Added (underline) deleted (strikethrough)

2.           What you need to know before you are given Cyramza

Warnings and precautions

- A rare but serious brain condition called ‘posterior reversible encephalopathy syndrome’ or ‘PRES’: Cyramza may increase the risk of developing this brain condition. Symptoms may include fits (seizures), headache, feeling sick (nausea), being sick (vomiting), blindness or reduced level of consciousness, with or without high blood pressure. Cyramza will be stopped if you experience this brain condition.
4.           Possible side effects

Rare side effects (may affect up to 1 in 1000 people):

- a brain condition called posterior reversible encephalopathy syndrome: symptoms may include fits (seizures), headache, feeling sick (nausea), being sick (vomiting), blindness or reduced level of consciousness, with or without high blood pressure.

Common side effects (may affect up to 1 in 10 people):

-          hoarseness

 This leaflet was last revised in January May 2020

Added (underline) deleted (strikethrough)

Various minor grammar and format updates.  Table referance numbers updated after insertion of new Table 8

4.4            Special warnings and precautions for use

              Posterior Reversible Encephalopathy Syndrome

Cases of posterior reversible encephalopathy syndrome (PRES), including fatal cases, have been rarely reported in patients receiving ramucirumab. PRES symptoms may include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension. A diagnosis of PRES can be confirmed by brain imaging (e.g., magnetic resonance imaging). Discontinue ramucirumab in patients who experience PRES. The safety of reinitiating ramucirumab in patients who develop PRES and recover is not known.

4.8            Undesirable effects

[…]

Summary of the safety profile

The most serious adverse reactions associated with ramucirumab treatment (as a single agent or in combination with cytotoxic chemotherapy) were:

Gastrointestinal perforation (see section 4.4)

Severe gastrointestinal haemorrhage (see section 4.4)

Arterial thromboembolic events (see section 4.4)

Posterior reversible encephalopathy syndrome (see section 4.4)

[…]

Not known (cannot be estimated from the available data)

[…]

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

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

10.      DATE OF REVISION OF THE TEXT

 23 January 202028 May 2020

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4.1            Therapeutic indications   

Cyramza in combination with erlotinib is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutations (see section 5.1).

4.2            Posology and method of administration

Cyramza in combination with erlotinib for the treatment of NSCLC with activating EGFR mutations

The recommended dose of ramucirumab in combination with erlotinib is 10 mg/kg every two weeks.

EGFR mutation status should be determined prior to initiation of treatment with ramucirumab and erlotinib using a validated test method. See erlotinib prescribing information for the posology and method of administration of erlotinib.

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

4.4            Special warnings and precautions for use

Patients receiving any kind of therapeutic anticoagulation were excluded from the REVEL NSCLC clinical trial and/or patients receiving chronic therapy with non-steroidal anti-inflammatory drugs or anti-platelet agents were excluded from the REVEL and RELAY NSCLC clinical trials. Aspirin use at doses up to 325 mg/day was permitted (see section 5.1).

For ramucirumab used in combination with erlotinib for the first line treatment of NSCLC with activating EGFR mutations, patients aged 70 years and older compared to patients under 70 years of age, experienced a higher incidence of grade ≥3 adverse events and all grade serious adverse events.

4.5            Interaction with other medicinal products and other forms of interaction

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

4.8            Undesirable effects

The most common adverse reactions observed in patients treated with ramucirumab as monotherapy-treated patients are: peripheral oedema, hypertension neutropenia, fatigue/asthenia, leukopenia, epistaxis, diarrhoea, abdominal pain, headache, proteinuria and thrombocytopeniastomatitis.

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

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

Tabulated list of adverse reactions

Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase III clinical trials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCC or in combination with different chemotherapy regimens or erlotinib for the treatment of gastric cancer, mCRC and NSCLC. ADRs are listed below by MedDRA body system organ class The following convention has been used for classification of frequency:

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

^a    Terms represent a group of events that describe a medical concept rather than a single event or preferred term.

