Special Warning : אזהרת שימוש

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.

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 hemorrhage, 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, dyspnea, wheezing, hypoxia, and paresthesia.
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

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

Polysorbate

This medicinal product contains approximately 1 mg of polysorbate 80 in each 10 ml, and 5 mg of polysorbate 80 in each 50 ml vial.

Effects on Driving

4.7    Effects on ability to drive and use machines

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.