy outcome in REACH-2 was supported by a statistically significant improvement in progression 
free survival in Cyramza treated patients compared to placebo treated patients. The relative treatment 
effect (assessed by HR) of Cyramza compared to placebo was generally consistent across subgroups, 
including age, race, aetiology of disease and reason for discontinuation of sorafenib (progressive 
disease vs. intolerance). A relevant exposure-efficacy association was observed for ramucirumab in 
REACH-2 (see section 5.2). REACH-2 efficacy results are shown in Table 14 and Figure 9. 
 



26 

Table 14: Summary of efficacy data in REACH-2 – Intent to treat (ITT) population 
 

 Cyramza 
N=197 

Placebo 
N=95 

Overall survival, months 
   Median (95% CI) 8.51 (7.00, 10.58) 7.29 (5.42, 9.07) 
   Hazard ratio (95% CI) 0.710 (0.531, 0.949) 
   Stratified log-rank p-value 0.0199 
Progression free survival, months 
   Median (95% CI) 2.83 (2.76, 4.11) 1.61 (1.45, 2.69) 
   Hazard ratio (95% CI) 0.452 (0.339, 0.603) 
   Stratified log-rank p-value <0.0001 
Objective Response Rate (CR + PR) 
   ORR % (95% CI) 4.6 (1.7, 7.5) 1.1 (0.0, 3.1) 
   p-value 0.1697 

Abbreviations: CI = confidence interval, CR = complete response, ORR = objective response rate and 
PR = partial response 
 
Figure 9: Kaplan-Meier curves of Overall Survival for Cyramza versus placebo in REACH-2 
 

 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2 patients 
Patients with ECOG score ≥2 were excluded from the pivotal studies in all indications, therefore the 
safety and efficacy of Cyramza in this patient population is unknown. 
 
Immunogenicity 
Patients in two Phase 3 studies, RAINBOW and REGARD were tested at multiple time-points for 
anti-drug antibodies (ADAs). Samples were tested from 956 patients: 527 ramucirumab treated 
patients and 429 control treated patients. Eleven (2.2%) of ramucirumab treated patients and 
two (0.5%) of control treated patients developed ADAs. None of the patients with ADAs experienced 
an IRR. No patients had neutralising antibodies to ramucirumab. There is insufficient data to evaluate 
the effects of ADAs on the efficacy or safety of ramucirumab. 
 



27 

Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Cyramza in all subsets of the paediatric population in gastric adenocarcinoma, in adenocarcinoma of 
the colon and rectum, in lung carcinoma, and liver cancer (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab Cmin 
prior to administration of the fourth and seventh dose of ramucirumab given as a single agent in 
advanced gastric cancer patients’ serum were 49.5 μg/ml (range of 6.3-228 μg/ml) and 74.4 μg/ml 
(range of 13.8-234 μg/ml), respectively. In HCC patients’ serum the geometric means of ramucirumab 
Cmin prior to administration of the second, fourth and seventh dose of ramucirumab were 23.5 μg/ml 
(range of 2.9-76.5 μg/ml), 44.1 μg/ml (range of 4.2-137 μg/ml) and 60.2 μg/ml (range of 
18.3-123 μg/ml), respectively.  
 
Following the dose regimen of 8 mg/kg ramucirumab every 2 weeks in combination with FOLFIRI, 
the geometric means of ramucirumab Cmin were 46.3 μg/ml (range of 7.7-119 μg/ml) and 65.1 μg/ml 
(range of 14.5-205 μg/ml) prior to administration of the third and fifth dose, respectively, in serum 
from patients with mCRC. 
 
Following the dose regimen of 10 mg/kg ramucirumab every 3 weeks, the geometric means of 
ramucirumab Cmin were 28.3 μg/ml (range of 2.5-108 μg/ml) and 38.4 μg/ml (range of 3.1-128 μg/ml) 
prior to administration of the third and fifth dose, respectively of ramucirumab given in combination 
with docetaxel, in serum from patients with NSCLC. 
 
Following the dose regimen of 10 mg/kg ramucirumab every 2 weeks, the geometric means of 
ramucirumab Cmin were 68.5 μg/ml (range of 20.3-142 μg/ml) and 85.7 μg/ml (range of 
36.0-197 μg/ml) prior to administration of the fourth and seventh dose, respectively of ramucirumab 
given in combination with erlotinib, in serum from patients with NSCLC. 
 
Absorption 
Cyramza is administered as an intravenous infusion. There have been no studies performed with other 
routes of administration.  
 
Distribution 
Based on population pharmacokinetic approach (PopPK), the mean (% coefficient of variation 
[CV%]) volume of distribution at steady state for ramucirumab was 5.4L (15%).  
 
Biotransformation 
The metabolism of ramucirumab has not been studied. Antibodies are principally cleared by 
catabolism.  
 
Elimination  
Based on PopPK, the mean (CV%) clearance of ramucirumab was 0.015 L/hour (30%) and the mean 
half-life was 14 days (20%).  
 
