Gastric Cancer

CYRAMZA, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy.
Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.
Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.
Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
Hepatocellular Carcinoma
CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib

Premedication
• Prior to each CYRAMZA infursion, premedicate all patients with an intravenous
• histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride) [see Special warnings and precautions for use (4.4)].
For patients who have experienced a Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each CYRAMZA infusion.
Recommended Dosage for Gastric Cancer
• The recommended dosage of CYRAMZA, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
• When given in combination with paclitaxel, administer CYRAMZA prior to administration of paclitaxel.
• Refer to the prescribing information for paclitaxel for dosage information.
Recommended Dosage for Non-Small Cell Lung Cancer
• The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity.
• Refer to the prescribing information for docetaxel for dosage information.

Recommended Dosage for Colorectal Cancer
• The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue CYRAMZA until disease progression or unacceptable toxicity.
• Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information.
Recommended Dosage for Hepatocellular Carcinoma
• The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
Dosage Modifications for Adverse Reactions
Infusion-Related Reactions (IRR)
Reduce dose, withhold dose, or discontinue CYRAMZA to manage adverse reactions as described in Table 1.

Table 1: Dosage Modifications for CYRAMZA

Preparation and Administration
Preparation
• Visually inspect vials for particulate matter and discoloration. Discard if particulate matter or discolorations are identified. Calculate the dose and the required volume of CYRAMZA needed for the calculated dose.
• Withdraw the required volume of CYRAMZA and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250mL. Do not use dextrose containing solutions.
• Do not shake. Gently invert the container to ensure adequate mixing.
• Do not dilute with other solutions or co-infuse with other electrolytes or medications.
• Do not freeze. Store diluted solution for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 30°C [86°F]).
• Discard any unused portion of CYRAMZA.

Administration
• Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Discard If particulate matter or discolorations are identified.
• Do not administer CYRAMZA as an intravenous push or bolus.
• Administer diluted CYRAMZA solution via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile 0.9% Sodium Chloride Injection at the end of the infusion.

Traceability

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

Arterial thromboembolic events

Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia have been reported in clinical studies. Ramucirumab should be permanently discontinued in patients who experience a severe ATE (see section 4.2).

Gastrointestinal perforations

Ramucirumab is an antiangiogenic therapy and may increase the risk of gastrointestinal perforations. Cases of gastrointestinal perforation have been reported in patients treated with ramucirumab. Ramucirumab should be permanently discontinued in patients who experience gastrointestinal perforations (see section 4.2).

Severe bleeding

Ramucirumab is an antiangiogenic therapy and may increase the risk of severe bleeding. Ramucirumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding (see section 4.2). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. For HCC patients with evidence of portal hypertension or prior history of oesophageal variceal bleeding, screening for and treatment of oesophageal varices should be performed as per standard of care before starting ramucirumab treatment.

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

Pulmonary haemorrhage in NSCLC

Patients with squamous histology are at higher risk of developing serious pulmonary bleeding, however, no excess of Grade 5 pulmonary haemorrhage was observed in ramucirumab treated patients with squamous histology in REVEL. NSCLC patients with recent pulmonary bleeding (>2.5 ml or bright red blood) as well as patients with evidence of baseline tumour cavitation, regardless of histology, or those with any evidence of tumour invasion or encasement of major blood vessels have been excluded from clinical trials (see section 4.3). Patients receiving any kind of therapeutic anticoagulation were excluded from the REVEL NSCLC clinical trial and patients receiving chronic therapy with non-steroidal anti-inflammatory drugs or anti-platelet agents were excluded from the REVEL and RELAY NSCLC clinical trials. Aspirin use at doses up to 325 mg/day was permitted (see section 5.1).