^b    Based on study RAINBOW (ramucirumab plus paclitaxel).

^c    Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell count decreased.

^d    Based on study REVEL (ramucirumab plus docetaxel).

^e    Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy.

^f       Based on study RAINBOW (ramucirumab plus paclitaxel) and study RAISE (ramucirumab plus FOLFIRI). Includes: anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory‑Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage.

^g       Based on study RAISE (ramucirumab plus FOLFIRI).

^h    Includes cases of nephrotic syndrome.

ⁱ        Based on study RAINBOW (ramucirumab plus paclitaxel) and study REVEL (ramucirumab plus docetaxel). Includes: fatigue and asthenia.

j              Based on study RELAY (ramucirumab plus erlotinib).

k             Infections includes all preferred terms that are part of the System Organ Class Infections and infestations. Most common (³1%) Grade ³3 infections include pneumonia, cellulitis, paronychia, skin infection, and urinary tract infection.

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

5.1      Pharmacodynamic properties

NSCLC

RELAY

RELAY was a global, randomised, double-blind, phase 3 study of Cyramza plus erlotinib versus placebo plus erlotinib that randomised (1:1) 449 previously untreated patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) activating mutations at study entry. Eligible patients were ECOG PS 0 or 1. Patients with CNS metastases or known T790M EGFR mutations at baseline were excluded from the study. Patients at a high risk of bleeding, cardiovascular events, including those who had experienced any arterial thrombotic event within 6 months of enrolment, were also excluded from the study.

Demographics and baseline characteristics were balanced between arms. 77% of patients were Asian and 22% were Caucasian. Patients treated with Cyramza plus erlotinib experienced a statistically significant improvement in progression-free survival (PFS) compared to patients treated with placebo plus erlotinib (Table 11). Consistent results were observed across subgroups including exon 19 deletions and exon 21 (L858R) substitution, age, race (Caucasian HR: 0.618, Asian HR: 0.638), smokers and never smokers. Overall survival data were immature at the time of the final PFS analysis (17.6% maturity). RELAY efficacy results are shown in Table 11 and Figure 6.

Table 11: Summary of efficacy data in RELAY – Intent to treat (ITT) population

Abbreviations: CI = confidence interval, NR= not reached, CR = complete response, PR = partial response. A hierarchal testing procedure was employed to test OS. OS was tested only if PFS was significant. Both endpoints were alpha-protected.

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

……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 121.

Table 121: Summary of efficacy data – ITT population

Figure 76: Kaplan-Meier curves of overall survival for Cyramza plus docetaxel versus placebo plus docetaxel in REVEL

Figure 87: Kaplan-Meier curves of progression-free survival for Cyramza plus docetaxel versus placebo plus docetaxel in REVEL

In REACH-2, baseline patient demographics and disease characteristics were generally balanced between arms, except for AFP, which was lower in the placebo arm. Patients treated with Cyramza experienced a statistically significant improvement in OS, compared to placebo (Table 132). The major efficacy outcome in REACH-2 was supported by a statistically significant improvement in progression free survival in Cyramza treated patients compared to placebo treated patients. The relative treatment effect (assessed by HR) of Cyramza compared to placebo was generally consistent across subgroups, including age, race, aetiology of disease and reason for discontinuation of sorafenib (progressive disease vs. intolerance). A relevant exposure-efficacy association was observed for ramucirumab in REACH-2 (see section 5.2). REACH-2 efficacy results are shown in Table 132 and Figure 98.

Table 123: Summary of efficacy data in REACH-2 – Intent to treat (ITT) population

Figure 98: Kaplan-Meier curves of Overall Survival for Cyramza versus placebo in REACH-2

5.2            Pharmacokinetic properties

Following the dose regimen of 10 mg/kg ramucirumab every 2 weeks, the geometric means of ramucirumab Cmin were 68.5 μg/ml (range of 20.3-142 μg/ml) and 85.7 μg/ml (range of 36.0‑197 μg/ml) prior to administration of the fourth and seventh dose, respectively of ramucirumab given in combination with erlotinib, in serum from patients with NSCLC.