Time and dose dependency 
There was no clear deviation from dose proportionality in pharmacokinetics of ramucirumab from 
6 mg/kg to 20 mg/kg. An accumulation ratio of 1.5 was observed for ramucirumab when dosed every 
2 weeks. Based on simulations using the PopPK model, steady state would be attained by the sixth 
dose. 
 



28 

Elderly 
Based on PopPK, there was no difference in ramucirumab exposure in patients ≥65 years of age 
compared to patients <65 years old. 
 
Renal impairment  
No formal studies have been conducted to evaluate the effect of renal impairment on the 
pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure was similar in patients 
with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 ml/min), moderate renal 
impairment (CrCl ≥30 to <60 ml/min) or severe renal impairment (CrCl 15 to 29 ml/min) as compared 
to patients with normal renal function (CrCl ≥90 ml/min).  
 
Hepatic impairment  
No formal studies have been conducted to evaluate the effect of hepatic impairment on the 
pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure in patients with mild 
hepatic impairment (total bilirubin >1.0-1.5 upper limit of normal (ULN) and any AST or total 
bilirubin ≤1.0 ULN and AST >ULN) or moderate hepatic impairment (total bilirubin > 1.5-3.0 ULN 
and any AST) was similar to patients with normal hepatic function (total bilirubin and AST ≤ ULN). 
Ramucirumab has not been studied in patients with severe hepatic impairment (total 
bilirubin >3.0 ULN and any AST). 
 
Other special populations 
Based on PopPK, the following covariates were found to have no impact on ramucirumab disposition: 
age, sex, race, albumin levels. These and other factors investigated had < 20 % effect on ramucirumab 
disposition. Body weight is considered a significant co-variate of ramucirumab pharmacokinetics 
supporting the dosing based on body weight. 
 
Exposure response relationships 
 
Efficacy 
Exposure-response analyses indicated that efficacy was correlated with ramucirumab exposure across 
pivotal studies. Efficacy, as measured by improvements in OS, was associated with increasing 
ramucirumab exposure range produced by 8 mg/kg ramucirumab given every 2 weeks and by 
10 mg/kg ramucirumab given every 3 weeks. An improvement in PFS was also associated with 
increasing ramucirumab exposure for advanced gastric cancer, NSCLC with disease progression after 
platinum-based chemotherapy and mCRC. 
 
In the REACH-2 study for HCC, a relevant exposure-efficacy association was observed for 
ramucirumab which showed that only patients with above-median exposure experienced an 
improvement in OS, compared to placebo, and these exposure-efficacy relationships remained after 
attempts to adjust for other prognostic factors. A treatment effect on PFS was observed for all 
exposure levels produced by 8 mg/kg ramucirumab given every 2 weeks. No such relation was 
observed in the RELAY study for NSCLC with 10 mg/kg ramucirumab plus erlotinib given every 
2 weeks. 
 
Safety 
In RAINBOW, the incidences of Grade  ≥3 hypertension, neutropenia, and leukopenia were increased 
with higher ramucirumab exposure.  
 
In RAISE, the incidence of Grade ≥3 neutropenia was increased with higher ramucirumab exposure. 
 
In RELAY, no exposure-safety relationship was identified for the selected safety endpoints, including 
Grade ≥3 hypertension, diarrhoea, proteinuria and dermatitis acneiform. 
 
In REVEL, the incidences of Grade ≥3 febrile neutropenia and hypertension were increased with 
higher ramucirumab exposure. 
 



29 

In the pooled data from REACH-2 and REACH (patients with alpha fetoprotein ≥ 400 ng/ml), the 
incidences of Grade ≥ 3 hypertension was increased with higher ramucirumab exposure. 
 
5.3 Preclinical safety data 
 
No animal studies have been performed to test ramucirumab for potential of carcinogenicity or 
genotoxicity. 
 
The target organs identified in repeated dose cynomolgus monkey toxicity studies were kidney 
(glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphyseal 
growth plate) and female reproductive organs (decreased weight of ovaries and uterus). A minimal 
grade of inflammation and/or mononuclear cell infiltration was seen in several organs.  
 
Reproductive toxicity studies with ramucirumab have not been performed, however, animal models 
link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, 
embryo-foetal development, and postnatal development. Based on ramucirumab’s mechanism of 
action, it is likely that in animals, ramucirumab will inhibit angiogenesis and result in adverse effects 
on fertility (ovulation), placental development, developing foetuses and postnatal development. 
 
A single dose of ramucirumab did not impair wound healing in monkeys using a full-thickness 
incisional model. 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Histidine 
Histidine monohydrochloride 
Sodium chloride 
Glycine (E640) 
Polysorbate 80 (E433) 
Water for injections 
 
6.2 Incompatibilities 
 
Cyramza should not be administered or mixed with dextrose solutions. 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
3 years. 
 
After dilution 
When prepared as directed, infusion solutions of Cyramza contain no antimicrobial preservatives.  
 