Infusion-related reactions

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

Hypertension

An increased incidence of severe hypertension was reported in patients receiving ramucirumab as compared to placebo. In most cases hypertension was managed using standard antihypertensive treatment. Patients with uncontrolled hypertension were excluded from the trials: ramucirumab treatment should not be initiated in such patients until and unless their pre-existing hypertension is controlled. Patients who are treated with ramucirumab should have their blood pressure monitored. Ramucirumab should be temporarily discontinued for severe hypertension until controlled with medical management. Ramucirumab should be permanently discontinued if medically significant hypertension cannot be controlled with antihypertensive therapy (see section 4.2).

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

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

Impaired wound healing

The impact of ramucirumab has not been evaluated in patients with serious or non-healing wounds. In a study conducted in animals, ramucirumab did not impair wound healing. However, since ramucirumab is an antiangiogenic therapy and may have the potential to adversely affect wound healing, ramucirumab treatment should be withheld for at least 4 weeks prior to scheduled surgery. The decision to resume ramucirumab following surgical intervention should be based on clinical judgment of adequate wound healing.

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

Hepatic impairment

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

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

Cardiac Failure

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

Fistula

Patients may be at increased risk for the development of fistula when treated with Cyramza. Ramucirumab treatment should be discontinued in patients who develop fistula (see section 4.2).

Proteinuria

An increased incidence of proteinuria was reported in patients receiving ramucirumab as compared to placebo. Patients should be monitored for the development, or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose level. A second dose reduction is recommended if a urine protein level ≥2 g/24 hours reoccurs. Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome (see section 4.2).

Stomatitis

An increased incidence of stomatitis was reported in patients receiving ramucirumab in combination with chemotherapy as compared to patients treated with placebo plus chemotherapy. Symptomatic treatment should be instituted promptly if stomatitis occurs.

Renal impairment

There are limited safety data available for patients with severe renal impairment (creatinine clearance 15 to 29 ml/min) treated with ramucirumab (see sections 4.2 and 5.2).

Elderly patients with NSCLC

A trend towards less efficacy with increasing age has been observed in patients receiving ramucirumab plus docetaxel for the treatment of advanced NSCLC with disease progression after platinum-based chemotherapy (see section 5.1). Comorbidities associated with advanced age, performance status and the likely tolerability to chemotherapy should therefore be thoroughly evaluated prior to the initiation of treatment in the elderly (see sections 4.2 and 5.1).

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

Sodium 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.

No clinically meaningful changes in the exposure of either ramucirumab or its concomitant drugs in the approved combinations, including paclitaxel, docetaxel, and irinotecan (or its active metabolite, SN-38), were observed in patients with solid tumors.

Pregnancy
Risk Summary
Based on its mechanism of action [see Pharmacological properties (5.1)], CYRAMZA can cause fetal harm when administered to a pregnant woman. There are no available data on CYRAMZA use in pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise a pregnant woman of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryo-fetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates.
Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.
Lactation

Risk Summary

There is no information on the presence of ramucirumab in human milk or its effects on the breastfed child or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating CYRAMZA.
Contraception
Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman.
Females
Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

Infertility
Females
Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

No studies have been conducted to determine the effects of ramucirumab on the ability to drive or use machines.

The following serious adverse reactions are described elsewhere in the labelling:
- Hemorrhage [see Special warnings and precautions for use (4.4)].
- Gastrointestinal Perforations [see Special warnings and precautions for use (4.4)].
- Impaired Wound Healing [see Special warnings and precautions for use (4.4)].
- Arterial Thromboembolic Events [see Special warnings and precautions for use (4.4)].
- Hypertension [see Special warnings and precautions for use (4.4)].
- Infusion-Related Reactions [see Special warnings and precautions for use (4.4)].
- Worsening of Pre-existing Hepatic Impairment [see Special warnings and precautions for use (4.4)].
- Reversible Posterior Leukoencephalopathy Syndrome [see Special warnings and precautions for use(4.4)].
- Proteinuria Including Nephrotic Syndrome [see Special warnings and precautions for use (4.4)].
- Thyroid Dysfunction [see Special warnings and precautions for use (4.4)].

Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in the Warnings and Precautions section reflect exposure to CYRAMZA in 1916 patients from five studies: REGARD, RAINBOW, RAISE, REVEL, and REACH-2.
Gastric Cancer
The safety of CYRAMZA was evaluated in REGARD and RAINBOW [see Pharmacological properties (5.1)]. Patients in both trials had locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) and had previously received platinum- or fluoropyrimidine-containing chemotherapy. Patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Both trials excluded patients with uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. REGARD excluded patients with bilirubin ≥1.5 mg/dL and RAINBOW excluded patients with bilirubin >1.5 times the upper limit of normal (ULN).
CYRAMZA Administered as a Single Agent (REGARDS)
Patients received either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. Patients randomized to CYRAMZA received a median of 4 doses; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.
The most common serious adverse reactions with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.
The most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. Table 2 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in REGARD.

Table 2: Adverse Reactions Occurring in ≥5% of Petients with a ≥2% Difference Between Arms in REGARD

a: Hypertension is a consolidated term.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in REGARD were:
• Neutropenia (4.7%)
• Epistaxis (4.7%)
• Rash (4.2%)
• Intestinal obstruction (2.1%),
Arterial thromboembolic events (1.7%). Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and IRRs. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in REGARD was 0.8% and the rate of IRRs was 0.4%.
CYRAMZA Administered in Combination with Paclitaxel (RAINBOW)
Patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle with either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. Patients randomized to CYRAMZA received a median of 9 doses; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.
The most common serious adverse reactions in patients who received CYRAMZA with paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients who received CYRAMZA with paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA with paclitaxel combination in ≥2% of patients in RAINBOW were neutropenia (4%) and thrombocytopenia (3%).
The most common adverse reactions (all grades) observed in patients who received CYRAMZA with paclitaxel at a rate of ≥30% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. Table 3 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAINBOW.

Table 3: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RAINBOW

Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with paclitaxel were:
Sepsis (3.1%), including 5 fatal events
Gastrointestinal perforations (1.2%), including 1 fatal event

Non-Small Cell Lung Cancer

The safety of CYRAMZA was evaluated in REVEL [see Pharmacological properties (5.1)]. Patients had NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease and ECOG PS 0 or 1. REVEL excluded patients with bilirubin greater than the ULN,
uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. Patients received either CYRAMZA 10 mg/kg or placebo intravenously in combination with docetaxel 75 mg/m2 intravenously every 21 days. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, REVEL was amended and 24 patients (11 patients receiving CYRAMZA with docetaxel, 13 patients receiving placebo with docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every three weeks. Patients randomized to CYRAMZA received a median of 4.5 doses; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months.

The most common serious adverse reactions in patients who received CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel.
The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%).

The most common adverse reactions (all grades) observed in CYRAMZA with docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Table 4 provides the frequency and severity of adverse reactions (NCI CTCAE, version 4.0) in REVEL.

Table 4: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in REVEL

^a Neutropenia, thrombocytopenia, and hypertension are consolidated terms.

Clinically relevant adverse drug reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were:

• Hyponatremia (4.8%)
• Proteinuria (3.3%)

Colorectal Cancer

The safety of CYRAMZA was evaluated in RAISE [see Pharmacological properties (5.1)]. Patients had mCRC with disease progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine and ECOG PS 0 or 1. RAISE excluded patients with uncontrolled hypertension, major surgery within 28 days, and those who experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 3 proteinuria; a Grade 3-4 bleeding event; or bowel perforation.

Patients received either CYRAMZA 8 mg/kg or placebo intravenously in combination with FOLFIRI intravenously every two weeks. Patients randomized to CYRAMZA received a median of 8 doses (range 1-68); the median duration of exposure was 4.4 months, and 169  (32% of 529) patients received CYRAMZA for at least six months.

The most common serious adverse reactions with CYRAMZA with were diarrhea, (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8).

Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA with FOLFIRI-treated patients (29%) than in placebo with FOLFIRI- treated patients (13%).

