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.

Excipient with known effect:

Each 10 ml vial contains approximately 17 mg sodium.

Each 50 ml vial contains approximately 85 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

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

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).

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 eva luate 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

Cyramza as a single agent

The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks.

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 (as per the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]), 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 paclitaxel prescribing information 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 (6 mg/kg every 2 weeks). A second dose reduction (to 5 mg/kg every 2 weeks) 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.

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).

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).

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.

Special populations

Elderly patients

In the pivotal studies there has been no indication 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.

Patients with 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 or moderate renal impairment.

There are no data regarding ramucirumab administration in patients with severe renal impairment (calculated creatinine clearance <30 ml/min) (see section 5.2). No dose reductions are recommended.

Patients with hepatic impairment

There have been no formal studies with Cyramza in patients with hepatic impairment. There are no data regarding ramucirumab administration in patients with moderate or severe hepatic impairment (see section 5.2). No dose reductions are recommended.

Paediatric population

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

No data are available.

There is no relevant use of ramucirumab in the paediatric population in the advanced gastric cancer or gastro-oesophageal indication.

Method of administration

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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 has the potential to increase the risk of gastrointestinal perforations. Ramucirumab should be permanently discontinued in patients who experience gastrointestinal perforations (see section 4.2).

Severe bleeding

Ramucirumab is an antiangiogenic therapy and has the potential to 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.

Severe gastrointestinal haemorrhage, including fatal events, were reported in patients with gastric cancer treated with ramucirumab in combination with paclitaxel.

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).

Impaired wound healing

The impact of ramucirumab has not been eva luated 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. In these patients, ramucirumab should only be used if the potential benefits of treatment are judged to outweigh the potential risk of progressive hepatic failure.

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).

Renal impairment

There are no safety data available for patients with severe renal impairment (calculated creatinine clearance < 30 ml/min) treated with ramucirumab (see sections 4.2 and 5.2).

Sodium restricted diet

Each 10 ml vial contains approximately 17 mg sodium and each 50 ml vial contains approximately 85 mg sodium. To be taken into account for patients on a sodium restricted diet.

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.

Women of childbearing potential/Contraception in females

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

Pregnancy

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

Breast-feeding

It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorption is expected to be low. As a risk to 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 ramcuirumab based on studies in animals (see section 5.3).

Cyramza has no known 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.

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)

The most common adverse reactions observed in ramucirumab-treated patients are: fatigue/asthenia, neutropenia, leukopenia, diarrhoea, epistaxis, and hypertension.

Tabulated list of adverse reactions

Adverse Drug Reactions (ADRs) which were reported in patients with advanced gastric cancer are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency:

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)

Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Ramucirumab in combination with paclitaxel

The following table provides the frequency and severity of ADRs based on results from RAINBOW, a phase 3 study in adult patients with advanced gastric cancer randomised to treatment with ramucirumab in combination with paclitaxel or placebo plus paclitaxel.

Table 2 ADRs reported in ≥ 5 % of ramucirumab treated patients in RAINBOW

^a Includes hypertensive cardiomyopathy.

^b MedDRA preferred terms included anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory-Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage.

Clinically relevant ADRs reported in ≥ 1% and < 5% of the ramucirumab plus paclitaxel-treated patients in RAINBOW were gastrointestinal perforation (1.2% ramucirumab plus paclitaxel versus 0.3% for placebo plus paclitaxel) and sepsis (3.1% ramucirumab plus paclitaxel versus 1.8% placebo plus paclitaxel).

Ramucirumab as a single agent

The following table provides the frequency and severity of the ADRs based on results from REGARD, a phase 3 study in adult patients with advanced gastric cancer randomised to treatment with single-agent ramucirumab plus Best Supportive Care (BSC) or placebo plus BSC.

Table 3 ADRs reported in ≥ 5 % of ramucirumab treated patients in REGARD

^a MedDRA preferred term (Version 15.0)

^b There were no Grade 5 ADRs for Cyramza. There was one Grade 4 ADR of hypokalaemia and one of hyponatraemia.

^c Refer to NCI CTCAE Criteria (Version 4.0) for each Grade of toxicity.

^d MedDRA preferred terms included are: blood potassium decreased and hypokalaemia.

^e MedDRA preferred terms included are: blood pressure increased and hypertension.

^f MedDRA preferred terms included are: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain.