Chemical and physical in-use stability of Cyramza in sodium chloride 9 mg/ml (0.9%) solution for 
injection has been demonstrated for 24 hours at 2 ºC to 8 ºC or for 4 hours at 25 ºC. From a 
microbiological point of view, the product should be used immediately. If not used immediately, in-
use storage times and conditions prior to use are the responsibility of the user and would normally not 
be longer than 24 hours at 2 ºC to 8 ºC, unless dilution has taken place in controlled and validated 
aseptic conditions.  
 



30 

6.4 Special precautions for storage 
 
Store in a refrigerator (2 ºC - 8 ºC). 
Do not freeze.  
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
10 ml solution in a vial (Type I glass) with a chlorobutyl rubber stopper, an aluminium seal and a 
polypropylene cap.  
50 ml solution in a vial (Type I glass) with a chlorobutyl rubber stopper, an aluminium seal and a 
polypropylene cap.  
 
Pack of 1 vial of 10 ml. 
Pack of 2 vials of 10 ml. 
Pack of 1 vial of 50 ml. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Do not shake the vial. 
 
Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution. 
 
Each vial is intended for single use only. Inspect the content of the vials for particulate matter and 
discolouration (the concentrate for solution for infusion should be clear to slightly opalescent and 
colourless to slightly yellow without visible particles) prior to dilution. If particulate matter or 
discolouration is identified, discard the vial. 
 
Calculate the dose and volume of ramucirumab needed to prepare the infusion solution. Vials contain 
either 100 mg or 500 mg as a 10 mg/ml solution of ramucirumab. Only use sodium chloride 9 mg/ml 
(0.9%) solution for injection as a diluent. 
 
In case of pre-filled intravenous infusion container usage 
Based on the calculated volume of ramucirumab, remove the corresponding volume of sodium 
chloride 9 mg/ml (0.9%) solution for injection from the pre-filled 250 ml intravenous container. 
Aseptically transfer the calculated volume of ramucirumab to the intravenous container. The final total 
volume in the container should be 250 ml. The container should be gently inverted to ensure adequate 
mixing. Do not freeze or shake the infusion solution. Do not dilute with other solutions or co-infuse 
with other electrolytes or medicinal products. 
 
In case of empty intravenous infusion container usage 
Aseptically transfer the calculated volume of ramucirumab into an empty intravenous infusion 
container. Add a sufficient quantity of sodium chloride 9 mg/ml (0.9%) solution for injection to the 
container to make the total volume 250 ml. The container should be gently inverted to ensure adequate 
mixing. Do not freeze or shake the infusion solution. Do not dilute with other solutions or co-infuse 
with other electrolytes or medicinal products. 
 
Parenteral medicinal products should be inspected visually for particulate matter prior to 
administration. If particulate matter is identified, discard the infusion solution. 
 
Discard any unused portion of ramucirumab left in a vial, as the product contains no antimicrobial 
preservatives. 



31 

 
Administer via infusion pump. A separate infusion line with a protein sparing 0.22 micron filter must 
be used for the infusion and the line must be flushed with sodium chloride 9 mg/ml (0.9%) solution for 
injection at the end of the infusion. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V. 
Papendorpseweg 83  
3528 BJ Utrecht  
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/957/001-003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 December 2014 
Date of latest renewal: 26 September 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURERS RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



33 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substance  
 
ImClone Systems LLC 
33 ImClone Drive, 
Branchburg 
New Jersey 
NJ 08876 
UNITED STATES 
 
Eli Lilly Kinsale Limited 
Dunderrow 
Kinsale 
County Cork 
Ireland 
 
Name and address of the manufacturers responsible for batch release 
 
Lilly, S.A. 
Avda de la Industria, 30 
Alcobendas 
28108 Madrid 
Spain 
 
Lilly France Fegersheim 
2 rue du Colonel Lilly 
67640 Fegersheim 
France 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
 



34 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



37 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON - 10 ml vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cyramza 10 mg/ml concentrate for solution for infusion 
ramucirumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml of concentrate contains 10 mg ramucirumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: histidine, histidine monohydrochloride, sodium chloride, glycine, polysorbate 80, water 
for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
100 mg/10 ml 
1 vial 
2 vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
For single use only. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not shake. 
 