Efficacy

…An improvement in PFS was also associated with increasing ramucirumab exposure for advanced gastric cancer, NSCLC with disease progression after platinum-based chemotherapy, and mCRC.

…No such relation was observed in the RELAY study for NSCLC with 10 mg/kg ramucirumab plus erlotinib given every 2 weeks.

Safety

…In RELAY, no exposure-safety relationship was identified for the selected safety endpoints, including Grade ≥3 hypertension, diarrhoea, proteinuria and dermatitis acneiform.

10.      DATE OF REVISION OF THE TEXT

30 September 2019 23 January 2020

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4.4          Special warnings and precautions for use

Aneurysms and artery dissections
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Cyramza, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

4.8          Undesirable effects

ADRs of aneurysms and artery dissections have a frequency of ‘not known’.

10.      DATE OF REVISION OF THE TEXT

               26 September 201930 September 2019

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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.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient with known effect:

4.2             Posology and method of administration

Table 3: Ramucirumab dose reductions for proteinuria

…

Permanent discontinuation

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 eventsdrug reactions.

…

Table 5: Dose modification of FOLFIRI components due to specific AEDRs [Minor changes to table 5]

*The 28 day time period begins on day 1 of the cycle subsequent to the AEDR.

…

Cyramza is for intravenous use.

4.4             Special warnings and precautions for use

Traceability

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

…

Sodium restricted diet

Each 10 ml vial contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’. Each 50 ml vial contains approximately 85 mg sodium. This is equivalent to approximately 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

…

Sodium restricted diet

Each 10 ml vial contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’. Each 50 ml vial contains approximately 85 mg sodium. This is equivalent to approximately 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.6          Fertility, pregnancy and lactation

Breast-feeding

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

4.7             Effects on ability to drive and use machines

Cyramza has no or negligible influence on the ability to drive and use machines.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

^c    Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell count decreased.

5.1          Pharmacodynamic properties

Gastric cancer:

6.4             Special precautions for storage

(2 ºC to-8 ºC-).

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 DO NOT FREEZE OR SHAKE the infusion solution. Do notDO 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 DO NOT FREEZE OR SHAKE the infusion solution. Do notDO NOT dilute with other solutions or co-infuse with other electrolytes or medicinal products.

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

               Date of first authorisation: 19 December 2014

               Date of latest renewal: 26 September 2019

10.      DATE OF REVISION OF THE TEXT

               01 August 201926 September 2019

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4.1             Therapeutic indications   

Gastric cancer

…

Colorectal cancer

…

Non-small cell lung cancer

…

Hepatocellular carcinoma

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

4.2             Posology and method of administration

…

Hepatocellular carcinoma (HCC)

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

Alpha fetoprotein (AFP) testing in HCC

Patients with HCC should be selected based on a serum AFP concentration of ≥ 400 ng/ml with a validated AFP test prior to ramucirumab treatment (see section 5.1).

…

Hepatic encephalopathy or hepatorenal syndrome (see section 4.4).

…

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

4.4             Special warnings and precautions for use

…

For HCC patients with evidence of portal hypertension or prior history of oesophageal variceal bleeding, screening for and treatment of oesophageal varices should be performed as per standard of care before starting ramucirumab treatment.

…

Hepatic impairment

Ramucirumab should be used with caution in patients with severe liver cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal syndrome. There are very limited efficacy and safety data available in these patients. In these patients, rRamucirumab should only be used in these patients if the potential benefits of treatment are judged to outweigh the potential risk of progressive hepatic failure.

