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Cyramza 10 mg/ml concentrate for solution for infusion

Last Updated on eMC 16-Feb-2016 View changes  | Eli Lilly and Company Limited Contact details

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Cyramza 10 mg/ml concentrate for solution for infusion

2. Qualitative and quantitative composition

One ml of concentrate for solution for infusion contains 10 mg ramucirumab.

Each 10 ml vial contains 100 mg of ramucirumab.

Each 50 ml vial contains 500 mg of ramucirumab.

Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology.

Excipient with known effect:

Each 10 ml vial contains approximately 17 mg sodium.

Each 50 ml vial contains approximately 85 mg sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

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

4. Clinical particulars
4.1 Therapeutic indications

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).

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.

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.

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)

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.

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).

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.

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 events.

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 AEs

AE

NCI CTCAE grade

Dose modification at day 1 of cycle subsequent to AE

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 28⃰ 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 AE.

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 patients

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).

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, moderate or severe renal impairment (see sections 4.4 and 5.2). No dose reductions are recommended.

Patients with hepatic impairment

There have been no formal studies with Cyramza in patients with hepatic impairment. Clinical data suggest that no dose adjustments are required in patients with mild or moderate hepatic impairment. There are no data regarding ramucirumab administration in patients with severe hepatic impairment (see sections 4.4 and 5.2). No dose reductions are recommended.

Paediatric population

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

No data are available.

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

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.

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

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.

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 and/or chronic therapy with non-steroidal anti-inflammatory drugs or anti-platelet agents were excluded from the REVEL NSCLC clinical trial. 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).

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. 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).

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).

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.

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).

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 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 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 ramucirumab based on studies in animals (see section 5.3).

4.7 Effects on ability to drive and use machines

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.

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)

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

Tabulated list of adverse reactions

Adverse Drug Reactions (ADRs) which were reported in patients with advanced gastric cancer, mCRC or NSCLC 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.

 

Gastric cancer

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 6: ADRs reported in ≥5% of ramucirumab treated patients in RAINBOW

System organ class

Frequency

ADR

Cyramza plus paclitaxel

(N=327)

Placebo plus paclitaxel

(N=329)

All grades toxicity

(%)

Grade ≥3 toxicity

(%)

All grades toxicity

(%)

Grade ≥3 toxicity

(%)

Blood and lymphatic system disorders

Very common

Neutropenia

54.4

40.7

31.0

18.8

Very common

Leukopenia

33.9

17.4

21.0

6.7

Very common

Thrombocytopenia

13.1

1.5

6.1

1.8

Metabolism and nutrition disorders

Very common

Hypoalbuminaemia

11.0

1.2

4.9

0.9

Vascular disorder

Very common

Hypertensiona

25.1

14.7

5.8

2.7

Respiratory, thoracic, and mediastinal disorders

Very common

Epistaxis

30.6

0.0

7.0

0.0

Gastrointestinal disorders

Very common

Gastrointestinal haemorrhage eventsb

10.1

3.7

6.1

1.5

Very common

Stomatitis

19.6

0.6

7.3

0.6

Very common

Diarrhoea

32.4

3.7

23.1

1.5

Renal and urinary disorders

Very common

Proteinuria

16.8

1.2

6.1

0.0

General disorders and administration site disorders

Very common

Fatigue/Asthenia

56.9

11.9

43.8

5.5

Very common

Peripheral oedema

25.1

1.5

13.7

0.6

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 7: ADRs reported in ≥5% of ramucirumab treated patients in REGARD

System organ class

Frequency

ADRa,b

Cyramza

(N=236)

Placebo

(N=115)

All gradesc toxicity

(%)

Grade 3-4 toxicity

(%)

All grades toxicity

(%)

Grade 3-4 toxicity

(%)

Metabolism and nutrition disorders

Common

Hypokalaemiad

5.9

2.1

5.2

0.9

Common

Hyponatraemia

5.5

3.4

1.7

0.9

Nervous system disorders

Common

Headache

9.3

0.0

3.5

0.0

Vascular disorders

Very common

Hypertensione

16.1

7.6

7.8

2.6

Gastrointestinal disorders

Very common

Abdominal painf

28.8

5.9

27.8

2.6

Very common

Diarrhoea

14.4

0.8

8.7

1.7

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).

Colorectal cancer

Ramucirumab in combination with FOLFIRI

The following table provides the frequency and severity of the ADRs based on results from RAISE, a phase 3 study in adult patients with mCRC randomised to treatment with ramucirumab plus FOLFIRI or placebo plus FOLFIRI.