 
8. EXPIRY DATE 
 
EXP 



38 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V. 
Papendorpseweg 83  
3528 BJ Utrecht  
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/957/001 - 1 vial of 10 ml. 
EU/1/14/957/002 - 2 vials of 10 ml. 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 



39 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL – 10 ml vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Cyramza 10 mg/ml sterile concentrate 
ramucirumab 
For IV use after dilution. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg/10 ml 
 
 
6. OTHER 
 



40 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON – 50 ml vial 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cyramza 10 mg/ml concentrate for solution for infusion 
ramucirumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml of concentrate contains 10 mg ramucirumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: histidine, histidine monohydrochloride, sodium chloride, glycine, polysorbate 80, water 
for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
500 mg/50 ml 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
For single use only. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not shake. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



41 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V. 
Papendorpseweg 83  
3528 BJ Utrecht  
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/957/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  



42 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL – 50 ml vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Cyramza 10 mg/ml sterile concentrate 
ramucirumab 
For IV use after dilution. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 mg/50 ml 
 
 
6. OTHER 
 



43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



44 

Package leaflet: Information for the user 
 

Cyramza 10 mg/ml concentrate for solution for infusion 
ramucirumab 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Cyramza is and what it is used for 
2. What you need to know before you are given Cyramza 
3. How you are given Cyramza 
4. Possible side effects 
5. How to store Cyramza 
6. Contents of the pack and other information 
 
 
1. What Cyramza is and what it is used for 
 
Cyramza is a cancer medicine that contains the active substance ramucirumab, which is a monoclonal 
antibody. This is a specialised protein that can recognise and attach to another protein found on blood 
vessels called ‘VEGF receptor 2’. This receptor is needed in the development of new blood vessels. To 
grow, cancer needs new blood vessels to develop. By attaching to ‘VEGF receptor 2’ and blocking it 
the medicine cuts off the blood supply to the cancer cells. 
 
Cyramza is given in combination with paclitaxel, another anti-cancer medicine, for the treatment of 
advanced stomach cancer (or cancer of the junction between the oesophagus and the stomach) in 
adults whose disease has worsened after treatment with medicines to treat cancer. 
 
Cyramza is used for the treatment of advanced stomach cancer (or cancer of the junction between the 
oesophagus and the stomach) in adults whose disease has worsened after treatment with medicines to 
treat cancer and for whom treatment of Cyramza in combination with paclitaxel is not suitable. 
 
Cyramza is used to treat advanced cancers of the colon or rectum (parts of the large intestine) in 
adults. It is given with other medicines called ‘FOLFIRI chemotherapy’, including ‘5-fluorouracil’, 
‘folinic acid’, and ‘irinotecan’. 
 
Cyramza is given in combination with erlotinib, another anti-cancer medicine, as the first therapy for 
the treatment of adult patients with advanced non-small cell lung cancer when the cancer cells have 
specific changes (mutations) in the epidermal growth factor receptor gene. 
 
Cyramza is given in combination with docetaxel, another anti-cancer medicine, for the treatment of 
adult patients with advanced stage of lung cancer whose disease has worsened after treatment with 
medicines to treat cancer. 
 
Cyramza is used to treat liver cancer that is advanced or cannot be taken out by surgery, in adults who 
have been previously treated with another anticancer medicine (sorafenib) and who have an elevated 
level of a particular protein in the blood (alpha fetoprotein). 
 
 



45 

2. What you need to know before you are given Cyramza 
 
You must not be given Cyramza 
- if you are allergic to ramucirumab or any of the other ingredients of this medicine (listed in 

section 6).  
- if there is X-ray evidence that the lung cancer has a cavity or hole in it or if the lung cancer is 

close to major blood vessels. 
 
Warnings and precautions 
Talk to your doctor or nurse before you are given Cyramza if you: 
 
- have any condition which increases the risk of bleeding. Also tell your doctor if you are taking 

any medicines which may increase the risk of bleeding or which affect blood clotting ability. In 
such cases, your doctor will perform regular blood tests to monitor the risk of bleeding. 

 
- have liver cancer and have had previous bleeding from enlarged veins in your food pipe 

(oesophagus) or have high blood pressure in the portal vein, which carries the blood from the 
bowel and spleen to the liver.  

 
- have lung cancer and have had recent bleeding in the lung (coughing up bright red blood) or you 

are regularly taking non-steroidal anti-inflammatory medicines, or medicines which affect blood 
clotting ability. 

 
- have high blood pressure. Cyramza can increase the incidence of high blood pressure. Your 

doctor will make sure that if you already have high blood pressure, it is brought under control 
before starting Cyramza. Your doctor will monitor your blood pressure and adjust your blood 
pressure medicine as needed during treatment with Cyramza. Treatment with Cyramza may 
need to be stopped temporarily until high blood pressure is controlled with medicines, or 
stopped permanently if it cannot be adequately controlled.  

 
- have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a 

blood vessel wall. 
 
- are going to have planned surgery, if you had recent surgery or if you have poor wound healing 

after surgery. Cyramza may increase the risk of problems with wound healing. You should not 
receive Cyramza for at least 4 weeks before you undergo planned surgery and your doctor will 
decide when to re-start treatment. If you have a wound that heals poorly during treatment, 
dosing of Cyramza will be stopped until the wound is fully healed.  

 
- have severe liver disease (‘cirrhosis’) and associated conditions, such as excessive accumulation 

of fluid in your abdomen (‘ascites’). Your doctor will discuss with you if the potential benefits 
of treatment are judged to outweigh the potential risks for you. If you have liver cancer your 
doctor will monitor you for signs and symptoms of confusion and/or disorientation associated 
with chronic liver problems and will stop treatment with Cyramza if you develop these signs 
and symptoms. 

