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.

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.

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.

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.

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 adverse drug reactions (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, 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.

Currently available data are described in section 4.8, 5.1 and 5.2. Due to limited data no recommendation on posology can be made.

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.

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 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.

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).

Cardiac Failure

In pooled data from ramucirumab clinical trials, cardiac failure was reported at a numerically higher incidence 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 observed in 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 with paclitaxel. Patients should be monitored for clinical signs and symptoms of cardiac failure during treatment, and suspension of treatment should be considered if clinical signs and symptoms of cardiac failure develop. See section 4.8.

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

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

This medicinal product contains approximately 85 mg sodium in each 50 ml vial. This is equivalent to approximately 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 of polysorbate 80 in each 50 ml vial.

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.

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 events 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.

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

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

Uncommon

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

Cardiac disorders

Cardiac failure

Vascular disorders

Hypertensiona,e

Arterial thromboembolic eventsa

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), study REVEL (ramucirumab plus docetaxel) 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).

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: 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

Endocrine disorders

Hypothyroidism

Nervous system disorders

Posterior reversible encephalopathy syndrome

Cardiac disorders

Cardiac failurea

Vascular disorders

Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Dysphonia

a In the post-marketing setting, cardiac failure has been observed for ramucirumab mostly in combination with paclitaxel. See section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after 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 Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Paediatric population

No new safety concerns were identified based on the limited number of paediatric patients treated with ramucirumab monotherapy in study I4T‑MC‑JVDA (see section 5.1). One patient in this study had progressive widening of distal femoral growth plate. The impact of this finding on growth is not known. No new safety concerns were reported in the limited number of paediatric patients treated with ramucirumab in combination therapy in study J1S-MC-JV02 (see section 5.1).

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.