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

4.8             Undesirable effects

…

Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase  III clinical trials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCC or in combination with different chemotherapy regimens for the treatment of gastric cancer, mCRC and NSCLC. 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:

…

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 patients treated with ramucirumab as monotherapy in phase 3 clinical trials (REGARD, REACH-2 and REACH patients with alpha fetoprotein ≥ 400 ng/ml)

in ≥5% of ramucirumab treated patients in RAINBOW

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

b             Includes: hypokalaemia and blood potassium decreased.

c             Based on study REACH-2 and REACH (single-agent ramucirumab in HCC). Includes hepatic encephalopathy and hepatic coma.

d             Includes: blood pressure increased and hypertension.

e             Includes: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain.

f              Includes one case of nephrotic syndrome

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

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

b             Based on study RAINBOW (ramucirumab plus paclitaxel).

c             Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white cell count decreased.

d             Based on study REVEL (ramucirumab plus docetaxel).

e             Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy.

f              Based on study RAINBOW (ramucirumab plus paclitaxel) and study RAISE (ramucirumab plus FOLFIRI). Includes: anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory‑Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage.

g             Based on study RAISE (ramucirumab plus FOLFIRI).

h             Includes cases of nephrotic syndrome.

i              Based on study RAINBOW (ramucirumab plus paclitaxel) and study REVEL (ramucirumab plus docetaxel). Includes: fatigue and asthenia.

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

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

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).

Colorectal cancer

Ramucirumab in combination with FOLFIRI

…

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

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).

5.1       Pharmacodynamic properties

Efficacy results are shown in Table 108.

Table 108: Summary of efficacy data – Intent to treat (ITT) population

…

Efficacy results are shown in Table 119.

…

Table 119: Summary of efficacy data – ITT population

…

Efficacy results are shown in Table 1210 and Figures 4 and 5.

…

Table 1210: Summary of efficacy data – ITT population

…

Efficacy results are shown in Table 1311.

…

Table 1311: Summary of efficacy data – ITT population

Hepatocellular carcinoma

REACH-2

REACH-2 was a global, randomised, double-blind study of Cyramza plus BSC versus placebo plus BSC that randomised (2:1) 292 patients with HCC who had a serum AFP ≥ 400 ng/ml at study entry. Patients enrolled into the study had disease progression on or after prior sorafenib therapy or were intolerant to sorafenib. Eligible patients were Child Pugh A (score < 7), had creatinine clearance ≥ 60 ml/min, and ECOG PS of 0 or 1. In addition, patients were either Barcelona Clinic Liver Cancer (BCLC) stage B and no longer amenable to locoregional therapy, or were BCLC stage C. Patients with brain metastases, leptomeningeal disease, uncontrolled spinal cord compression, a history of or current hepatic encephalopathy or clinically meaningful ascites, severe variceal bleeding in the 3 months prior to treatment, or gastric or oesophageal varices at high risk of bleeding were excluded from the study. The primary endpoint was overall survival. The threshold for the elevated AFP study entry requirement for REACH-2 was determined based on the survival results from a pre-specified subgroup, exploratory analysis from REACH, a previously completed, supportive phase 3 clinical study in 565 HCC patients randomised (1:1) to either Cyramza plus BSC or placebo plus BSC that had disease progression on or after prior sorafenib therapy.

In REACH-2, baseline patient demographics and disease characteristics were generally balanced between arms, except for AFP, which was lower in the placebo arm. Patients treated with Cyramza experienced a statistically significant improvement in OS, compared to placebo (Table 12). The major efficacy outcome in REACH-2 was supported by a statistically significant improvement in progression free survival in Cyramza treated patients compared to placebo treated patients. The relative treatment effect (assessed by HR) of Cyramza compared to placebo was generally consistent across subgroups, including age, race, aetiology of disease and reason for discontinuation of sorafenib (progressive disease vs. intolerance). A relevant exposure-efficacy association was observed for ramucirumab in REACH-2 (see section 5.2). REACH-2 efficacy results are shown in Table 12 and Figure 8.