The most common adverse reactions leading to discontinuation of any component of CYRAMZA with FOLFIRI as compared to placebo with FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).

The most common adverse reactions (all grades) observed in CYRAMZA with FOLFIRI treated patients at a rate of ≥30% and ≥2% higher than placebo with FLOFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. Twenty percent of patients treated with CYRAMZA with FOLFIRI received granulocyte colony-stimulating factors. . Table 5 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) in RAISE.

Table 5: Adverse Reactions Occurring in ≥5% of Patients with a ≥2% Difference Between Arms in RAISE

^a   Gastrointestinal hemorrhage events, neutropenia, thrombocytopenia, hypertension, proteinuria, and hypoalbuminemia, are consolidated terms.

^b Includes 3 fatal events in the CYRAMZA arm.

^c   Includes 3 patients with nephrotic syndrome in the CYRAMZA arm.

Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with FOLFIRI were:

• Gastrointestinal perforation (1.7%), including 4 fatal events

Thyroid stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA with FOLFIRI-treated patients and 109 placebo with FOLFIRI-treated patients) with normal baseline TSH levels. Patients underwent periodic TSH laboratory assessments until 30 days after the last dose of study treatment. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA with FOLFIRI compared with 4 (4%) patients treated with placebo with FOLFIRI.

Hepatocellular Carcinoma

The safety of CYRAMZA was evaluated in REACH-2 [see Pharmacological properties (5.1)]. Patients had Barcelona Clinic Liver Cancer (BCLC) stage B HCC who were no longer amenable to locoregional therapy, or BCLC stage C HCC, Child-Pugh score A, and baseline AFP ≥400 ng/mL. Patients had ECOG PS 0 or 1. REACH-2 excluded patients with clinically meaningful ascites, history of or current hepatic encephalopathy, uncontrolled hypertension, major surgery within 28 days, bilirubin >1.5 times ULN, severe variceal bleeding in the 3 months prior to treatment or with varices at high risk of bleeding, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin.

Patients received either CYRAMZA 8 mg/kg or placebo intravenously every two weeks. Patients received a median of 6 doses (range 1‑51) of CYRAMZA; the median duration of exposure was 12 weeks (range 2‑107 weeks) and 48 patients (24% of 197) received CYRAMZA for at least six months.

The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%).

Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%).

The most common adverse reactions reported in ≥15% of patients and ≥2% higher than placebo were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities ≥30% and ≥2% higher than placebo were thrombocytopenia, hypoalbuminemia, and hyponatremia. Table 6 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 7 provides the incidence and severity of laboratory abnormalities in REACH-2.

Table 6: Adverse Reactions Occurring in ≥10% of Patients with a ≥2% Difference Between Arms in REACH-2

^a           Fatigue, hypertension, abdominal pain, and proteinuria are consolidated terms.

^b           Includes 1 fatal event in the CYRAMZA arm.

^c           Includes 1 patient with nephrotic syndrome in the CYRAMZA arm.

Clinically relevant adverse drug reactions reported in ≥1% and <10% of CYRAMZA treated patients in REACH-2 were:

•           IRRs (9%)

•           Hepatic encephalopathy (5%) including 1 fatal event

•           Hepatorenal syndrome (2%) including 1 fatal event

Table 7: Laboratory Abnormalities Worsening from Baseline in ≥15% (All Grades) of Patients Receiving CYRAMZA with a Difference Between Arms of ≥2% in REACH-2

^a Laboratory abnormalities were not included if the ≥ Grade 3 percentage was less than placebo-treated patients.

^b The denominator used to calculate the incidence varied based on the number of patients with a baseline and at least one on study laboratory measurement: CYRAMZA-treated patients (range 179‑193 patients) and placebo-treated patients (range 84‑92 patients).