Clinically relevant ADRs reported in ≥ 1% and < 5% of the ramucirumab treated patients in REGARD were: neutropenia, arterial thromboembolic events (see sections 4.2 and 4.4), intestinal obstruction, epistaxis, and rash.

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).

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 United Kingdom: Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard or Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517;

Website: www.hpra.ie; e-mail: medsafety@hpra.ie

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.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies ATC code: Not yet assigned.

Mechanism of action

Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF induced angiogenesis. Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand stimulated activation of VEGF Receptor 2 and its downstream signalling components, including p44/p42 mitogen-activated protein kinases, neutralizing ligand-induced proliferation and migration of human endothelial cells.

Clinical efficacy and safety

RAINBOW

RAINBOW, a global, randomised, double-blind, study of Cyramza plus paclitaxel versus placebo plus paclitaxel, was conducted in 665 patients with locally recurrent and unresectable or metastatic gastric cancer (including GEJ adenocarcinoma) following platinum- and fluoropyrimidine-containing chemotherapy, with or without anthracycline. The primary endpoint was overall survival (OS) and the secondary endpoints included progression free survival (PFS) and overall response rate (ORR). Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy and with ECOG PS 0-1. Patients were randomised in a 1:1 ratio to receive Cyramza plus paclitaxel (n=330) or placebo plus paclitaxel (n=335). Randomisation was stratified by geographic region, time to progression from the start of first-line therapy (<6 months versus ≥6 months) and disease measurability. Cyramza at 8 mg/kg or placebo was administered by intravenous infusion every 2 weeks (on days 1 and 15) of a 28-day cycle. Paclitaxel at 80 mg/m² was administered by intravenous infusion on days 1, 8, and 15 of each 28-day cycle.

A majority (75%) of patients randomised in the study received prior platinum and fluoropyrimidine combination therapy without anthracycline. The remainder (25%) received prior platinum and fluoropyrimidine combination therapy with anthracycline. Two-thirds of the patients experienced disease progression while still on first-line therapy (66.8%). Baseline patient demographics and disease characteristics were generally balanced between arms: the median age was 61 years; 71% of patients were male; 61% were Caucasian, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 81% of patients had measurable disease and 79% had gastric cancer; 21% had GEJ adenocarcinoma. The majority of patients (76%) had experienced disease progression within 6 months from the start of first-line therapy. For patients treated with Cyramza plus paclitaxel the median duration of therapy was 19 weeks, and for patients treated with placebo plus paclitaxel the median duration of therapy was 12 weeks. The median relative dose intensity of Cyramza was 98.6% and of placebo was 99.6%. The median relative dose intensity of paclitaxel was 87.7% for the Cyramza plus paclitaxel arm and 93.2% for the placebo plus paclitaxel arm. A similar percentage of patients discontinued treatment due to adverse events: 12% of patients treated with Cyramza plus paclitaxel compared with 11% of patients treated with placebo plus paclitaxel. Post discontinuation systemic anti-cancer therapy was given to 47.9% of patients receiving Cyramza plus paclitaxel and 46.0% of patients receiving placebo plus paclitaxel.

Overall survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.807; 95%CI: 0.678 to 0.962; p=0.0169). There was an increase in median survival of 2.3 months in favour of the Cyramza plus paclitaxel arm: 9.63 months in the Cyramza plus paclitaxel arm and 7.36 months in the placebo plus paclitaxel arm. Progression-free survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.635; 95%CI: 0.536 to 0.752; p<0.0001). There was an increase in median PFS of 1.5 months in favour of the Cyramza plus paclitaxel arm: 4.4 months in the Cyramza plus paclitaxel arm and 2.9 months in the placebo plus paclitaxel arm. Objective response rate (complete response [CR] + partial response [PR]) was significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (Odds ratio 2.140; 95% CI: 1.499 to 3.160; p=0.0001). The ORR in the Cyramza plus paclitaxel arm was 27.9% and in the placebo plus paclitaxel arm was 16.1%. 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 4.

