CYRAMZA 10mg / ml concentrate for solution for infusion medication leaflet

Cyramza 10 mg/ml concentrate for solution for infusion

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.

Each 10 ml vial contains approximately 17 mg sodium and 1 mg polysorbate 80.

Each 50 ml vial contains approximately 85 mg sodium and 5 mg polysorbate 80.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

The concentrate is a clear to slightly opalescent and colourless to slightly yellow solution, pH 6.0.

Gastric cancer

Cyramza in combination with paclitaxel is indicated for the treatment of adult patients with advancedgastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after priorplatinum and fluoropyrimidine chemotherapy (see section 5.1).

Cyramza monotherapy is indicated for the treatment of adult patients with advanced gastric cancer orgastro-oesophageal junction adenocarcinoma with disease progression after prior platinum orfluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate(see section 5.1).

Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated forthe treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression onor after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine.

Cyramza in combination with erlotinib is indicated for the first-line treatment of adult patients withmetastatic 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 locallyadvanced or metastatic non-small cell lung cancer with disease progression after platinum-basedchemotherapy.

Hepatocellular carcinoma

Cyramza monotherapy is indicated for the treatment of adult patients with advanced or unresectablehepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who havebeen previously treated with sorafenib.

Ramucirumab therapy must be initiated and supervised by physicians experienced in oncology.

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 topaclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m2 administered by intravenousinfusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxelinfusion, patients should have a complete blood count and blood chemistry performed to evaluatehepatic 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 No liver metastases: ALT/AST ≤ 3 x ULN(AST) /Alanineaminotransferase (ALT) 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.

The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered by intravenousinfusion, prior to FOLFIRI administration. Prior to chemotherapy, patients should have a completeblood count. Criteria to be met prior to FOLFIRI are provided in Table 2.

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- ≤ Grade 1 (National Cancer Institute Commonintestinal toxicity Terminology Criteria for Adverse Events [NCI

CTCAE])

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 anderlotinib using a validated test method. See erlotinib prescribing information for the posology andmethod of administration of erlotinib.

Cyramza in combination with docetaxel for the treatment of NSCLC after platinum-basedchemotherapy

The recommended dose of ramucirumab is 10 mg/kg on day 1 of a 21 day cycle, prior to docetaxelinfusion. The recommended dose of docetaxel is 75 mg/m2 administered by intravenous infusion overapproximately 60 minutes on day 1 of a 21 day cycle. For East Asian patients, a reduced docetaxelstarting dose of 60 mg/m2 on day 1 of a 21 day cycle should be considered. See docetaxel prescribinginformation 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 avalidated AFP test prior to ramucirumab treatment (see section 5.1).

It is recommended that treatment be continued until disease progression or until unacceptable toxicityhas occurred.

Premedication

Premedication is recommended with a histamine H1 antagonist (for example diphenhydramine) priorto infusion of ramucirumab. If a patient experiences a Grade 1 or 2 infusion-related reactionpremedication must be given for all subsequent infusions. If a patient experiences a second Grade 1 or2 infusion-related reaction (IRR) administer dexamethasone (or equivalent); then, for subsequentinfusions, 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, asapplicable, for premedication requirements and additional information.

Posology adjustments for ramucirumab

The infusion rate of ramucirumab should be reduced by 50 % for the duration of the infusion and allsubsequent infusions if the patient experiences a grade 1 or 2 IRR. Ramucirumab should beimmediately and permanently discontinued in the event of a grade 3 or 4 IRR (see section 4.4).

The blood pressure of patients should be monitored prior to each ramucirumab administration andtreated as clinically indicated. Ramucirumab therapy should be temporarily discontinued in the eventof severe hypertension, until controlled with medical management. If there is medically significanthypertension that cannot be controlled safely with antihypertensive therapy, ramucirumab therapyshould be permanently discontinued (see section 4.4).

Proteinuria

Patients should be monitored for the development or worsening of proteinuria during ramucirumabtherapy. 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 doselevel (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 hoursor in the event of nephrotic syndrome.

Table 3: Ramucirumab dose reductions for proteinuria

Initial ramucirumab dose First dose reduction to Second dose reduction to8 mg/kg 6 mg/kg 5 mg/kg10 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 electivesurgery. Ramucirumab therapy should be temporarily discontinued if there are wound healingcomplications, 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-haematologicaltoxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m2 for all following cycles. Asecond reduction of 10 mg/m2 is recommended if these toxicities persist or reoccur.

FOLFIRI dose adjustments

Dose reductions for individual components of FOLFIRI may be made for specific toxicities. Dosemodifications 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 thenext cycle based on maximum grade of specific adverse drug reactions.

Table 4: FOLFIRI dose reductions

FOLFIRI Dose levelcomponenta Initial dose -1 -2 -3

Irinotecan 180 mg/m2 150 mg/m2 120 mg/m2 100 mg/m25-FU bolus 400 mg/m2 200 mg/m2 0 mg/m2 0 mg/m25-FU infusion 2,400 mg/m2 2,000 mg/m2 1,600 mg/m2 1,200 mg/m2over 46-48 hours over 46-48 hours over 46-48 hours over 46-48 hoursa 5-FU = 5-fluorouracil.

Table 5: Dose modification of FOLFIRI components due to specific adverse drugreactions (ADRs)

ADR NCI Dose modification at day 1 of cycle subsequent to ADR

CTCAEgrade

Diarrhoea 2 If diarrhoea has recovered to Grade ≤1, reduce by 1 dose levelfor 5-FU.

For recurrent Grade 2 diarrhoea, reduce by 1 dose level for5-FU and irinotecan.

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

4 If diarrhoea has recovered to Grade ≤1, reduce by 2 dose levelsfor 5-FU and irinotecan.

If Grade 4 diarrhoea does not resolve to Grade ≤1, withhold5-FU and irinotecan for a maximum of 28* days untilresolution to Grade ≤1.