Table 8: ADRs reported in ≥5% of ramucirumab treated patients in RAISE

System organ class

Frequency

ADR

Cyramza plus

FOLFIRI (N=529)

Placebo plus

FOLFIRI (N=528)

All grades toxicity

(%)

Grade ≥3 toxicity

(%)

All grades toxicity

(%)

Grade ≥3 toxicity

(%)

Blood and lymphatic system disorders

Very common

Neutropenia

58.8

38.4

45.6

23.3

Very common

Thrombocytopenia

28.4

3.0

13.6

0.8

Metabolism and nutrition disorders

Common

Hypoalbuminaemia

5.9

1.1

1.9

0.0

Vascular disorder

Very common

Hypertension

26.1

11.2

8.5

2.8

Respiratory, thoracic, and mediastinal disorders

Very common

Epistaxis

33.5

0.0

15.0

0.0

Gastrointestinal disorders

Very common

Gastrointestinal haemorrhage events

12.3

1.9

6.8

1.1

Very common

Stomatitis

30.8

3.8

20.8

2.3

Renal and urinary disorders

Very common

Proteinuriaa

17.0

3.0

4.5

0.2

Skin and subcutaneous tissue disorders

Very common

Palmar-plantar erthyrodysaesthesia syndrome

12.9

1.1

5.5

0.4

General disorders and administration site disorders

Very common

Peripheral oedema

20.4

0.2

9.1

0.0

a Includes cases of nephrotic syndrome.

Clinically relevant ADRs reported in ≥1% and <5% of the ramucirumab plus FOLFIRI-treated patients in RAISE: gastrointestinal perforation (1.7% ramucirumab plus FOLFIRI versus 0.6% for placebo plus 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.

NSCLC

Ramucirumab in combination with docetaxel

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

Table 9: ADRs reported in ≥5% of ramucirumab treated patients in REVEL

System Organ Class

Frequency

ADR

Cyramza plus docetaxel

(N=627)

Placebo plus docetaxel

(N=618)

All grades toxicity

(%)

Grade 3-4 toxicity

(%)

All grades toxicity

(%)

Grade 3-4 toxicity

(%)

Blood and lymphatic system disorders

Very common

Febrile neutropenia

15.9

15.9

10.0

10.0

Very common

Neutropenia

55.0

48.8

46.0

39.8

Very common

Thrombocytopenia

13.4

2.9

5.2

0.6

Vascular disorders

Very common

Hypertension

10.8

5.6

4.9

2.1

Respiratory, thoracic, and mediastinal disorders

Very common

Epistaxis

18.5

0.3

6.5

0.2

Gastrointestinal disorders

Very common

Stomatitis

23.3

4.3

12.9

1.6

General disorders and administration site disorders

Very common

Fatigue/Asthenia

54.7

14.0

50.0

10.5

Very common

Mucosal inflammation

16.1

2.9

7.0

0.5

Very common

Peripheral oedema

16.3

0

8.6

0.3

Clinically relevant ADRs reported in ≥1% and <5% of the ramucirumab plus docetaxel-treated patients in REVEL were hyponatraemia (4.8% ramucirumab plus docetaxel versus 2.4% for placebo plus docetaxel), proteinuria (3.3% ramucirumab plus docetaxel versus 0.8% placebo plus docetaxel) and gastrointestinal perforation (1% ramucirumab plus docetaxel versus 0.3% placebo plus docetaxel).

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 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, or United Kingdom: Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There is no data on overdose in humans. Cyramza has been administered in a Phase 1 study up to 10 mg/kg every two weeks without reaching a maximum tolerated dose. In case of overdose, supportive therapy should be used.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies ATC code: L01XC21.

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

Gastric cancer:

RAINBOW

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

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

Overall survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.807; 95% CI: 0.678 to 0.962; p=0.0169). There was an increase in median survival of 2.3 months in favour of the Cyramza plus paclitaxel arm: 9.63 months in the Cyramza plus paclitaxel arm and 7.36 months in the placebo plus paclitaxel arm. Progression-free survival was statistically significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (HR 0.635; 95% CI: 0.536 to 0.752; p<0.0001). There was an increase in median PFS of 1.5 months in favour of the Cyramza plus paclitaxel arm: 4.4 months in the Cyramza plus paclitaxel arm and 2.9 months in the placebo plus paclitaxel arm. Objective response rate [ORR(complete response [CR] + partial response [PR])] was significantly improved in patients receiving Cyramza plus paclitaxel compared with those receiving placebo plus paclitaxel (Odds ratio 2.140; 95% CI: 1.499 to 3.160; p=0.0001). The ORR in the Cyramza plus paclitaxel arm was 27.9% and in the placebo plus paclitaxel arm was 16.1%. 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 10.