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti‑ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CYRAMZA. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•     Blood and lymphatic system: Thrombotic microangiopathy

•     Neoplasms benign, malignant and unspecified: Hemangioma

•    Respiratory, thoracic, and mediastinal: Dysphonia

•    Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

•           Cardiac: Heart failure

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in below.

In case of overdose, use supportive therapy. There is no known antidote to ramucirumab overdose.

Group: Antineoplastic agents, monoclonal antibodies

ATC code: LO1XC

Mechanism of action

Ramucirumab is a VEGFR2 antagonist that specifically binds VEGFR2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.

Clinical data

Gastric Cancer

The efficacy of CYRAMZA was evaluated in REGARD (NCT00917384), a multinational, randomized, double-blind, multicenter study in patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the GEJ) who previously received platinum- or fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients were randomized (2:1) to receive either an intravenous infusion of CYRAMZA 8 mg/kg or placebo every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ). The major efficacy outcome measure was overall survival (OS). An additional efficacy outcome measure was progression-free survival (PFS).

A total of 355 patients were randomized, 238 to the CYRAMZA-treatment group and 117 to the placebo-treatment group. Baseline demographic and disease characteristics were similar between treatment arms. The median age was 60 years (range 24-87); 70% were men; 77% were White, 16% Asian; 28% had ECOG PS 0 and 72% had ECOG PS 1; 91% had measurable disease; 75% had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). Patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo.

Efficacy results are shown in Table 8 and Figure 1.

Table 8: Efficacy Results in REGARD

Abbreviations: BSC = best supportive care; CI = confidence interval

^a 65 of 199 events in CYRAMZA-treated patients and 31 of 108 events in placebo-treated patients were deaths.

Figure 1: Kaplan-Meier Curves for Overall Survival - in REGARD

RAINBOW

The efficacy of CYRAMZA was evaluated in RAINBOW (NCT01170663),a multinational, randomized, double-blind study in patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the GEJ) who previously received platinum- and fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1.

Patients were randomized (1:1) to receive either CYRAMZA 8 mg/kg  or placebo as an intravenous infusion every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m² by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Prior to administration of each dose of paclitaxel, patients were required to have adequate hematopoietic and hepatic function. The paclitaxel dose was permanently reduced in increments of 10 mg/m², for a maximum of two dose reductions for Grade 4 hematologic toxicity or Grade 3 paclitaxel-related non-hematologic toxicity. Randomization was stratified by geographic region, time to progression from the start of first-line therapy (<6 months versus ≥6 months), and disease measurability. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and overall response rate (ORR).

A total of 665 patients were randomized, 330 to the CYRAMZA-treatment group and 335 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 61 years (range: 24-84); 71% were men; 61% were White, 35% Asian; 39% had ECOG PS 0 and 61% had ECOG PS 1; 78% had measurable disease; 79% had gastric cancer; and 21% had adenocarcinoma of the GEJ. Two-thirds of the patients experienced disease progression while on first-line therapy (67%) and 25% of patients received an anthracycline in combination with platinum/fluoropyrimidine combination therapy.

Efficacy results are shown in Table 9 and Figure 2.

Table 9: Efficacy Results in RAINBOW

Abbreviations: CI = confidence interval, CMH = Cochran-Mantel- Haenszel

^a 56 of 279 events in CYRAMZA-treated patients and 55 of 296 events in placebo-treated patients were deaths.

^b 2 complete responses in CYRAMZA-treated patients and 1 complete response in placebo-treated patients.

Figure 2: Kaplan-Meier Curves for Overall Survival - in RAINBOW

Non-Small Cell Lung Cancer

The efficacy of CYRAMZA was evaluated in REVEL (NCT01168973), a multinational, randomized, double-blind study in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients in REVEL were also required to have ECOG PS 0 or 1. Patients were randomized (1:1) to receive either CYRAMZA at 10 mg/kg or placebo by intravenous infusion, in combination with docetaxel at 75 mg/m², every 21 days. Sites in East Asia administered a reduced dose of docetaxel at 60 mg/m² every 21 days. Patients who discontinued combination therapy because of an adverse reaction attributed to either CYRAMZA/placebo or docetaxel were permitted to continue monotherapy with the other treatment component until disease progression or intolerable toxicity. Randomization was stratified by geographic region, gender, prior maintenance therapy, and ECOG PS. The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS and ORR.