Neutropenia or Haematological criteria in Haematological criteria in

Thrombocytopenia Table 2 are met Table 2 are not met2 No dose modification. Reduce by 1 dose level for5-FU and irinotecan.

3 Reduce by 1 dose level for Delay 5-FU and irinotecan for5-FU and irinotecan. a maximum of 28* days untilresolution to Grade ≤1, thendose reduce by 1 level for5-FU and irinotecan.

4 Reduce by 2 dose levels for Delay 5-FU and irinotecan for5-FU and irinotecan. a maximum of 28* days untilresolution to Grade ≤1, thendose reduce by 2 levels for5-FU and irinotecan.

Stomatitis/Mucositis 2 If stomatitis/mucositis has recovered to Grade ≤1, reduce by1 dose level for 5-FU.

For recurrent Grade 2 stomatitis, reduce by 2 dose levels for5-FU.

3 If stomatitis/mucositis has recovered to Grade ≤1, reduce by1 dose level for 5-FU.

If Grade 3 mucositis/stomatitis does not resolve to Grade ≤1,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 Haematological criteria in

Table 2 are met and fever Table 2 are not met and feverresolved resolved

Reduce by 2 dose levels for Delay 5-FU and irinotecan for5-FU and irinotecan. a maximum of 28* days untilresolution to Grade ≤1, thendose reduce by 2 levels for5-FU and irinotecan.

Consider use of colony-stimulating factor prior to nextcycle.

*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 duringdocetaxel treatment should have treatment withheld until resolution of the toxicity. It is recommendedto reduce the docetaxel dose by 10 mg/m2 for all following cycles. A second reduction of 15 mg/m2 isrecommended if these toxicities persist or reoccur. In this case, East Asian patients with a starting doseof 60 mg/m² should have docetaxel treatment discontinued (see Posology).

In the pivotal studies there is limited evidence that patients 65 years of age or older are at increasedrisk of adverse events compared to patients younger than 65 years old. No dose reductions arerecommended (see sections 4.4 and 5.1).

There have been no formal studies with Cyramza in patients with renal impairment. Clinical datasuggest that no dose adjustments are required in patients with mild, moderate or severe renalimpairment (see sections 4.4 and 5.2). No dose reductions are recommended.

There have been no formal studies with Cyramza in patients with hepatic impairment. Clinical datasuggest 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.

The safety and efficacy of Cyramza in children and adolescents (< 18 years) has not been established.

Currently available data are described in section 4.8, 5.1 and 5.2. Due to limited data norecommendation on posology can be made.

There is no relevant use of ramucirumab in the paediatric population for the indications of advancedgastric cancer or gastro-oesophageal adenocarcinoma, adenocarcinoma of the colon and rectum, lungcarcinoma, and hepatocellular carcinoma.

Cyramza is for intravenous use. After dilution, Cyramza is administered as an intravenous infusionover approximately 60 minutes. It should not be administered as an intravenous bolus or push. Toachieve the required infusion duration of approximately 60 minutes, the maximum infusion rate of25 mg/minute should not be exceeded, instead the infusion duration should be increased. The patientshould be monitored during infusion for signs of infusion-related reactions (see section 4.4) and theavailability of appropriate resuscitation equipment should be ensured.

For instructions on dilution of the medicinal product before administration, see section 6.6.

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 tumourinvolvement of major vessels (see section 4.4).

In order to improve traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.

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 (seesection 4.2).

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 gastrointestinalperforations (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 withconditions predisposing to bleeding, and in those treated with anticoagulants or other concomitantmedicinal products that increase the risk of bleeding. For HCC patients with evidence of portalhypertension or prior history of oesophageal variceal bleeding, screening for and treatment ofoesophageal varices should be performed as per standard of care before starting ramucirumabtreatment.

Severe gastrointestinal haemorrhage, including fatal events, were reported in patients with gastriccancer treated with ramucirumab in combination with paclitaxel, and in patients with mCRC treatedwith 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 patientswith squamous histology in REVEL. NSCLC patients with recent pulmonary bleeding (> 2.5 ml orbright red blood) as well as patients with evidence of baseline tumour cavitation, regardless ofhistology, or those with any evidence of tumour invasion or encasement of major blood vessels havebeen excluded from clinical trials (see section 4.3). Patients receiving any kind of therapeuticanticoagulation were excluded from the REVEL NSCLC clinical trial and patients receiving chronictherapy 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 (seesection 5.1).

Infusion-related reactions were reported in clinical studies with ramucirumab. The majority of eventsoccurred during or following a first or second ramucirumab infusion. Patients should be monitoredduring the infusion for signs of hypersensitivity. Symptoms included rigors/tremors,back-pain/spasms, chest pain and/or tightness, chills, flushing, dyspnoea, wheezing, hypoxia, andparaesthesia. In severe cases symptoms included bronchospasm, supraventricular tachycardia, andhypotension. Ramucirumab should be immediately and permanently discontinued in patients whoexperience a Grade 3 or 4 IRR (see section 4.2).

An increased incidence of severe hypertension was reported in patients receiving ramucirumab ascompared to placebo. In most cases hypertension was managed using standard antihypertensivetreatment. Patients with uncontrolled hypertension were excluded from the trials: ramucirumabtreatment should not be initiated in such patients until and unless their pre-existing hypertension iscontrolled. Patients who are treated with ramucirumab should have their blood pressure monitored.

Ramucirumab should be temporarily discontinued for severe hypertension until controlled withmedical management. Ramucirumab should be permanently discontinued if medically significanthypertension 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 rarelyreported in patients receiving ramucirumab. PRES symptoms may include seizure, headache,nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension. Adiagnosis 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 inpatients who develop PRES and recover is not known.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Cyramza, this risk should becarefully 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. Ina study conducted in animals, ramucirumab did not impair wound healing. However, sinceramucirumab is an antiangiogenic therapy and may have the potential to adversely affect woundhealing, 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 clinicaljudgment of adequate wound healing.