Table 10: Summary of efficacy data – Intent to treat (ITT) population

 

Cyramza plus paclitaxel

N=330

Placebo plus paclitaxel

N=335

Overall survival, months

  

Median (95% CI)

9.6 (8.5, 10.8)

7.4 (6.3, 8.4)

Hazard ratio (95% CI)

0.807 (0.678, 0.962)

Stratified log-rank p-value

0.0169

Progression free survival, months

  

Median (95% CI)

4.4 (4.2, 5.3)

2.9 (2.8, 3.0)

Hazard ratio (95% CI)

0.635 (0.536, 0.752)

Stratified log-rank p-value

<0.0001

Objective response rate (CR +PR)

  

Rate- percent (95% CI)

27.9 (23.3, 33.0)

16.1 (12.6, 20.4)

Odd ratio

2.140 (1.449, 3.160)

Stratified CMH p-value

0.0001

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

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

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 11.

Table 11: Summary of efficacy data – ITT population

 

Cyramza

N=238

Placebo

N=117

Overall survival, months

  

Median (95% CI)

5.2 (4.4, 5.7)

3.8 (2.8, 4.7)

Hazard ratio (95% CI)

0.776 (0.603, 0.998)

Stratified log-rank p-value

0.0473

Progression free survival, months

  

Median (95% CI)

2.1 (1.5, 2.7)

1.3 (1.3, 1.4)

Hazard ratio (95% CI)

0.483 (0.376, 0.620)

Stratified log-rank p-value

<0.0001

12-week PFS rate% (95% CI)

40.1 (33.6, 46.4)

15.8 (9.7, 23.3)

Abbreviations: CI = confidence interval

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

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

Colorectal cancer

RAISE

RAISE was a global, randomised, double-blind, study of Cyramza plus FOLFIRI versus placebo plus FOLFIRI, in patients with mCRC, who had disease progression on or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were required to have ECOG PS 0 or 1 and to have disease progression within 6 months of the last dose of first-line therapy. Patients were required to have adequate hepatic, renal and coagulation function. Patients with a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders, a recent history of severe (Grade ≥3) bleeding or who had experienced an arterial thrombotic event (ATE) in the 12 months prior to randomisation were excluded. Patients were also excluded if they had experienced any of: an ATE, Grade 4 hypertension, Grade 3 proteinuria, a grade 3-4 bleeding event, or bowel perforation during first-line bevacizumab therapy.

A total of 1072 patients were randomised (1:1) to receive either Cyramza (n=536) at 8 mg/kg or placebo (n=536), in combination with FOLFIRI. All medicinal products were administered intravenously. The FOLFIRI regimen was: irinotecan 180 mg/m2 administered over 90 minutes and folinic acid 400 mg/m2 administered, simultaneously over 120 minutes; followed by bolus 5-fluorouracil(5-FU) 400 mg/m2 over 2 to 4 minutes; followed by 5-FU 2400 mg/m2 administered by continuous infusion over 46 to 48 hours. Treatment cycles on both arms were repeated every 2 weeks. Patients who discontinued one or more components of treatment because of an adverse event were permitted to continue therapy with the other treatment component(s) until disease progression or unacceptable toxicity. The primary endpoint was OS and the secondary endpoints included PFS, objective response rate (ORR) and quality of life (QoL) using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Randomisation was stratified by geographic region, tumour KRAS status (mutant or wild-type), and time to disease progression (TTP) after commencing first-line treatment (<6 months versus ≥6 months).

Demographic and baseline characteristics for the ITT population were similar between treatment arms. Median age was 62 years and 40% of patients were ≥65 years; 57% of patients were male; 76% were White and 20% Asian; 49% had ECOG PS 0; 49% of patients had KRAS mutant tumours; and 24% of patients had TTP <6 months after commencing first-line treatment. Post discontinuation systemic anti-cancer therapy was given to 54% of patients receiving Cyramza plus FOLFIRI and 56% of patients receiving placebo plus FOLFIRI.