Table 12: Summary of efficacy data in REACH-2 – Intent to treat (ITT) population

Abbreviations: CI = confidence interval, CR = complete response, ORR = objective response rate and PR = partial response

Figure 8: Kaplan-Meier curves of Overall Survival for Cyramza versus placebo in REACH-2

…

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, and liver cancer (see section 4.2 for information on paediatric use).

5.2      Pharmacokinetic properties

Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab C_min prior to administration of the fourth and seventh dose of ramucirumab given as a single agent in advanced gastric cancer patients’ serum were 49.5 μg/ml (range of 6.3-228 μg/ml) and 74.4 μg/ml (range of 13.8-234 μg/ml), respectively. In HCC patients’ serum the geometric means of ramucirumab Cmin prior to administration of the second, fourth and seventh dose of ramucirumab were 23.5 μg/ml (range of 2.9‑76.5 μg/ml), 44.1 μg/ml (range of 4.2‑137 μg/ml) and 60.2 μg/ml (range of 18.3‑123 μg/ml), respectively. 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.

…

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. These and other factors investigated had < 20 % effect on ramucirumab disposition. Body weight is considered a significant co-variate of ramucirumab pharmacokinetics supporting the dosing based on body weight.

Exposure response relationships

Efficacy

Exposure-response analyses indicated that efficacy was correlated with ramucirumab exposure across pivotal studies. Efficacy, as measured by improvements in OS 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. An improvement in PFS was also associated with increasing ramucirumab exposure for advanced gastric cancer, NSCLC, and mCRC.

In the REACH-2 study for HCC, a relevant exposure-efficacy association was observed for ramucirumab which showed that only patients with above-median exposure experienced an improvement in OS, compared to placebo, and these exposure-efficacy relationships remained after attempts to adjust for other prognostic factors. A treatment effect on PFS was observed for all exposure levels produced by 8 mg/kg ramucirumab given every 2 weeks.

…

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

10.      DATE OF REVISION OF THE TEXT

04 April 201901 August 2019

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4.8             Undesirable effects                          

…

Adverse reactions from other sources

ADRs of haemangioma and thrombotic microangiopathy were reported in ramucirumab clinical trials at a frequency of common (1.5%) and rare (0.03%), respectively, and through post-marketing reporting.

...                          

Website: www.mhra.gov.uk/yellowcard Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

10.      DATE OF REVISION OF THE TEXT

20 September 201804 April 2019

Changes

Added (underline), deleted (strikethrough), additional notes:

CYRAMZA^®
 

4.2       Posology and method of administration

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…

RPatients with renal impairment

There have been no formal studies with Cyramza in patients with renal impairment…

HPatients with hepatic impairment

There have been no formal studies with Cyramza in patients with hepatic impairment…

4.4       Special warnings and precautions for use

Sodium restricted diet

Each 10 ml vial contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’. Each 50 ml vial contains approximately 85 mg sodium. This is equivalent to approximately 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

5.2       Pharmacokinetic properties

Elderly patients

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

10.     DATE OF REVISION OF THE TEXT

20 September 201825 January 2016

The SPC has been extensively updated, with the main change relating to the addition of two new indications in section 4.1:

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.

In association with these new indications, new or changed text, has been introduced into sections 4.2, 4.3, 4.4, 4.5, 4.8, 5.1, 5.2 and 10.

Separately, further changes have been made to 4.4, 5.2 and 9.

Changes

Added (bold), Deleted (strikethrough):

10      MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V.

Grootslag 1‑5

NL‑3991 RA, Houten

Papendorpseweg 83

3528 BJ Utrecht

The Netherlands

10.     DATE OF REVISION OF THE TEXT

31 August 201501 January 2015

Changes

Added (bold, underlined), Deleted (strikethrough):

5.       PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies ATC code: Not yet assignedL01XC21.

10.     DATE OF REVISION OF THE TEXT

19 December 2014 31 August 2015