If a patient develops wound healing complications during therapy, ramucirumab should bediscontinued until the wound is fully healed (see section 4.2).

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 hepatorenalsyndrome. There are very limited efficacy and safety data available in these patients. Ramucirumabshould only be used in these patients if the potential benefits of treatment are judged to outweigh thepotential risk of progressive hepatic failure.

In HCC patients, hepatic encephalopathy was reported at a higher rate in the ramucirumab-treatedpatients compared to the placebo-treated patients (see section 4.8). Patients should be monitored forclinical signs and symptoms of hepatic encephalopathy. Ramucirumab should be permanentlydiscontinued in the event of hepatic encephalopathy or hepatorenal syndrome (see section 4.2).

Cardiac Failure

In pooled data from ramucirumab clinical trials, cardiac failure was reported at a numerically higherincidence in patients receiving ramucirumab in combination with a variety of chemotherapy regimens,or erlotinib, compared to chemotherapy or erlotinib alone. This increased incidence was not observedin patients receiving ramucirumab compared to placebo from single agent clinical trials. In the post-marketing setting, cardiac failure was observed for ramucirumab, mostly in combination withpaclitaxel. Patients should be monitored for clinical signs and symptoms of cardiac failure duringtreatment, and suspension of treatment should be considered if clinical signs and symptoms of cardiacfailure develop. See section 4.8.

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 toplacebo. Patients should be monitored for the development, or worsening of proteinuria duringramucirumab therapy. If the urine protein is ≥ 2+ on a dipstick, a 24 hour urine collection should beperformed. 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 ata reduced dose level. A second dose reduction is recommended if a urine protein level ≥ 2 g/24 hoursreoccurs. 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 combinationwith chemotherapy as compared to patients treated with placebo plus chemotherapy. Symptomatictreatment should be instituted promptly if stomatitis occurs.

There are limited safety data available for patients with severe renal impairment (creatinine clearance15 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 ramucirumabplus docetaxel for the treatment of advanced NSCLC with disease progression after platinum-basedchemotherapy (see section 5.1). Comorbidities associated with advanced age, performance status andthe likely tolerability to chemotherapy should therefore be thoroughly evaluated prior to the initiationof 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 withactivating EGFR mutations, patients aged 70 years and older compared to patients under 70 years ofage, experienced a higher incidence of grade ≥ 3 adverse events and all grade serious adverse events.

This medicinal product contains less than 1 mmol sodium (23 mg) in each 10 ml vial, that is to sayessentially ‘sodium free’.

This medicinal product contains approximately 85 mg sodium in each 50 ml vial. This is equivalent toapproximately 4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Polysorbate

This medicinal product contains approximately 1 mg of polysorbate 80 in each 10 ml, and 5 mg ofpolysorbate 80 in each 50 ml vial.

No drug-drug interactions were observed between ramucirumab and paclitaxel. The pharmacokineticsof paclitaxel were not affected when co-administered with ramucirumab and the pharmacokinetics oframucirumab were not affected when co-administered with paclitaxel. The pharmacokinetics ofirinotecan and its active metabolite, SN-38, were not affected when co-administered withramucirumab. The pharmacokinetics of docetaxel or erlotinib were not affected when co-administeredwith ramucirumab.

Women of childbearing potential should be advised to avoid becoming pregnant while on Cyramzaand should be informed of the potential hazard to the pregnancy and foetus. Women of childbearingpotential should use effective contraception during and up to 3 months after the last dose oframucirumab treatment.

There are no data from the use of ramucirumab in pregnant women. Animal studies are insufficientwith respect to reproductive toxicity (see section 5.3). As angiogenesis is critical to maintenance ofpregnancy and to foetal development, the inhibition of angiogenesis following ramucirumabadministration may result in adverse events on pregnancy, including the foetus. Cyramza should onlybe used if the potential benefit to the mother justifies the potential risk during pregnancy. If the patientbecomes pregnant while being treated with ramucirumab, she should be informed of the potential riskto the maintenance of pregnancy and the risk to the foetus. Cyramza is not recommended duringpregnancy and in women of childbearing potential not using contraception.

It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorptionis expected to be low. As a risk to breast-fed newborns/infants cannot be excluded, breast-feedingshould be discontinued during treatment with Cyramza and for at least 3 months after the last dose.

There are no data on the effect of ramucirumab on human fertility. Female fertility is likely to becompromised during treatment with ramucirumab based on studies in animals (see section 5.3).

Cyramza has no or negligible influence on the ability to drive and use machines. If patients experiencesymptoms affecting their ability to concentrate and react, it is recommended that they do not drive oruse machines until the effect subsides.

The most serious adverse reactions associated with ramucirumab treatment (as a single agent or incombination 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 monotherapyare: peripheral oedema, hypertension, diarrhoea, abdominal pain, headache, proteinuria andthrombocytopenia.

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

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

Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase III clinicaltrials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCCor in combination with different chemotherapy regimens or erlotinib for the treatment of gastriccancer, 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 3clinical trials (REGARD, REACH-2 and REACH patients with alpha fetoprotein ≥ 400 ng/ml)

System Organ Very Common Common Uncommon

Class (MedDRA)

Blood and Thrombocytopeniaa Neutropeniaalymphatic systemdisorders

Metabolism and Hypokalaemiaa,bnutrition disorders Hyponatraemiaa

Hypoalbuminaemiaa

Nervous system Headache Hepatic encephalopathycdisorders

Vascular disorders Hypertensiona,d Arterial thromboemboliceventsa

Respiratory, Epistaxisthoracic, andmediastinaldisorders

Gastrointestinal Abdominal paina,e Intestinal obstructiona Gastrointestinaldisorders Diarrhoea perforationa

Skin and Rashasubcutaneous tissuedisorders

Renal and urinary Proteinuriaa,fdisorders

General disorders Peripheral oedema Infusion-related reactionsaand administrationsite disordersa Terms represent a group of events that describe a medical concept rather than a single event or preferredterm.