Overall survival was statistically significantly improved in patients receiving Cyramza plus FOLFIRI compared with those receiving placebo plus FOLFIRI (HR 0.844; 95% CI: 0.730 to 0.976; p=0.0219). There was an increase in median survival of 1.6 months in favour of the Cyramza plus FOLFIRI arm: 13.3 months in the Cyramza plus FOLFIRI arm and 11.7 months in the placebo plus FOLFIRI arm. Progression-free survival was statistically significantly improved in patients receiving Cyramza plus FOLFIRI compared with those receiving placebo plus FOLFIRI (HR 0.793; 95% CI: 0.697 to 0.903; p=0.0005). There was an increase in median PFS of 1.2 months in favour of the Cyramza plus FOLFIRI arm: 5.7 months in the Cyramza plus FOLFIRI arm and 4.5 months in the placebo plus FOLFIRI arm. Efficacy results are shown in Table 12 and Figures 4 and 5.

Pre-specified analyses for OS and PFS by stratification factors were performed. The HR of OS was 0.82 (95% CI: 0.67 to 1.0) in patients with a KRAS wild type tumour, and 0.89 (95% CI: 0.73 to 1.09) in patients with a KRAS mutant tumour. For patients with TTP ≥6 months after commencing first-line treatment the HR of OS was 0.86 (95% CI: 0.73 to 1.01), and 0.86 (95% CI: 0.64 to 1.13) in patients with TTP <6 months after commencing first-line treatment. Pre-specified subgroup analyses for both PFS and OS according to age (<65 and ≥65 years), gender, race, ECOG PS (0 or ≥1), number of organs involved, liver metastases only, site of primary tumour (colon or rectum), carcinoembryonic antigen levels (<200 μg/L, ≥200 μg/L), all showed a treatment effect favouring Cyramza plus FOLFIRI treatment over placebo plus FOLFIRI. In 32 of the 33 pre-specified sub-group analyses for OS, the HR was <1.0. The one sub-group with HR >1 was for patients with disease progression from start of first-line bevacizumab treatment of <3 months (HR 1.02 [95% CI: 0.68 to 1.55]). This one sub-group is a group which can be considered to have aggressive disease that is relatively refractory to first-line treatment. In both treatment arms, patients who experienced neutropenia had a longer median OS compared to patients who did not experience neutropenia. The median OS in patients with any grade neutropenia was greater in the ramucirumab arm (16.1 months) than in the placebo arm (12.6 months). Median OS in patients who did not experience neutropenia was 10.7 months in both arms.

Table 12: Summary of efficacy data – ITT population

 

Cyramza plus FOLFIRI

N=536

Placebo plus FOLFIRI

N=536

Overall survival, months

  

Median (95% CI)

13.3 (12.4, 14.5)

11.7 (10.8, 12.7)

Hazard ratio (95% CI)

0.84 (0.73, 0.98)

Stratified log-rank p-value

0.022

Progression free survival, months

  

Median (95% CI)

5.7 (5.5, 6.2)

4.5 (4.2, 5.4)

Hazard ratio (95% CI)

0.79 (0.70, 0.90)

Stratified log-rank p-value

<0.001

Abbreviations: CI = confidence interval

Figure 4: Kaplan-Meier curves of overall survival for Cyramza plus FOLFIRI versus placebo plus FOLFIRI in RAISE

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

The ORR was similar for both treatment arms (13.4% versus 12.5%, ramucirumab plus FOLFIRI versus placebo plus FOLFIRI, respectively). The disease control rate (complete response plus partial response plus stable disease) was numerically higher in patients on the ramucirumab plus FOLFIRI arm as compared to the placebo plus FOLFIRI arm (74.1% versus 68.8%, respectively). For the EORTC QLQ-C30, patients in the ramucirumab plus FOLFIRI treatment arm reported a transient decrease in QoL compared to the patients in the placebo plus FOLFIRI treatment arm in most of the scales. Few between-arm differences were reported after the first month of treatment.

NSCLC

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 placebo plus docetaxel (n=625). Randomisation was stratified by geographic region, gender, prior maintenance, and ECOG PS. Cyramza at 10 mg/kg or placebo and docetaxel at 75 mg/m2 were each administered by intravenous infusion on day 1 of a 21-day cycle. Sites in East Asia administered a reduced dose of docetaxel at 60 mg/m2 every 21 days. Patients with recent serious pulmonary, gastrointestinal, or postoperative bleeding, evidence of CNS haemorrhage, tumour involvement of major airway or blood vessel, intra-tumour cavitation, and history of significant bleeding or uncontrolled thrombotic disorders were excluded. Also, patients receiving any kind of therapeutic anticoagulation and/or chronic therapy with non-steroidal anti-inflammatory drugs or other anti-platelets agents or those with untreated, clinically unstable brain/CNS metastases were excluded Aspirin use at doses up to 325 mg/day was permitted. (see section 4.4). A limited number of non-Caucasian, especially Black patients (2.6%) were included. Therefore there is limited experience with the combination of ramucirumab and docetaxel in these patients with advanced NSCLC as well as in patients with renal impairment, cardiovascular disease and obesity.