 
- have severe kidney problems. There are limited data available about the use of Cyramza in 

patients with severely impaired kidney function. 
 
Talk to your doctor or nurse immediately if any of the following applies to you (or you are not sure) 
during treatment with Cyramza or anytime thereafter: 
 
- Blocking of the arteries by a blood clot (‘arterial thromboembolic events’): 
 Cyramza can cause blood clots in your arteries. Arterial blood clots can lead to serious 

conditions, including heart attack or stroke. Symptoms of a heart attack may include chest pain 
or heaviness in the chest. Symptoms of a stroke may include sudden numbness or weakness of 
the arm, leg and face, feeling confused, difficulty speaking or understanding others, sudden 



46 

difficulty in walking or loss of balance or coordination or sudden dizziness. Cyramza will be 
permanently stopped if you develop a blood clot in your arteries. 

 
- A hole in the wall of your gut (‘gastrointestinal perforation’): Cyramza may increase the risk 

of developing a hole in the wall of your gut. Symptoms include severe abdominal pain, being 
sick (vomiting), fever or chills. Cyramza will be permanently stopped if you develop a hole in 
the wall of your gut. 

 
- Severe bleeding: Cyramza may increase the risk of severe bleeding. Symptoms may include: 

extreme tiredness, weakness, dizziness or changes in the colour of your stools. Cyramza will be 
permanently stopped if you experience severe bleeding. 

 
- Infusion-related reaction: Infusion-related reactions may happen during treatment because 

Cyramza is given as an intravenous infusion via a drip (see section 3). Your doctor or nurse will 
check for side effects during your infusion. Symptoms may include: increased muscle tension, 
back pain, chest pain and/or tightness, chills, flushing, difficulty in breathing, wheezing, and 
feeling of tingling or numbness in hands or feet. In severe cases, symptoms may include 
breathing distress caused by narrowing of the airways, faster heartbeat, and feeling faint. 
Cyramza will be permanently stopped if you experience a severe infusion-related reaction. 

 
- A rare but serious brain condition called ‘posterior reversible encephalopathy syndrome’ or 

‘PRES’: Cyramza may increase the risk of developing this brain condition. Symptoms may 
include fits (seizures), headache, feeling sick (nausea), being sick (vomiting), blindness or 
reduced level of consciousness, with or without high blood pressure. Cyramza will be stopped if 
you experience this brain condition. 

 
- Abnormal tube-like connections or passageways inside the body (‘fistula’): Cyramza may 

increase the risk of abnormal tube-like connections or passageways inside the body between 
internal organs and skin or other tissues. Cyramza will be permanently stopped if you develop a 
fistula. 

 
- Abnormal urine test (‘proteinuria’): Cyramza may increase the risk of developing or 

worsening of abnormal levels of protein in the urine. Treatment with Cyramza may need to be 
stopped temporarily until the levels of protein in the urine decrease and then treatment resumed 
at a lower dose, or stopped permanently if the urine protein level does not reduce sufficiently. 

 
- Inflammation of the mouth (‘stomatitis’): Cyramza, when given in combination with 

chemotherapy may increase the risk of developing inflammation of the mouth. Symptoms may 
include a burning sensation in the mouth, ulceration, blisters or swelling. Your doctor may 
prescribe treatment to help with the symptoms. 

 
- Fever or infection: You may develop a temperature of 38 ºC or greater during treatment (since 

you might have fewer white blood cells than normal which is very common). Symptoms may 
include sweating or other signs of infection, such as headache, pain in the limbs or decreased 
appetite. Infection (sepsis) may be severe and could lead to death. 

 
- Elderly people with lung cancer: Your doctor will carefully evaluate the most appropriate 

treatment for you. 
 
Children and adolescents 
Cyramza should not be given to patients under the age of 18 years because there is no information 
about how it works in this age group. 
 
Other medicines and Cyramza 
Tell your doctor if you are taking, have recently taken or might take any other medicines. This 
includes medicines obtained without a prescription and herbal medicines. 
 



47 

Pregnancy, breast-feeding and fertility 
Before starting treatment you must tell your doctor if you are pregnant or breast-feeding, think you 
may be pregnant or you are planning to have a baby. You should avoid getting pregnant while 
receiving this medicine and for at least 3 months after the last dose of Cyramza. Talk to your doctor 
about the best contraception for you. 
 
As Cyramza inhibits the development of new blood vessels, it may decrease the likelihood of you 
becoming pregnant or maintaining a pregnancy. It may also cause damage to your unborn baby. You 
should not use this medicine during pregnancy. If you become pregnant during treatment with 
Cyramza, your doctor will discuss with you if the benefit of treatment for you is greater than any 
possible risk to you or your unborn baby. 
 
It is not known if the medicine passes into breast milk and could affect a breastfed baby. Therefore, 
you should not breast-feed your baby during treatment with Cyramza and for at least 3 months after 
you receive the last dose. 
 
