Ramucirumab

Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology. It is directed against vascular endothelial growth factor receptor 2 (VEGFR2), a transmembrane tyrosine kinase receptor on endothelial cells and the key mediator of VEGF-induced angiogenesis, the formation of new blood vessels.

Mechanism of Action

• Receptor binding: ramucirumab binds VEGFR2 specifically and blocks the binding of its ligands VEGF-A, VEGF-C and VEGF-D.
• Signalling: as a result, ligand-stimulated activation of VEGFR2 and of its downstream signalling components, including the p44/p42 mitogen-activated protein kinases, is inhibited. This neutralises ligand-induced proliferation and migration of human endothelial cells; DrugBank adds permeability.
• Anti-angiogenic therapy: by limiting the growth of new blood vessels, ramucirumab acts as an anti-angiogenic therapy. The SmPC warnings on bleeding, gastrointestinal perforation and wound healing relate to this class effect.

Pharmacokinetics

• Administration: given only as an intravenous infusion; other routes have not been studied.
• Exposure: with 8 mg/kg every 2 weeks as a single agent, geometric mean trough serum concentrations before the fourth and seventh doses were 49.5 and 74.4 µg/mL in advanced gastric cancer. In hepatocellular carcinoma, troughs before the second, fourth and seventh doses were 23.5, 44.1 and 60.2 µg/mL. Troughs for the combination regimens are listed in the SmPC; with FOLFIRI, for example, they were 46.3 and 65.1 µg/mL before the third and fifth doses.
• Distribution: the mean steady-state volume of distribution is about 5.4 L (CV 15%).
• Metabolism: not studied. Antibodies are cleared mainly by catabolism.
• Elimination: mean clearance is about 0.015 L/hour (CV 30%) and the mean half-life 14 days (CV 20%).
• Dose proportionality and accumulation: there was no clear deviation from dose proportionality between 6 and 20 mg/kg, and an accumulation ratio of 1.5 was seen with dosing every 2 weeks.
• Special populations: there have been no formal studies in renal or hepatic impairment. Clinical data suggest that no dose adjustment is needed in mild, moderate or severe renal impairment, or in mild or moderate hepatic impairment; there are no data in severe hepatic impairment.

• Gastric cancer, with paclitaxel: adults with advanced gastric cancer or gastro-oesophageal junction (GEJ) adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy.
• Gastric cancer, alone: adults with advanced gastric cancer or GEJ adenocarcinoma with disease progression after prior platinum or fluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate.
• Colorectal cancer: in combination with FOLFIRI (irinotecan, folinic acid and 5-fluorouracil), adults with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine.
• Non-small cell lung cancer (NSCLC), with erlotinib: first-line treatment of adults with metastatic NSCLC with activating epidermal growth factor receptor (EGFR) mutations.
• NSCLC, with docetaxel: adults with locally advanced or metastatic NSCLC with disease progression after platinum-based chemotherapy.
• Hepatocellular carcinoma (HCC): alone, adults with advanced or unresectable HCC who have a serum alpha-fetoprotein (AFP) of 400 ng/mL or more and who have been previously treated with sorafenib.

• Hypersensitivity to ramucirumab or to any of the excipients (see Composition).
• NSCLC with tumour cavitation or tumour involvement of major blood vessels.

The most serious reactions with ramucirumab, alone or with cytotoxic chemotherapy, are gastrointestinal perforation, severe gastrointestinal haemorrhage, arterial thromboembolic events and posterior reversible encephalopathy syndrome. The most common reactions as monotherapy are peripheral oedema, hypertension, diarrhoea, abdominal pain, headache, proteinuria and thrombocytopenia. With chemotherapy they are fatigue or asthenia, neutropenia, diarrhoea, epistaxis and stomatitis; with erlotinib they are infections, diarrhoea, hypertension, stomatitis, proteinuria, alopecia and epistaxis.