Table 4: Summary of efficacy data –ITT population

Abbreviations: CI = confidence interval, CR= complete response, PR= partial response, CMH= Cochran-Mantel-Haenszel

Figure 1: Kaplan-Meier curves of overall survival for Cyramza plus paclitaxel versus placebo plus paclitaxel in RAINBOW

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

REGARD

REGARD, a multinational, randomised, double-blind study of Cyramza plus BSC versus placebo plus BSC, was conducted in 355 patients with locally recurrent and unresectable, or metastatic gastric cancer (including GEJ adenocarcinoma) following platinum- or fluoropyrimidine-containing chemotherapy. The primary endpoint was OS and secondary endpoints included PFS. Patients were required to have experienced disease progression during, or within 4 months after the last dose of, first-line therapy for metastatic disease, or during adjuvant treatment or within 6 months after the last dose of adjuvant therapy, and had ECOG PS 0-1. To be included in the study, patients were required to have total bilirubin of ≤ 1.5mg/dl and AST and ALT ≤ 3 times ULN, or ≤ 5 times ULN if liver metastases were present.

Patients were randomised in a 2:1 ratio to receive an intravenous infusion of Cyramza 8 mg/kg (n= 238) or placebo (n= 117) every 2 weeks. Randomisation was stratified by weight loss over the prior 3 months (≥ 10% versus < 10%), geographic region, and location of the primary tumour (gastric versus GEJ). Baseline demographics and disease characteristics were balanced. The ECOG PS was 1 for 72% of patients. There were no patients with Child-Pugh B or C liver cirrhosis enrolled in REGARD. 11% of patients treated with Cyramza and 6% of patients on placebo discontinued therapy due to adverse events. Overall survival was statistically significantly improved in patients receiving Cyramza as compared with patients receiving placebo (hazard ratio [HR] 0.776; 95%CI: 0.603 to 0.998; p= 0.0473), corresponding to a 22% reduction in the risk of death and an increase in median survival to 5.2 months for Cyramza from 3.8 months for placebo. Progression-free survival was statistically significantly improved in patients receiving Cyramza as compared with patients receiving placebo (HR 0.483; 95%CI: 0.376 to 0.620; p<0.0001), corresponding to a 52% reduction in the risk of progression or death and an increase in median PFS to 2.1 months for Cyramza from 1.3 months for placebo. Efficacy results are shown in Table 5.

Table 5: Summary of efficacy data – Intent to treat (ITT) population

Abbreviations: CI = confidence interval

Figure 3: Kaplan-Meier curves of overall survival for Cyramza versus placebo in REGARD

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2 patients

Patients with ECOG score ≥2 were excluded from the pivotal studies, therefore the safety and efficacy of Cyramza in this patient population is unknown.

Based on limited data from REGARD patients with HER2-positive gastric or GEJ adenocarcinoma and patients previously treated with trastuzumab (in RAINBOW), it is considered unlikely that Cyramza has a detrimental effect or that it has no effect in patients with HER2-positive gastric cancer. Post hoc unstratified subgroup analyses from RAINBOW patients previously treated with trastuzumab (n= 39) suggested a survival benefit in such patients (HR 0.679, 95% CI 0.327, 1.419) and demonstrated a benefit for progression free survival (PFS) (HR 0.399, 95% CI 0.194, 0.822).

Immunogenicity

Patients in two Phase 3 studies, RAINBOW and REGARD were tested at multiple time-points for anti-drug antibodies (ADAs). Samples were tested from 956 patients: 527 ramucirumab treated patients and 429 control treated patients. Eleven (2.2%) of ramucirumab treated patients and two (0.5%) of control treated patients developed ADAs. None of the patients with ADAs experienced an IRR. No patients had neutralising antibodies to ramucirumab. There is insufficient data to eva luate the effects of ADAs on the efficacy or safety of ramucirumab.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Cyramza in all subsets of the paediatric population in gastric adenocarcinoma (see section 4.2 for information on paediatric use).

Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab C_min were 49.5 μg/ml (range of 6.3-228 μg/ml) and 74.4 μg/ml (range of 13.8-234 μg/ml) prior to administration of the fourth and seventh dose, respectively of ramucirumab given as a single agent, in serum from patients with advanced gastric cancer.

Absorption

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

Distribution

Based on population pharmacokinetic approach PK (PopPK), the mean volume of distribution at steady state for ramucirumab was 5.5L.

Biotransformation

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

Elimination

Based on PopPK, the mean clearance of ramucirumab was 0.014L/hour and the mean half-life was 15 days.

Time and dose dependency

There was no clear deviation from dose proportionality in pharmacokinetics of ramucirumab from 6 mg/kg to 20 mg/kg. An accumulation ratio of 1.5 was observed for ramucirumab when dosed every 2 weeks. Based on simulations using the PopPK model, steady state would be attained by the sixth dose.