Driving and using machines 
Cyramza has no or negligible influence on your ability to drive and use machines. If you experience 
any symptoms affecting your ability to concentrate and react, do not drive or use machines until the 
effect goes away. 
 
Cyramza contains sodium 
Each 10 ml vial contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’.  
Each 50 ml vial contains approximately 85 mg sodium (main component of cooking/table salt). This is 
equivalent to approximately 4% of the recommended maximum daily dietary intake of sodium for an 
adult.  
 
 
3. How you are given Cyramza 
 
This cancer treatment will be given to you by a doctor or nurse. 
 
Dosage and frequency of administration 
The correct amount of Cyramza needed to treat your disease will be calculated by your doctor or 
hospital pharmacist depending on your body weight.  
 
The recommended dose of Cyramza for the treatment of gastric cancer, for the treatment of advanced 
cancer of the colon or rectum and for the treatment of liver cancer is 8 mg per kilogram of your body 
weight once every 2 weeks. 
 
The recommended dose of Cyramza for the treatment of lung cancer is 10 mg per kilogram of your 
body weight once every 2 weeks when given in combination with erlotinib or once every 3 weeks 
when given in combination with docetaxel. 
 
The number of infusions you will receive depends on how you are responding to treatment. Your 
doctor will discuss this with you. 
 
Premedication 
You may be given another medicine to reduce the risk of an infusion-related reaction before you 
receive Cyramza. If you experience an infusion-related reaction during Cyramza therapy, you will be 
given premedication for all future infusions. 
 
Dose adjustments 
During each infusion, your doctor or nurse will check for side effects.  
 
If you experience an infusion-related reaction during treatment, the time taken to give your infusion 
will be increased for the rest of that infusion and for all future infusions.  



48 

 
The amount of protein in your urine will be checked regularly during treatment. Depending on the 
protein level measured, Cyramza may be temporarily discontinued. Once the urine protein level has 
decreased to a certain level, treatment may be restarted with a lower dose. 
 
Route and method of administration 
Cyramza is a concentrate for solution for infusion (also called “sterile concentrate”). A hospital 
pharmacist, nurse or doctor will have diluted the contents of the vial with sodium chloride 9 mg/ml 
(0.9%) solution before use. This medicine is given by infusion via a drip over a period of 
approximately 60 minutes.  
 
Cyramza treatment will be temporarily stopped if you: 
- develop high blood pressure, until it is controlled with anti-hypertensive medicine 
- develop wound healing problems, until the wound is healed 
- will undergo planned surgery, four weeks prior to surgery 
 
Cyramza treatment will be permanently stopped if you: 
- develop a blood clot in your arteries 
- develop a hole in the wall of your gut 
- experience severe bleeding 
- experience a severe infusion-related reaction 
- develop high blood pressure that cannot be controlled with medicine 
- are passing more than a certain amount of protein with your urine or if you develop a severe 

kidney disease (nephrotic syndrome) 
- develop abnormal tube-like connections or passageways inside the body between internal 

organs and skin or other tissues (fistula) 
- develop confusion and/or disorientation associated with chronic liver problems 
- decline in kidney function (in the setting of liver failure) 
 
When receiving Cyramza in combination with paclitaxel or docetaxel 
Paclitaxel and docetaxel are also given by a drip into a vein (intravenous infusion) over a period of 
approximately 60 minutes. If you are receiving Cyramza in combination with either paclitaxel or 
docetaxel on the same day, Cyramza will be given first. 
 
The amount of paclitaxel or docetaxel needed depends on the surface area of your body. Your doctor 
or hospital pharmacist will calculate your body surface area by measuring your height and weight and 
will work out the right dose for you.  
 
The recommended dose of paclitaxel is 80 mg for every square metre (m²) of your body’s surface area 
once every week for 3 weeks followed by 1 week without treatment.  
 
The recommended dose of docetaxel is 75 mg for every square metre (m²) of your body’s surface area 
once every 3 weeks. If you are of East Asian origin, you may receive a reduced docetaxel starting dose 
of 60 mg per every m2 of your body’s surface area once every 3 weeks. 
 
Prior to being given any paclitaxel infusion, you will have blood tests to check that your blood counts 
are high enough and that your liver is functioning well. 
 
Read the paclitaxel or docetaxel package leaflet for further information. 
 
When receiving Cyramza in combination with FOLFIRI 
FOLFIRI chemotherapy is given by intravenous infusion, after the Cyramza infusion has finished. 
Please read the package leaflets for the other medicines that are part of your treatment, to see if they 
are suitable for you. If you are unsure, ask your doctor, pharmacist or nurse if there are any reasons 
why you can't use these medicines. 
 



49 

When receiving Cyramza in combination with erlotinib 
Please read the erlotinib package leaflet for information on erlotinib and whether it is suitable for you. 
If you are unsure, ask your doctor, pharmacist or nurse if there are any reasons why you can't use 
erlotinib. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately if you experience any of the following serious side effects that have 
been observed during Cyramza treatment (see also What you need to know before you are given 
Cyramza): 
 
Common side effects (may affect up to 1 in 10 people): 
- hole in the wall of your gut: this is a hole that develops in the stomach, gut or bowel. 