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

Table 7: ADRs reported in patients treated with ramucirumab in combination withchemotherapy or erlotinib in phase 3 clinical trials (RAINBOW, REVEL, RAISE and RELAY)

System Organ Class Very Common Common Uncommon(MedDRA)

Infections and infestations Infectionsj,k Sepsisa,b

Blood and lymphatic Neutropeniaa Febrile neutropeniadsystem disorders Leukopeniaa,c

Thrombocytopeniaa

Anaemiaj

Metabolism and nutrition Hypoalbuminaemiaadisorders Hyponatraemiaa

Nervous system disorders Headachej

Cardiac disorders Cardiac failure

Vascular disorders Hypertensiona,e Arterial thromboemboliceventsa

Respiratory, thoracic, and Epistaxis Pulmonary haemorrhagej,lmediastinal disorders

Gastrointestinal disorders Stomatitis Gastrointestinal

Diarrhoea haemorrhage eventsa,f

Gastrointestinalperforationa

Gingival bleedingj

Skin and subcutaneous Alopeciaj Palmar-plantartissue disorders erthyrodysaesthesiasyndromeg

Renal and urinary disorders Proteinuriaa,h

General disorders and Fatiguea,iadministration site disorders Mucosalinflammationd

Peripheraloedemaa Terms represent a group of events that describe a medical concept rather than a single event or preferredterm.

b Based on study RAINBOW (ramucirumab plus paclitaxel).c Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell countdecreased.d Based on study REVEL (ramucirumab plus docetaxel).e Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy.f Based on study RAINBOW (ramucirumab plus paclitaxel), study REVEL (ramucirumab plus docetaxel) andstudy RAISE (ramucirumab plus FOLFIRI). Includes: anal haemorrhage, diarrhoea haemorrhage, gastrichaemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage,

Mallory-Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinalhaemorrhage.

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, andurinary tract infection.

l Includes haemoptysis, laryngeal haemorrhage, haemothorax (a fatal event occurred) and pulmonaryhaemorrhage.

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

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 mostfrequent (≥ 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 mostfrequent component of FOLFIRI to be discontinued was the 5-FU bolus.

Adverse reactions from other sources

Table 8: ADRs associated with ramucirumab reported in clinical trials and through post-marketing reporting

System Organ Class Common Uncommon Rare Not known(MedDRA)

Neoplasms benign, Haemangiomamalignant andunspecified(including cysts andpolyps)

Blood and lymphatic Thromboticsystem disorders microangiopathy

Endocrine disorders Hypothyroidism

Nervous system Posteriordisorders reversibleencephalopathysyndrome

Cardiac disorders Cardiac failurea

Vascular disorders Aneurysms andarterydissections

Respiratory, thoracic Dysphoniaand mediastinaldisordersa In the post-marketing setting, cardiac failure has been observed for ramucirumab mostly in combination withpaclitaxel. See section 4.4.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No new safety concerns were identified based on the limited number of paediatric patients treated withramucirumab monotherapy in study I4T-MC-JVDA (see section 5.1). One patient in this study hadprogressive widening of distal femoral growth plate. The impact of this finding on growth is notknown. No new safety concerns were reported in the limited number of paediatric patients treated withramucirumab in combination therapy in studies J1S-MC-JV01 and J1S-MC-JV02 (see section 5.1).

There is no data on overdose in humans. Cyramza has been administered in a phase 1 study up to10 mg/kg every two weeks without reaching a maximum tolerated dose. In case of overdose,supportive therapy should be used.

Pharmacotherapeutic group: Antineoplastic agents, VEGF/VEGFR (Vascular Endothelial Growth

Factor) inhibitors, ATC code: L01FG02.

Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF inducedangiogenesis. 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 inhibitsligand stimulated activation of VEGF Receptor 2 and its downstream signalling components,including p44/p42 mitogen-activated protein kinases, neutralising ligand-induced proliferation andmigration of human endothelial cells.

Gastric cancer

RAINBOW

RAINBOW, a global, randomised, double-blind, study of Cyramza plus paclitaxel versus placebo pluspaclitaxel, was conducted in 665 patients with locally recurrent and unresectable or metastatic gastriccancer (including GEJ adenocarcinoma) following platinum- and fluoropyrimidine-containingchemotherapy, with or without anthracycline. The primary endpoint was overall survival (OS) and thesecondary 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 thelast dose of first-line therapy and with ECOG PS 0-1. Patients were randomised in a 1:1 ratio toreceive Cyramza plus paclitaxel (n = 330) or placebo plus paclitaxel (n = 335). Randomisation wasstratified by geographic region, time to progression from the start of first-line therapy (< 6 monthsversus ≥ 6 months) and disease measurability. Cyramza at 8 mg/kg or placebo was administered byintravenous infusion every 2 weeks (on days 1 and 15) of a 28-day cycle. Paclitaxel at 80 mg/m2 wasadministered 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 fluoropyrimidinecombination therapy without anthracycline. The remainder (25 %) received prior platinum andfluoropyrimidine combination therapy with anthracycline. Two-thirds of the patients experienceddisease progression while still on first-line therapy (66.8 %). Baseline patient demographics anddisease characteristics were generally balanced between arms: the median age was 61 years; 71 % ofpatients were male; 61 % were Caucasian, 35 % Asian; the ECOG PS was 0 for 39 % of patients, 1 for61 % of patients; 81 % of patients had measurable disease and 79 % had gastric cancer; 21 % had GEJadenocarcinoma. The majority of patients (76 %) had experienced disease progression within6 months from the start of first-line therapy. For patients treated with Cyramza plus paclitaxel themedian duration of therapy was 19 weeks, and for patients treated with placebo plus paclitaxel themedian 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 ofpatients discontinued treatment due to adverse events: 12 % of patients treated with Cyramza pluspaclitaxel compared with 11 % of patients treated with placebo plus paclitaxel. Post discontinuationsystemic anti-cancer therapy was given to 47.9 % of patients receiving Cyramza plus paclitaxel and46.0 % of patients receiving placebo plus paclitaxel.