Baseline patient demographics and disease characteristics were generally balanced between arms: the median age was 62 years; 67% of patients were male; 82% were Caucasian, 13% Asian; the ECOG PS was 0 for 32% of patients, 1 for 67% of patients; 73% of patients had non-squamous histology and 26% had squamous histology. The most common prior therapies included pemetrexed (38%), gemcitabine (25%), taxane (24%), and bevacizumab (14%); 22% of patients received prior maintenance therapy. The median duration of docetaxel therapy was 14.1 weeks for the ramucirumab plus docetaxel arm (with a median of 4.0 infusions received) and 12.0 weeks for the placebo plus docetaxel arm (with a median of 4.0 infusions received).

OS was statistically significantly improved in patients receiving Cyramza plus docetaxel compared with those receiving placebo plus docetaxel (HR 0.857; 95% CI: 0.751 to 0.979; p=0.024). There was an increase in median survival of 1.4 months in favour of the Cyramza plus docetaxel arm: 10.5 months in the Cyramza plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm. PFS was statistically significantly improved in patients receiving Cyramza plus docetaxel compared with those receiving placebo plus docetaxel (HR 0.762; 95% CI: 0.677 to 0.859; p<0.001). There was an increase in median PFS of 1.5 months in favour of the Cyramza plus docetaxel arm: 4.5 months in the Cyramza plus docetaxel arm and 3 months in the placebo plus docetaxel arm. ORR was significantly improved in patients receiving Cyramza plus docetaxel compared with those receiving placebo plus docetaxel (22.9% vs. 13.6%, p<0.001). The primary QoL analysis showed similar time to deterioration for all Lung Cancer Symptom Scale (LCSS) scores between treatment arms.

A consistent improvement (ramucirumab plus docetaxel vs placebo plus docetaxel) was observed in important subgroups for PFS and OS. OS subgroup results included the following: non-squamous histology (HR 0.83; 95% CI: 0.71 to 0.97; median OS [mOS]: 11.1 vs 9.7 months) and squamous histology (HR 0.88; 95% CI: 0.69 to 1.13; mOS: 9.5 vs 8.2 months); patients with prior maintenance (HR 0.69; 95% CI: 0.51 to 0.93; mOS: 14.4 vs 10.4 months); time since start of prior therapy <9 months (HR 0.75; 95% CI: 0.64 to 0.88; mOS: 9.3 vs 7.0 months); patients <65 years old (HR 0.74, 95% CI: 0.62, 0.87; mOS: 11.3 vs 8.9 months). A trend towards less efficacy with increasing age has been observed in patients receiving ramucirumab plus docetaxel for the treatment of advanced NSCLC with disease progression after platinum-based chemotherapy (see section 5.1). No differences in efficacy between treatment arms have been observed in the subgroups of patients ≥65 years old (OS HR 1.10, 95% CI: 0.89, 1.36; median OS [mOS]: 9.2 vs 9.3 months, see section 4.4), patients pre-treated with taxanes (HR 0.81; 95% CI:0.62 to 1.07; mOS 10.8 vs 10.4 months) and those with time since start of prior therapy ≥9 months (HR 0.95; 95% CI: 0.75 to 1.2; mOS: 13.7 vs 13.3 months). Efficacy results are shown in Table 13.

Table 13: Summary of efficacy data – ITT population

 

Cyramza plus docetaxel

N=628

Placebo plus docetaxel

N=625

Overall survival, months

Median – months (95% CI)

10.5 (9.5, 11.2)

9.1 (8.4, 10.0)

Hazard ratio (95% CI)

0.857 (0.751, 0.979)

Stratified log-rank p-value

0.024

Progression free survival, months

 

Median (95% CI)

4.5 (4.2, 5.4)

3.0 (2.8, 3.9)

Hazard Ratio (95% CI)

0.762 (0.677, 0.859)

Stratified log-rank p-value

<0.001

Objective response rate (CR + PR)

 

Rate – percent (95% CI)

22.9 (19.7, 26.4)

13.6 (11.0, 16.5)

Stratified CMH p-value

<0.001

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

Figure 6: Kaplan-Meier curves of overall survival for Cyramza plus docetaxel versus placebo plus docetaxel in REVEL

Figure 7: Kaplan-Meier curves of progression-free survival for Cyramza plus docetaxel versus placebo plus docetaxel in REVEL

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

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

Immunogenicity

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

Paediatric population

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

5.2 Pharmacokinetic properties

Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab Cmin 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.