A total of 1253 patients were randomized, 628 to the CYRAMZA-treatment group and 625 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 62 years (range 21-86); 67% were men; 82% were White and 13% were Asian; 32% had ECOG PS 0; 73% had nonsquamous histology and 26% had squamous histology. In addition to platinum chemotherapy (99%), the most common prior therapies were pemetrexed (38%), gemcitabine (25%), taxane (24%), and bevacizumab (14%). Twenty-two percent of patients received prior maintenance therapy. Tumor EGFR status was unknown for the majority of patients (65%). Where tumor EGFR  status was known (n=445), 7.4% were positive for EGFR mutation (n=33). No data were collected regarding tumor ALK rearrangement status.

Overall response rate (complete response + partial response) was 23% (95% CI: 20, 26) for CYRAMZA with docetaxel and 14% (95% CI: 11, 17) for placebo with docetaxel, p-value of <0.001. Efficacy results are shown in Table 10 and Figure 3.

Table 10: Efficacy Results in REVEL

Abbreviations: CI = confidence interval

^a 126 of 558 events in CYRAMZA-treated patients and 109 of 583 events in placebo-treated patients were deaths

Figure 3: Kaplan-Meier Curves for Overall Survival – in REVEL

Colorectal Cancer

The efficacy of CYRAMZA was evaluated in RAISE (NCT01183780), a multinational, randomized, double-blind study, in patients with mCRC, who had disease progression on or after prior therapy with bevacizumab,  oxaliplatin, and a fluoropyrimidine. Patients in RAISE 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 randomized (1:1) to receive either CYRAMZA at 8 mg/kg as an intravenous infusion or placebo, in combination with FOLFIRI: irinotecan 180 mg/m² administered intravenously over 90 minutes and folinic acid 400 mg/m² administered intravenously simultaneously over 120 minutes; followed by fluorouracil 400 mg/m² intravenous bolus over 2 to 4 minutes; followed by fluorouracil 2400 mg/m² administered intravenously 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 reaction were permitted to continue therapy with the other treatment component(s) until disease progression or unacceptable toxicity. Randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment (<6 months versus ≥6 months). The major efficacy outcome measure was OS. An additional efficacy outcome measure was PFS.

A total of 1072 patients were randomized, 536 to the CYRAMZA-treatment group and 536 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 62 years (range 21-87); 57% were men; 76% were White and 20% were Asian; 49% had ECOG PS 0; 49% had KRAS mutant tumors; and 24% had <6 months from time to disease progression after beginning first-line treatment.

The treatment effect was consistent across the pre-specified stratification factors. Efficacy results are shown in Table 11 and Figure 4.

Table 11: Efficacy Results in RAISE

Abbreviations: CI = confidence interval.

^a 73 of 476 events in CYRAMZA-treated patients and 64 of 494 events in placebo-treated patients were deaths.

Figure 4: Kaplan-Meier Curves for Overall Survival – in RAISE

Hepatocellular Carcinoma

The efficacy of CYRAMZA was evaluated in REACH‑2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in patients with advanced HCC with AFP ≥400 ng/mL who had disease progression on or after prior sorafenib therapy or who were intolerant to sorafenib. Patients in REACH-2 were required to have ECOG PS of 0 or 1, Child-Pugh A, BCLC stage B and no longer amenable to locoregional therapy, or BCLC stage C. Patients were randomized (2:1) to receive CYRAMZA 8 mg/kg or placebo every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Randomization was stratified by geographic region, macrovascular invasion (yes versus no), and ECOG PS (0 versus 1). The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS and ORR based on investigator assessment.

A total of 292 patients were randomized, 197 to the CYRAMZA-treatment group and 95 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between the arms. The median age was 64 years (range 26‑88); 80% were men; 50% were Asian; 58% had ECOG PS 0; 35% had macrovascular invasion; 72% had extrahepatic spread; 17% were sorafenib intolerant, 37% had hepatitis B, 26% had hepatitis C, 24% had significant prior alcohol use, and 64% had prior locoregional therapy.

Efficacy results are shown in Table 12 and Figure 5.

Table 12: Efficacy Results in REACH‑2

Abbreviations: BSC = best supportive care; CI = confidence interval

^a 26 of 172 events in CYRAMZA-treated patients and 9 of 86 events in placebo-treated patients were deaths.

^b all responses were partial

Figure 5: Kaplan-Meier Curves for Overall Survival in REACH‑2

The pharmacokinetics (PK) of ramucirumab were studied in patients with various cancers over a dose range of 6‑12 mg/kg administered every two or three weeks. The PK characteristics of ramucirumab are similar for patients across cancer types based on a population PK analysis. Ramucirumab systemic exposure increased dose proportionally at doses of 8 mg/kg and above and steady state concentrations were achieved at approximately 12 weeks.

Distribution

The mean (% coefficient of variation [CV%]) volume of distribution of ramucirumab at steady-state (Vss) was 5.4 L (15%).

Elimination

The mean (CV%) clearance of ramucirumab was 0.015 L/hour (30%) and the mean limination half-life was 14 days (20%).

Specific Populations

Age (19-88 years), sex (68% male), race (70% White, 24% Asian), renal impairement

(creatinine clearance [CLcr] calculated by Cockcroft-Gault, 15-89 mL/min, mild hepatic impairement  (total bilirubin within ULN and AST>ULN or total bilirubin >1 to 1.5 times ULN and any AST, or moderate hepatic impairement (total bilirubin >1.5 to 3 times ULN had no clinically meaningful effect on the PK of ramucirumab. The effect of severe hepatic impairement (total bilirubin >3 times ULN and any AST) on the PK of ramucirumab is unknown.

Pediatric Use

The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

Juvenile Animal Toxicity Data

In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use

Of the 563 CYRAMZA-treated patients in REGARD and RAINBOW, 205 (36%) were 65 and over, while 41 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in revel, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA with docetaxel in REVEL, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of REVEL, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years and over was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received CYRAMZA with FOLFIRI in RAISE, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 197 patients who received CYRAMZA in REACH‑2, 95 (48%) were 65 years and over, while 37 (19%) were 75 years and over. Overall, no differences in efficacy were observed between these subjects and younger subjects.

Hepatic Impairment

No dose adjustment is recommended for patients with mild (total bilirubin within ULN and aspartate aminotransferase [AST] >ULN, or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA [see Special warnings and precautions for use (4.4)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.

 Animal Toxicology and/or Pharmacology

Adverse effects in the kidney (glomerulonephritis) occurred in monkeys at doses of 16-50 mg/kg (0.7-5.5  times the exposure in humans at the recommended dose of ramucirumab as a single agent).

A single dose of ramucirumab resulting in an exposure approximately 10 times the human exposure at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.

-                 L-Histidine [0.65mg/ml]

-                 L-Histidine Monohydrochloride [1.22 mg/ml]

-                 Glycine [9.98 mg/ml]

-                 Sodium Chloride [4.383 mg/ml]

-                 Polysorbatc 80 [0.10 mg/ml]

-                 Water for Injection q.s to 1 ml

Do not administer or mix with dextrose solution.

Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze or shake the vial.

None

CYRAMZA (ramucirumab) injection is a clear to slightly opalescent and colorless to slightly yellow, preservative-free solution supplied in single-dose vials.

•           100 mg/10 mL (10 mg/mL), individually packaged in a carton

•           500 mg/50 mL (10 mg/mL), individually packaged in a carton

Not all pack sizes may be marketed.