Overall survival was statistically significantly improved in patients receiving Cyramza plus paclitaxelcompared 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 pluspaclitaxel arm: 9.63 months in the Cyramza plus paclitaxel arm and 7.36 months in the placebo pluspaclitaxel 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 theplacebo plus paclitaxel arm. Objective response rate [ORR(complete response [CR] + partial response[PR])] was significantly improved in patients receiving Cyramza plus paclitaxel compared with thosereceiving placebo plus paclitaxel (Odds ratio 2.140; 95 % CI: 1.499 to 3.160; p = 0.0001). The ORR inthe Cyramza plus paclitaxel arm was 27.9 % and in the placebo plus paclitaxel arm was 16.1 %.

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 Placebo plus

N = 330 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 placeboplus paclitaxel in RAINBOW

Figure 2: Kaplan-Meier curves of progression-free survival for Cyramza plus paclitaxel versusplacebo plus paclitaxel in RAINBOW1.00.80.60.40.2

Cyramza+Paclitaxel

Placebo+Paclitaxel0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Time Since Randomization (Months)

Number at Risk

Cyramza+Paclitaxel 330 259 188 104 70 43 28 15 11 7 3 1

Placebo+Paclitaxel 335 214 124 50 34 21 12 8 5 3 3 3

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 gastriccancer (including GEJ adenocarcinoma) following platinum- or fluoropyrimidine-containingchemotherapy. The primary endpoint was OS and secondary endpoints included PFS. Patients wererequired 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 lastdose of adjuvant therapy, and had ECOG PS 0-1. To be included in the study, patients were required

Progression-free Survival Probabilityto have total bilirubin of ≤1.5 mg/dl and AST and ALT ≤ 3 times ULN, or ≤ 5 times ULN if livermetastases 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 theprior 3 months (≥ 10 % versus < 10 %), geographic region, and location of the primary tumour (gastricversus GEJ). Baseline demographics and disease characteristics were balanced. The ECOG PS was 1for 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 therapydue 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: 0.603to 0.998; p = 0.0473), corresponding to a 22 % reduction in the risk of death and an increase in mediansurvival to 5.2 months for Cyramza from3.8 months for placebo. Progression-free survival wasstatistically significantly improved in patients receiving Cyramza as compared with patients receivingplacebo (HR 0.483; 95 %CI: 0.376 to 0.620; p < 0.0001), corresponding to a 52 % reduction in the riskof progression or death and an increase in median PFS to 2.1 months for Cyramza from 1.3 months forplacebo. Efficacy results are shown in Table 10.

Table 10: Summary of efficacy data - ITT population

Cyramza Placebo

N=238 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 < 0.000112-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 REGARD1.00.80.60.40.2 Cyramza

Placebo0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28

Time Since Randomization (Months)

Number at Risk

Cyramza 238 154 92 49 17 7 3 0 0

Placebo 117 66 34 20 7 4 2 1 0

Probability of Overall Survival

Based on limited data from REGARD patients with HER2-positive gastric or GEJ adenocarcinomaand 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) anddemonstrated a benefit for progression free survival (PFS) (HR 0.399, 95 % CI 0.194, 0.822).

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 withbevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were required to have ECOG PS 0 or 1 andto have disease progression within 6 months of the last dose of first-line therapy. Patients wererequired to have adequate hepatic, renal and coagulation function. Patients with a history ofuncontrolled 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 monthsprior to randomisation were excluded. Patients were also excluded if they had experienced any of: an

ATE, Grade 4 hypertension, Grade 3 proteinuria, a Grade 3-4 bleeding event, or bowel perforationduring first-line bevacizumab therapy.

A total of 1072 patients were randomised (1:1) to receive either Cyramza (n = 536) at 8 mg/kg orplacebo (n = 536), in combination with FOLFIRI. All medicinal products were administeredintravenously. The FOLFIRI regimen was: irinotecan 180 mg/m2 administered over 90 minutes andfolinic acid 400 mg/m2 administered, simultaneously over 120 minutes; followed by bolus5-fluorouracil(5-FU) 400 mg/m2 over 2 to 4 minutes; followed by 5-FU 2400 mg/m2 administered bycontinuous 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 werepermitted to continue therapy with the other treatment component(s) until disease progression orunacceptable 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 Researchand 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 commencingfirst-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; and24 % of patients had TTP < 6 months after commencing first-line treatment. Post discontinuationsystemic anti-cancer therapy was given to 54 % of patients receiving Cyramza plus FOLFIRI and56 % of patients receiving placebo plus FOLFIRI.

Overall survival was statistically significantly improved in patients receiving Cyramza plus FOLFIRIcompared 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 theplacebo 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 was0.82 (95 % CI: 0.67 to 1.0) in patients with a KRAS wild type tumour, and 0.89 (95 % CI: 0.73 to1.09) in patients with a KRAS mutant tumour. For patients with TTP ≥ 6 months after commencingfirst-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) inpatients with TTP < 6 months after commencing first-line treatment. Pre-specified subgroup analysesfor 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-groupanalyses for OS, the HR was < 1.0. The one sub-group with HR > 1 was for patients with diseaseprogression from start of first-line bevacizumab treatment of < 3 months (HR 1.02 [95 % CI: 0.68 to1.55]). This one sub-group is a group which can be considered to have aggressive disease that isrelatively refractory to first-line treatment. In both treatment arms, patients who experiencedneutropenia had a longer median OS compared to patients who did not experience neutropenia. Themedian 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 was10.7 months in both arms.