Symptoms include severe abdominal pain, being sick (vomiting), fever or chills. 
- severe bleeding in your gut: symptoms may include extreme tiredness, weakness, dizziness or 

changes in the colour of your stools. 
- blood clots in the arteries: arterial blood clots can lead to a heart attack or stroke. Symptoms 

of a heart attack may include chest pain or heaviness in the chest. Symptoms of a stroke may 
include sudden numbness or weakness of the arm, leg and face, feeling confused, difficulty 
speaking or understanding others, sudden difficulty in walking or loss of balance or 
coordination or sudden dizziness.  

 
Rare side effects (may affect up to 1 in 1000 people): 
- a brain condition called posterior reversible encephalopathy syndrome: symptoms may include 

fits (seizures), headache, feeling sick (nausea), being sick (vomiting), blindness or reduced level 
of consciousness, with or without high blood pressure. 

 
Tell your doctor if you experience any of the following other side effects: 
 
Very common side effects (may affect more than 1 in 10 people): 
- feeling tired or weak 
- low white blood cell counts (may increase the risk of infection) 
- infections 
- diarrhoea 
- hair loss 
- nose bleed 
- inflammation of the lining of the mouth 
- high blood pressure 
- reduction in red blood cells which can make the skin pale 
- swelling of hands, feet and legs due to fluid retention 
- low platelet count (blood cells that help the blood to clot) 
- abdominal pain 
- protein in the urine (abnormal urine test) 
- headache 
- inflammation of mucous membranes, such as digestive and respiratory tracts 
 
Common side effects (may affect up to 1 in 10 people): 
- fever accompanied by low white blood cell counts 
- low blood levels of a protein called albumin 
- infusion-related reactions 
- rash 
- redness, swelling, numbness/tingling, or pain and/or skin peeling in hands and/or feet (called 

hand-foot syndrome) 
- hoarseness 



50 

- bleeding in your lungs 
- low blood levels of sodium (hyponatraemia) which can cause tiredness and confusion or muscle 

twitching 
- bleeding gums 
- confusion and/or disorientation in patients with chronic liver problems 
- intestinal blockage; symptoms may include constipation and abdominal pain 
- abnormal growth of blood vessels 
- serious infection (sepsis) 
- low blood levels of potassium (hypokalaemia) which can cause muscle weakness, twitching or 

abnormal heart rhythm  
 
 
Rare side effects (may affect up to 1 in 1000 people): 
- abnormal blood clotting in small blood vessels 
 
Not known (frequency cannot be estimated from the available data): 
- an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 

(aneurysms and artery dissections). 
 
Cyramza may cause changes in laboratory tests. From the side effects listed above, these are: low 
white blood cell counts; low platelet count in the blood; low blood levels of albumin, potassium or 
sodium; presence of protein in the urine. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Cyramza 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and vial label after 
EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze.  
Keep the vial in the outer carton in order to protect from light. 
 
Do not freeze or shake the infusion solution. Do not administer the solution if you notice any 
particulate matter or discolouration. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


51 

6. Contents of the pack and other information 
 
What Cyramza contains 
- The active substance is ramucirumab. One ml of concentrate for solution for infusion contains 

10 mg of ramucirumab. 
- Each 10 ml vial contains 100 mg of ramucirumab.  
- Each 50 ml vial contains 500 mg of ramucirumab.  
- The other ingredients are histidine, histidine monohydrochloride, sodium chloride, glycine 

(E640), polysorbate 80 (E433) and water for injections (see section 2 “Cyramza contains 
sodium”). 

 
What Cyramza looks like and contents of the pack 
The concentrate for solution for infusion (or sterile concentrate) is a clear to slightly opalescent and 
colourless to slightly yellow solution in a glass vial with a rubber stopper. 
 
Cyramza is available in packs of:  
- 1 vial of 10 ml 
- 2 vials of 10 ml 
- 1 vial of 50 ml 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Eli Lilly Nederland B.V. 
Papendorpseweg 83  
3528 BJ Utrecht  
The Netherlands 
 
Manufacturer 
Lilly, S.A. 
Avda de la Industria, 30 
Alcobendas 
28108 Madrid 
Spain 
 
Lilly France Fegersheim 
2 rue du Colonel Lilly 
67640 Fegersheim 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
Eli Lilly Benelux S.A./N.V. 
Tél/Tel: + 32-(0)2 548 84 84 
 

Lietuva 
Eli Lilly Lietuva 
Tel. +370 (5) 2649600 
 

България 
ТП "Ели Лили Недерланд" Б.В. - България 
тел. + 359 2 491 41 40 
 

Luxembourg/Luxemburg 
Eli Lilly Benelux S.A./N.V. 
Tél/Tel: + 32-(0)2 548 84 84 

Česká republika 
ELI LILLY ČR, s.r.o. 
Tel: + 420 234 664 111 
 

Magyarország 
Lilly Hungária Kft. 
Tel: + 36 1 328 5100 

Danmark 
Eli Lilly Danmark A/S  

Malta 
Charles de Giorgio Ltd. 