Following the dose regimen of 8 mg/kg ramucirumab every 2 weeks in combination with FOLFIRI, the geometric means of ramucirumab Cmin were 46.3 μg/ml (range of 7.7-119 μg/ml) and 65.1 μg/ml (range of 14.5-205 μg/ml) prior to administration of the third and fifth dose, respectively, in serum from patients with mCRC.

Following the dose regimen of 10 mg/kg ramucirumab every 3 weeks, the geometric means of ramucirumab Cmin were 28.3 μg/ml (range of 2.5-108 μg/ml) and 38.4 μg/ml (range of 3.1-128 μg/ml) prior to administration of the third and fifth dose, respectively of ramucirumab given in combination with docetaxel, in serum from patients with NSCLC.

Absorption

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

Distribution

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

Biotransformation

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

Elimination

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

Time and dose dependency

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

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 evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure was similar in patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 ml/min), moderate renal impairment (CrCl ≥30 to <60 ml/min) or severe renal impairment (CrCl 15 to 29 ml/min) as compared to patients with normal renal function (CrCl ≥90ml/min).

Hepatic impairment

No formal studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure in patients with mild hepatic impairment (total bilirubin >1.0-1.5 upper limit of normal (ULN) and any AST or total bilirubin ≤1.0 ULN and AST>ULN) or moderate hepatic impairment (total bilirubin >1.5-3.0 ULN and any AST) was similar to patients with normal hepatic function (total bilirubin and AST ≤ ULN). Ramucirumab has not been studied in patients with severe hepatic impairment (total bilirubin >3.0 ULN and any AST).

Other special populations

Based on PopPK, the following covariates were found to have no impact on ramucirumab disposition: age, sex, race, body weight, albumin levels.

Exposure response relationships

Efficacy

Exposure-response analyses indicated that efficacy was correlated with ramucirumab exposure across pivotal studies. Efficacy, as measured by improvements in OS and PFS, was associated with increasing ramucirumab exposure range produced by 8 mg/kg ramucirumab given every 2 weeks and by 10 mg/kg ramucirumab given every 3 weeks.

Safety

In RAINBOW, the incidences of Grade ≥3 hypertension, neutropenia, and leukopenia were increased with higher ramucirumab exposure.

In RAISE, the incidence of Grade ≥3 neutropenia was increased with higher ramucirumab exposure.

In REVEL, the incidences of Grade ≥3 febrile neutropenia and hypertension were increased with higher ramucirumab exposure.

5.3 Preclinical safety data

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

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

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

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

6. Pharmaceutical particulars
6.1 List of excipients

Histidine

Histidine monohydrochloride

Sodium chloride

Glycine (E640)

Polysorbate 80 (E433)

Water for injections

6.2 Incompatibilities

Cyramza should not be administered or mixed with dextrose solutions.

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

6.3 Shelf life

Unopened vial

3 years.

After dilution

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

Chemical and physical in-use stability of Cyramza in sodium chloride 9 mg/ml (0.9%) solution for injection has been demonstrated for 24 hours at 2 °C to 8 °C or for 4 hours at 25 °C. 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 °C to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2 °C to 8 °C ).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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

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

Pack of 1 vial of 10 ml.

Pack of 2 vials of 10 ml.

Pack of 1 vial of 50 ml.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Do not shake the vial.

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

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

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

In case of 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.

7. Marketing authorisation holder

Eli Lilly Nederland B.V.

Papendorpseweg 83

3528 BJ Utrecht

The Netherlands

8. Marketing authorisation number(s)

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

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19 December 2014

10. Date of revision of the text

25 January 2016

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

Legal category

POM

*CYRAMZA (Ramucirumab) is a trademark of Eli Lilly and Company. CZ4M

Company contact details

Eli Lilly and Company Limited

Company image
Address

Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL

Fax

+44 (0)1256 775 858

Medical Information Fax

+44 (0)1256 775 569

Telephone

+44 (0)1256 315 000

Medical Information e-mail

Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?

Active ingredients

ramucirumab

Legal categories

POM - Prescription Only Medicine

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