Table 11: Summary of efficacy data - ITT population

Cyramza plus FOLFIRI Placebo plus FOLFIRI

N = 536 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 placeboplus FOLFIRI in RAISE

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

The ORR was similar for both treatment arms (13.4 % versus 12.5 %, ramucirumab plus FOLFIRIversus placebo plus FOLFIRI, respectively). The disease control rate (complete response plus partialresponse plus stable disease) was numerically higher in patients on the ramucirumab plus FOLFIRIarm 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 transientdecrease in QoL compared to the patients in the placebo plus FOLFIRI treatment arm in most of thescales. Few between-arm differences were reported after the first month of treatment.

RELAY

RELAY was a global, randomised, double-blind, phase 3 study of Cyramza plus erlotinib versusplacebo 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 orexon 21 (L858R) activating mutations at study entry. Eligible patients were ECOG PS 0 or 1. Patientswith 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 anyarterial 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 Asianand 22 % were Caucasian. Patients treated with Cyramza plus erlotinib experienced a statisticallysignificant improvement in progression-free survival (PFS) compared to patients treated with placeboplus erlotinib (Table 12). Consistent results were observed across subgroups including exon 19deletions 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 primary PFSanalysis (17.6 % maturity). RELAY efficacy results are shown in Table 12 and Figure 6.

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

Cyramza plus erlotinib Placebo plus erlotinib

N = 224 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

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 = partialresponse. Endpoints were alpha-protected.

Figure 6: Kaplan-Meier curves of progression free survival for Cyramza plus erlotinib versusplacebo plus erlotinib in RELAY

A final analysis of OS, for which the study was not powered, was performed at 297 events (maturity66.1 %). The stratified OS HR was 0.98 [95 % CI 0.78 - 1.24, p = 0.864] with a median OS of51.1 months [95 % CI 44.85 - 57.26] for Cyramza plus erlotinib vs 46.0 months [95 %

CI 43.56 - 53.03] for placebo plus erlotinib.

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

OS. Patients were randomised in a 1:1 ratio to receive Cyramza plus docetaxel (n = 628) or placeboplus docetaxel (n = 625). Randomisation was stratified by geographic region, gender, priormaintenance, and ECOG PS. Cyramza at 10 mg/kg or placebo and docetaxel at 75 mg/m2 were eachadministered by intravenous infusion on day 1 of a 21-day cycle. Sites in East Asia administered areduced 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 ofmajor airway or blood vessel, intra-tumour cavitation, and history of significant bleeding oruncontrolled thrombotic disorders were excluded. Also, patients receiving any kind of therapeuticanticoagulation 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 ofnon-Caucasian, especially Black patients (2.6 %) were included. Therefore there is limited experiencewith the combination of ramucirumab and docetaxel in these patients with advanced NSCLC as wellas in patients with renal impairment, cardiovascular disease and obesity.

Baseline patient demographics and disease characteristics were generally balanced between arms: themedian 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 histologyand 26 % had squamous histology. The most common prior therapies included pemetrexed (38 %),gemcitabine (25 %), taxane (24 %), and bevacizumab (14 %); 22 % of patients received priormaintenance therapy. The median duration of docetaxel therapy was 14.1 weeks for the ramucirumabplus docetaxel arm (with a median of 4.0 infusions received) and 12.0 weeks for the placebo plusdocetaxel arm (with a median of 4.0 infusions received).

OS was statistically significantly improved in patients receiving Cyramza plus docetaxel comparedwith those receiving placebo plus docetaxel (HR 0.857; 95 % CI: 0.751 to 0.979; p = 0.024). Therewas 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 comparedwith those receiving placebo plus docetaxel (HR 0.762; 95 % CI: 0.677 to 0.859; p < 0.001). Therewas 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. ORRwas significantly improved in patients receiving Cyramza plus docetaxel compared with thosereceiving placebo plus docetaxel (22.9 % vs. 13.6 %, p < 0.001). The primary QoL analysis showedsimilar time to deterioration for all Lung Cancer Symptom Scale (LCSS) scores between treatmentarms.

A consistent improvement (ramucirumab plus docetaxel vs placebo plus docetaxel) was observed inimportant subgroups for PFS and OS. OS subgroup results included the following: non-squamoushistology (HR 0.83; 95 % CI: 0.71 to 0.97; median OS [mOS]: 11.1 vs 9.7 months) and squamoushistology (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 withincreasing age has been observed in patients receiving ramucirumab plus docetaxel for the treatmentof 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 section4.4), patients pre-treated with taxanes (HR 0.81; 95 % CI:0.62 to 1.07; mOS 10.8 vs 10.4 months) andthose with time since start of prior therapy ≥ 9 months (HR 0.95; 95 % CI: 0.75 to 1.2; mOS: 13.7 vs13.3 months). Efficacy results are shown in Table 13.

Table 13: Summary of efficacy data - ITT population

Cyramza plus docetaxel Placebo plus docetaxel

N = 628 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 placeboplus docetaxel in REVEL

Figure 8: Kaplan-Meier curves of progression-free survival for Cyramza plus docetaxel versusplacebo 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 wereintolerant 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 withbrain metastases, leptomeningeal disease, uncontrolled spinal cord compression, a history of or currenthepatic encephalopathy or clinically meaningful ascites, severe variceal bleeding in the 3 months priorto 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 entryrequirement for REACH-2 was determined based on the survival results from a pre-specifiedsubgroup, exploratory analysis from REACH, a previously completed, supportive phase 3 clinicalstudy in 565 HCC patients randomised (1:1) to either Cyramza plus BSC or placebo plus BSC that haddisease progression on or after prior sorafenib therapy.