52 

Tlf: +45 45 26 60 00 
 

Tel: + 356 25600 500 

Deutschland 
Lilly Deutschland GmbH 
Tel. + 49-(0) 6172 273 2222 
 

Nederland 
Eli Lilly Nederland B.V.  
Tel: + 31-(0) 30 60 25 800 

Eesti 
Eli Lilly Nederland B.V.  
Tel: +372 6 817 280 
 

Norge 
Eli Lilly Norge A.S.  
Tlf: + 47 22 88 18 00 

Ελλάδα 
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε.  
Τηλ: +30 210 629 4600 
 

Österreich 
Eli Lilly Ges.m.b.H.  
Tel: + 43-(0) 1 711 780 

España 
Lilly S.A. 
Tel: + 34-91 663 50 00 
 

Polska 
Eli Lilly Polska Sp. z o.o. 
Tel: +48 22 440 33 00 

France 
Lilly France SAS 
Tél: +33-(0) 1 55 49 34 34 
 

Portugal 
Lilly Portugal Produtos Farmacêuticos, Lda 
Tel: + 351-21-4126600 

Hrvatska 
Eli Lilly Hrvatska d.o.o. 
Tel: +385 1 2350 999 
 

România 
Eli Lilly România S.R.L. 
Tel: + 40 21 4023000 

Ireland 
Eli Lilly and Company (Ireland) Limited 
Tel: + 353-(0) 1 661 4377 
 

Slovenija 
Eli Lilly farmacevtska družba, d.o.o. 
Tel: +386 (0)1 580 00 10 

Ísland 
Icepharma hf. 
Sími + 354 540 8000 
 

Slovenská republika 
Eli Lilly Slovakia s.r.o. 
Tel: + 421 220 663 111 

Italia 
Eli Lilly Italia S.p.A. 
Tel: + 39- 055 42571 
 

Suomi/Finland 
Oy Eli Lilly Finland Ab  
Puh/Tel: + 358-(0) 9 85 45 250 

Κύπρος 
Phadisco Ltd  
Τηλ: +357 22 715000 
 

Sverige 
Eli Lilly Sweden AB 
Tel: + 46-(0) 8 7378800 

Latvija 
Eli Lilly (Suisse) S.A Pārstāvniecība Latvijā 
Tel: +371 67364000 
 

United Kingdom 
Eli Lilly and Company Limited 
Tel: + 44-(0) 1256 315000 

 
This leaflet was last revised in . 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


53 

-------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Do not shake the vial. 
 
Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution. 
 
Each vial is intended for single use only. Inspect the content of the vials for particulate matter and 
discolouration (the concentrate for solution for infusion should be clear to slightly opalescent and 
colourless to slightly yellow without visible particles) prior to dilution. If particulate matter or 
discolouration is identified, discard the vial. 
 
Calculate the dose and volume of ramucirumab needed to prepare the infusion solution. Vials contain 
either 100 mg or 500 mg as a 10 mg/ml solution of ramucirumab. Only use sodium chloride 9 mg/ml 
(0.9%) solution for injection as a diluent. 
 
In case of pre-filled intravenous infusion container usage 
Based on the calculated volume of ramucirumab, remove the corresponding volume of sodium 
chloride 9 mg/ml (0.9%) solution for injection from the pre-filled 250 ml intravenous container. 
Aseptically transfer the calculated volume of ramucirumab to the intravenous container. The final total 
volume in the container should be 250 ml. The container should be gently inverted to ensure adequate 
mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or 
co-infuse with other electrolytes or medicinal products. 
 
In case of empty intravenous infusion container usage 
Aseptically transfer the calculated volume of ramucirumab into an empty intravenous infusion 
container. Add a sufficient quantity of sodium chloride 9 mg/ml (0.9%) solution for injection to the 
container to make the total volume 250 ml. The container should be gently inverted to ensure adequate 
mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or 
co-infuse with other electrolytes or medicinal products. 
 
After dilution and preparation, the medicine must be used immediately. If not used immediately, in-
use storage times and conditions prior to use are the responsibility of the user and would normally not 
be longer than 24 hours at 2 °C to 8 °C. 
 
Parenteral medicinal products should be inspected visually for particulate matter prior to 
administration. If particulate matter is identified, discard the infusion solution. 
 
Discard any unused portion of ramucirumab left in a vial, as the product contains no antimicrobial 
preservatives. 
 
Administer via infusion pump. A separate infusion line with a protein sparing 0.22 micron filter must 
be used for the infusion and the line must be flushed with sodium chloride 9 mg/ml (0.9%) solution for 
injection at the end of the infusion. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET