CYRAMZA Concentrate for solution for infusion Ref.[8882] Active ingredients: Ramucirumab

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).

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).

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 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.

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 breast-fed newborns/infants cannot be excluded, breast-feeding should be discontinued during treatment with Cyramza and for at least 3 months after the last dose.

Fertility

There are no data on the effect of ramucirumab on human fertility. Female fertility is likely to be compromised during treatment with ramucirumab based on studies in animals (see section 5.3).

Cyramza has no or negligible influence on the ability to drive and use machines. If patients experience symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

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 patients treated with ramucirumab as monotherapy are: peripheral oedema, hypertension, diarrhoea, abdominal pain, headache, proteinuria and thrombocytopenia.

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

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

Tabulated list of adverse reactions

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

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):

Blood and lymphatic system disorders

Very Common: Thrombocytopenia^a

Common: Neutropenia^a

Metabolism and nutrition disorders

Common: Hypokalaemia^a,b, Hyponatraemia^a, Hypoalbuminaemia^a

Nervous system disorders

Very Common: Headache

Common: Hepatic encephalopathy^c

Vascular disorders

Very Common: Hypertension^a,d

Common: Arterial thromboembolic events^a

Respiratory, thoracic, and mediastinal disorders

Common: Epistaxis

Gastrointestinal disorders

Very Common: Abdominal pain^a,e, Diarrhoea

Common: Intestinal obstruction^a

Uncommon: Gastrointestinal perforation^a

Skin and subcutaneous tissue disorders

Common: Rash^a

Renal and urinary disorders

Very Common: Proteinuria^a,f

General disorders and administration site disorders

Very Common: Peripheral oedema

Common: Infusion-related reactions^a

^a Terms represent a group of events that describe a medical concept rather than a single event or preferred term.
^b Includes: hypokalaemia and blood potassium decreased.
^c Based on study REACH-2 and REACH (single-agent ramucirumab in HCC). Includes hepatic encephalopathy and hepatic coma.
^d Includes: blood pressure increased and hypertension.
^e Includes: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain.
^f Includes one case of nephrotic syndrome

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

Infections and infestations

Very Common: Infections^j,k

Common: Sepsis^a,b

Blood and lymphatic system disorders

Very Common: Neutropenia^a, Leukopenia^a,c, Thrombocytopenia^a, Anaemia^j

Common: Febrile neutropenia^d

Metabolism and nutrition disorders

Common: Hypoalbuminaemiaa Hyponatraemia^a

Nervous system disorders

Very Common: Headache^j

Vascular disorders

Very Common: Hypertension^a,e

Respiratory, thoracic, and mediastinal disorders

Very Common: Epistaxis

Common: Pulmonary haemorrhage^j,l

Gastrointestinal disorders

Very Common: Stomatitis, Diarrhoea

Common: Gastrointestinal haemorrhage events^a,f, Gastrointestinal perforation^a, Gingival bleeding^j

Skin and subcutaneous tissue disorders

Very Common: Alopecia^j

Common: Palmar-plantar erthyrodysaesthesia syndrome^g

Renal and urinary disorders

Very Common: Proteinuria^a,h

General disorders and administration site disorders

Very Common: Fatigue^a,i, Mucosal inflammation^d, Peripheral oedema

^a Terms represent a group of events that describe a medical concept rather than a single event or preferred term.
^b Based on study RAINBOW (ramucirumab plus paclitaxel).
^c Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell count decreased.
^d Based on study REVEL (ramucirumab plus docetaxel).
^e Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy.
^f Based on study RAINBOW (ramucirumab plus paclitaxel) and study RAISE (ramucirumab plus FOLFIRI). Includes: anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory-Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage.
^g Based on study RAISE (ramucirumab plus FOLFIRI).
^h Includes cases of nephrotic syndrome.
ⁱ Based on study RAINBOW (ramucirumab plus paclitaxel) and study REVEL (ramucirumab plus docetaxel). Includes: fatigue and asthenia.
^j Based on study RELAY (ramucirumab plus erlotinib).
^k Infections includes all preferred terms that are part of the System Organ Class Infections and infestations. Most common (≥1%) Grade ≥3 infections include pneumonia, cellulitis, paronychia, skin infection, and urinary tract infection.
^l Includes haemoptysis, laryngeal haemorrhage, haemothorax (a fatal event occurred) and pulmonary haemorrhage.

Clinically relevant reactions (including Grade ≥3) associated with antiangiogenic therapy observed in ramucirumab-treated patients across clinical studies were: gastrointestinal perforations, infusion-related reactions and proteinuria (see sections 4.2 and 4.4).

Colorectal cancer

Ramucirumab in combination with FOLFIRI

In the RAISE study, in mCRC patients treated with ramucirumab plus FOLFIRI, the most frequent (≥1%) ADR that led to the discontinuation of ramucirumab was proteinuria (1.5%). The most frequent (≥1%) ADRs leading to discontinuation of one or more components of FOLFIRI were: neutropenia (12.5%), thrombocytopenia (4.2%), diarrhoea (2.3%) and stomatitis (2.3%). The most frequent component of FOLFIRI to be discontinued was the 5-FU bolus.

Adverse reactions from other sources

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.

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

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 Appendix V.

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.