In REACH-2, baseline patient demographics and disease characteristics were generally balancedbetween arms, except for AFP, which was lower in the placebo arm. Patients treated with Cyramzaexperienced a statistically significant improvement in OS, compared to placebo (Table 14). The majorefficacy outcome in REACH-2 was supported by a statistically significant improvement in progressionfree survival in Cyramza treated patients compared to placebo treated patients. The relative treatmenteffect (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 (progressivedisease 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.

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

Cyramza Placebo

N = 197 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 thesafety and efficacy of Cyramza in this patient population is unknown.

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 patientsand 429 control treated patients. Eleven (2.2 %) of ramucirumab treated patients and two (0.5 %) ofcontrol treated patients developed ADAs. None of the patients with ADAs experienced an IRR. Nopatients had neutralising antibodies to ramucirumab. There is insufficient data to evaluate the effectsof ADAs on the efficacy or safety of ramucirumab.

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 ofthe colon and rectum, in lung carcinoma, and liver cancer (see section 4.2 for information onpaediatric use).

The safety and pharmacokinetics (PK) of ramucirumab, as a single agent, were evaluated in

I4T-MC-JVDA, a multicenter, open-label, phase 1 study in paediatric and young adult patients aged 1to 21 years to determine the recommended phase 2 dose (RP2D). The study consisted of 2 parts. In

Part A, ramucirumab was administered at a dose of 8 mg/kg or 12 mg/kg intravenously over60 minutes every 2 weeks to 23 patients with recurrent or refractory non-CNS tumours. A maximumtolerated dose was not reached. The RP2D was determined to be 12 mg/kg when given every 2 weeks.

In Part B, ramucirumab was administered at the RP2D to 6 patients with relapsed or refractory CNStumours for evaluation of tolerability in this population. No tumour responses were observed in either

Part A or B.

The efficacy and safety of ramucirumab in combination with cyclophosphamide and vinorelbineversus cyclophosphamide and vinorelbine alone was evaluated in J1S-MCJV01 (JV01), a randomised,multicentre, global, Phase 2 study in 30 paediatric patients and young adults aged 36 months to29 years, with relapsed, recurrent, or refractory desmoplastic small round cell tumour (DSRCT).

Randomisation (2:1) was stratified by staging at relapse (metastatic disease versus locally advanced).

JV01 did not meet the pre-specified success criterion for the study, which required a 99% posteriorprobability of superiority (HR<1) to declare success for the intervention. At the final analysis,according to the frequentist analysis, the median PFS was 6.75 months in the experimental arm and1.71 months in the control arm (HR 0.465 [80% CI: 0.261, 0.827]). There was one partial responseand one complete response in the experimental arm. One partial response and no complete responsewas observed in the control arm. Due to the limited size of this study, it is not possible to conclude thatthe benefits of the use outweigh the risks.

The efficacy and safety of ramucirumab in combination with gemcitabine and docetaxel compared togemcitabine and docetaxel alone was evaluated in J1S-MC-JV02 (JV02), a randomised, multicentre,global, Phase 2 study in 23 paediatric patients and young adults aged 36 months to 29 years withrelapsed, recurrent, or progressive synovial sarcoma (SS). Randomization (2:1) was stratified bystaging at relapse (metastatic disease versus locally advanced). The study was terminated withoutformal evaluation of the primary PFS endpoint since at the interim futility analysis, JV02 did not meetthe pre-specified 60 % confidence in treatment superiority (PFS HR of less than 1 for SS). There wasone partial response and no complete response in the experimental arm. No responses, complete orpartial, were observed in the control arm.

Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab Cminprior to administration of the fourth and seventh dose of ramucirumab given as a single agent inadvanced 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 of18.3-123 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 serumfrom patients with mCRC.

Following the dose regimen of 10 mg/kg ramucirumab every 3 weeks, the geometric means oframucirumab 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 combinationwith docetaxel, in serum from patients with NSCLC.

Following the dose regimen of 10 mg/kg ramucirumab every 2 weeks, the geometric means oframucirumab Cmin were 68.5 μg/ml (range of 20.3-142 μg/ml) and 85.7 μg/ml (range of36.0-197 μg/ml) prior to administration of the fourth and seventh dose, respectively of ramucirumabgiven in combination with erlotinib, in serum from patients with NSCLC.

Cyramza is administered as an intravenous infusion. There have been no studies performed with otherroutes of administration.

Based on population pharmacokinetic approach (PopPK), the mean (% coefficient of variation[CV%]) volume of distribution at steady state for ramucirumab was 5.4L (15 %).

The metabolism of ramucirumab has not been studied. Antibodies are principally cleared bycatabolism.

Based on PopPK, the mean (CV%) clearance of ramucirumab was 0.015 L/hour (30 %) and the meanhalf-life was 14 days (20 %).

Time and dose dependency

There was no clear deviation from dose proportionality in pharmacokinetics of ramucirumab from6 mg/kg to 20 mg/kg. An accumulation ratio of 1.5 was observed for ramucirumab when dosed every2 weeks. Based on simulations using the PopPK model, steady state would be attained by the sixthdose.

Based on PopPK, there was no difference in ramucirumab exposure in patients ≥65 years of agecompared to patients < 65 years old.

No formal studies have been conducted to evaluate the effect of renal impairment on thepharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure was similar in patientswith mild renal impairment (creatinine clearance [CrCl] ≥ 60 to < 90 ml/min), moderate renalimpairment (CrCl ≥ 30 to < 60 ml/min) or severe renal impairment (CrCl 15 to 29 ml/min) ascompared to patients with normal renal function (CrCl ≥ 90 ml/min).