Elderly patients

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

Renal impairment

No formal studies have been conducted to eva luate the effect of renal impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure was similar in patients with mild renal impairment (calculated creatinine clearance [CrCl] ≥ 60 to < 90 ml/min) and moderate renal impairment (CrCl ≥ 30 to <60 ml/min) as to patients with normal renal function (CrCl ≥ 90 ml/min). No data are available from patients with severe renal impairment (CrCl < 30 ml/min).

Hepatic impairment

No formal studies have been conducted to eva luate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure in patients with mild hepatic impairment (total bilirubin 1.0-1.5 upper limit of normal (ULN) or AST > ULN as defined using NCI criteria) were similar to those in patients with normal hepatic function (total bilirubin and AST ≤ ULN). Ramucirumab has not been studied in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 to ≤ 3.0 ULN and any AST; and total bilirubin > 3.0 ULN and any AST, respectively).

Other special populations

Based on PopPK, the following covariates were found to have no impact on ramucirumab disposition: age (range, 19 to 86 years), sex (316 males, 181 females), race (337 White and 139 Asians), body weight (range, 31.9 to 133.0 kg), albumin levels (range, 15.5 to 64.8 g/L).

Exposure response relationships: RAINBOW

Exposure-response analyses indicated that efficacy and specific measures of safety of ramucirumab were correlated with ramucirumab exposure. Efficacy, as measured by improvements in OS and PFS, was associated with increasing ramucirumab exposure range produced by 8 mg/kg ramucirumab given on days 1 and 15 of a 28 day cycle. The incidences of Grade ≥3 hypertension, neutropenia, and leukopenia were also increased with higher ramucirumab exposure.

Exposure response relationship: REGARD

Based on limited PK data, exposure-response analysis suggested that efficacy of ramucirumab was correlated with ramucirumab exposure.

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

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

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

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

Histidine

Histidine monohydrochloride

Sodium chloride

Glycine (E640)

Polysorbate 80 (E433)

Water for injections

Cyramza should not be administered or mixed with dextrose solutions.

This medicnal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial

3 years.

After dilution

When prepared as directed, infusion solutions of Cyramza contain no antimicrobial preservatives.

Chemical and physical in-use stability of Cyramza in sodium chloride 9 mg/ml (0.9%) solution for injection has been demonstrated for 24 hours at 2 ºC to 8 ºC or for 4 hours at 25 ºC. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 ºC to 8 ºC, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 ºC to 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 a polypropylene cap.

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

Pack of 1 vial of 10 ml.

Pack of 2 vials of 10 ml.

Pack of 1 vial of 50 ml.

Not all pack sizes may be marketed.

Do not shake the vial.

Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution.

Each vial is intended for single use only. Inspect the content of the vials for particulate matter and discolouration (the concentrate for solution for infusion should be clear to slightly opalescent and colourless to slightly yellow without visible particles) prior to dilution. If particulate matter or discolouration is identified, discard the vial.

Calculate the dose and volume of ramucirumab needed to prepare the infusion solution. Vials contain either 100 mg or 500 mg as a 10 mg/ml solution of ramucirumab. Only use sodium chloride 9 mg/ml (0.9%) solution for injection as a diluent.

In case of prefilled intravenous infusion container usage

Based on the calculated volume of ramucirumab, remove the corresponding volume of sodium chloride 9 mg/ml (0.9%) solution for injection from the prefilled 250 ml intravenous container. Aseptically transfer the calculated volume of ramucirumab to the intravenous container. The final total volume in the container should be 250 ml. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicinal products.

In case of empty intravenous infusion container usage

Aseptically transfer the calculated volume of ramucirumab into an empty intravenous infusion container. Add a sufficient quantity of sodium chloride 9 mg/ml (0.9%) solution for injection to the container to make the total volume 250 ml. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicinal products.

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

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

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

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

Eli Lilly Nederland B.V.

Grootslag 1-5

NL-3991 RA, Houten

The Netherlands

Cyramza 10 ml Vial (1 Vial):       EU/1/14/957/001

Cyramza 10 ml Vial (2 Vials):     EU/1/14/957/002

Cyramza 50 ml Vial (1 Vial):       EU/1/14/957/003

19 December 2014

19 December 2014

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.