No formal studies have been conducted to evaluate the effect of hepatic impairment on thepharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure in patients with mildhepatic impairment (total bilirubin >1.0-1.5 upper limit of normal (ULN) and any AST or totalbilirubin ≤ 1.0 ULN and AST >ULN) or moderate hepatic impairment (total bilirubin > 1.5-3.0 ULNand 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 (totalbilirubin > 3.0 ULN and any AST).

The mean peak concentration was 165 μg/mL following 8 mg/kg (study JVDA), 231 μg/mL following9 mg/kg (study JV02), 238 µg/mL (CV%=35) following 12 mg/kg (study JV01) and 285 μg/mL(CV%=26) following 12 mg/kg (study JVDA), respectively. The Ctrough was 41.6 (CV%=57) and48.3 µg/mL (CV%=41) at Day 15 Cycle 1 (n=19) in study JV01 and study JVDA, respectively.

Exposure to ramucirumab in paediatric and young adult patients (children > 12 months and < 21 years)with refractory solid tumours, including CNS tumours following a single dose or multiple doses of8 mg/kg or 12 mg/kg was similar to the exposure obtained in adult patients. Further, ramucirumabexposure following 12 mg/kg dose was similar across the age range of > 12 months to < 21 years.

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 ramucirumabdisposition. Body weight is considered a significant co-variate of ramucirumab pharmacokineticssupporting the dosing based on body weight.

Exposure response relationships

Exposure-response analyses indicated that efficacy was correlated with ramucirumab exposure acrosspivotal studies. Efficacy, as measured by improvements in OS, was associated with increasingramucirumab exposure range produced by 8 mg/kg ramucirumab given every 2 weeks and by10 mg/kg ramucirumab given every 3 weeks. An improvement in PFS was also associated withincreasing ramucirumab exposure for advanced gastric cancer, NSCLC with disease progression afterplatinum-based chemotherapy and mCRC.

In the REACH-2 study for HCC, a relevant exposure-efficacy association was observed forramucirumab which showed that only patients with above-median exposure experienced animprovement in OS, compared to placebo, and these exposure-efficacy relationships remained afterattempts to adjust for other prognostic factors. A treatment effect on PFS was observed for allexposure levels produced by 8 mg/kg ramucirumab given every 2 weeks. No such relation wasobserved in the RELAY study for NSCLC with 10 mg/kg ramucirumab plus erlotinib given every2 weeks.

Safety

In RAINBOW, the incidences of Grade ≥ 3 hypertension, neutropenia, and leukopenia were increasedwith 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 withhigher ramucirumab exposure.

In the pooled data from REACH-2 and REACH (patients with alpha fetoprotein ≥ 400 ng/ml), theincidences of Grade ≥ 3 hypertension was increased with higher ramucirumab exposure.

No animal studies have been performed to test ramucirumab for potential of carcinogenicity orgenotoxicity.

The target organs identified in repeated dose cynomolgus monkey toxicity studies were kidney(glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphysealgrowth plate) and female reproductive organs (decreased weight of ovaries and uterus). A minimalgrade of inflammation and/or mononuclear cell infiltration was seen in several organs.

Reproductive toxicity studies with ramucirumab have not been performed, however, animal modelslink angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction,embryo-foetal development, and postnatal development. Based on ramucirumab’s mechanism ofaction, it is likely that in animals, ramucirumab will inhibit angiogenesis and result in adversereactions on fertility (ovulation), placental development, developing foetuses and postnataldevelopment.

A single dose of ramucirumab did not impair wound healing in monkeys using a full-thicknessincisional model.

Histidine

Histidine monohydrochloride

Sodium chloride

Glycine (E 640)

Polysorbate 80 (E 433)

Water for injections

Cyramza should not be administered or mixed with dextrose solutions.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years.

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 forinjection has been demonstrated for 24 hours at 2 ºC to 8 ºC or for 4 hours at 25 ºC. From amicrobiological 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 notbe longer than 24 hours at 2 ºC to 8 ºC, unless dilution has taken place in controlled and validatedaseptic conditions.

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.

10 ml solution in a vial (Type I glass) with a chlorobutyl rubber stopper, an aluminium seal and apolypropylene cap.50 ml solution in a vial (Type I glass) with a chlorobutyl rubber stopper, an aluminium seal and apolypropylene 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.

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 anddiscolouration (the concentrate for solution for infusion should be clear to slightly opalescent andcolourless to slightly yellow without visible particles) prior to dilution. If particulate matter ordiscolouration is identified, discard the vial.

Calculate the dose and volume of ramucirumab needed to prepare the infusion solution. Vials containeither 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 sodiumchloride 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 totalvolume in the container should be 250 ml. The container should be gently inverted to ensure adequatemixing. Do not freeze or shake the infusion solution. Do not dilute with other solutions or co-infusewith other electrolytes or medicinal products.

In case of empty intravenous infusion container usage

Aseptically transfer the calculated volume of ramucirumab into an empty intravenous infusioncontainer. Add a sufficient quantity of sodium chloride 9 mg/ml (0.9 %) solution for injection to thecontainer to make the total volume 250 ml. The container should be gently inverted to ensure adequatemixing. Do not freeze or shake the infusion solution. Do not dilute with other solutions or co-infusewith other electrolytes or medicinal products.

Parenteral medicinal products should be inspected visually for particulate matter prior toadministration. If particulate matter is identified, discard the infusion solution.

Discard any unused portion of ramucirumab left in a vial, as the product contains no antimicrobialpreservatives.

Administer via infusion pump. A separate infusion line with a protein sparing 0.22 micron filter mustbe used for the infusion and the line must be flushed with sodium chloride 9 mg/ml (0.9 %) solutionfor injection at the end of the infusion.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V.

Orteliuslaan 10003528 BD Utrecht

The Netherlands

EU/1/14/957/001

EU/1/14/957/002

EU/1/14/957/003

Date of first authorisation: 19 December 2014

Date of latest renewal: 26 September 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.