Very common (≥1/10): as monotherapy (gastric cancer and HCC studies), thrombocytopenia, headache, hypertension, abdominal pain, diarrhoea, proteinuria, peripheral oedema. With chemotherapy or erlotinib, neutropenia, leucopenia (with paclitaxel), thrombocytopenia, anaemia (with erlotinib), infections (with erlotinib), headache (with erlotinib), hypertension, epistaxis, stomatitis, diarrhoea, alopecia (with erlotinib), proteinuria, fatigue or asthenia (with paclitaxel or docetaxel), mucosal inflammation (with docetaxel), peripheral oedema.

Common (≥1/100 to <1/10): as monotherapy, neutropenia, hypokalaemia, hyponatraemia, hypoalbuminaemia, hepatic encephalopathy (HCC studies), arterial thromboembolic events, epistaxis, intestinal obstruction, rash, infusion-related reactions. With chemotherapy or erlotinib, sepsis (with paclitaxel), febrile neutropenia (with docetaxel), hypoalbuminaemia, hyponatraemia, arterial thromboembolic events, pulmonary haemorrhage (with erlotinib), gastrointestinal haemorrhage, gastrointestinal perforation, gingival bleeding (with erlotinib), palmar-plantar erythrodysaesthesia syndrome (with FOLFIRI).

Uncommon (≥1/1,000 to <1/100): as monotherapy, gastrointestinal perforation. With chemotherapy or erlotinib, cardiac failure.

Reactions typical of anti-angiogenic therapy that were clinically relevant, including grade 3 or higher, were gastrointestinal perforation, infusion-related reactions and proteinuria. Posterior reversible encephalopathy syndrome, including fatal cases, has been reported rarely. Infusion-related reactions mostly occurred during or after the first or second infusion. With FOLFIRI, proteinuria (1.5%) was the most frequent reaction (≥1%) leading to stopping ramucirumab.

• Paclitaxel, irinotecan, docetaxel and erlotinib: no drug–drug interactions were observed. Ramucirumab did not change the pharmacokinetics of paclitaxel, of irinotecan and its active metabolite SN-38, of docetaxel or of erlotinib, and paclitaxel did not change the pharmacokinetics of ramucirumab.
• Anticoagulants and other medicines that raise bleeding risk: blood counts and coagulation parameters should be monitored in patients treated with them. In the NSCLC trials, patients on therapeutic anticoagulation (REVEL) and those on chronic non-steroidal anti-inflammatory drugs or antiplatelet agents (REVEL and RELAY) were excluded; aspirin up to 325 mg/day was allowed.

Treatment must be started and supervised by physicians experienced in oncology. Ramucirumab is given by intravenous infusion after dilution (dilution instructions are in section 6.6 of the SmPC), over approximately 60 minutes, and never as an intravenous bolus or push. The rate must never exceed 25 mg/minute: if the dose cannot be given in about 60 minutes at that rate, the infusion is lengthened rather than speeded up. Patients are monitored during the infusion for signs of infusion-related reactions, and resuscitation equipment must be available. Treatment continues until disease progression or unacceptable toxicity.

Recommended Doses

• Gastric cancer or GEJ adenocarcinoma with paclitaxel: ramucirumab 8 mg/kg on days 1 and 15 of a 28-day cycle, before paclitaxel 80 mg/m² given as an intravenous infusion over about 60 minutes on days 1, 8 and 15. Before each paclitaxel infusion a complete blood count and blood chemistry (hepatic function) are checked. Criteria: neutrophils at least 1.5 × 10⁹/L on day 1 and at least 1.0 × 10⁹/L on days 8 and 15; platelets at least 100 × 10⁹/L on day 1 and at least 75 × 10⁹/L on days 8 and 15; bilirubin below 1.5 times the upper limit of normal (ULN); ALT and AST up to 3 times ULN without liver metastases, or up to 5 times ULN with liver metastases.
• Gastric cancer or GEJ adenocarcinoma alone: 8 mg/kg every 2 weeks.
• Metastatic colorectal cancer with FOLFIRI: 8 mg/kg every 2 weeks, before FOLFIRI. A complete blood count is done before chemotherapy. Criteria before FOLFIRI: neutrophils at least 1.5 × 10⁹/L, platelets at least 100 × 10⁹/L, and chemotherapy-related gastrointestinal toxicity of grade 1 or lower (NCI CTCAE).
• NSCLC with erlotinib: 10 mg/kg every 2 weeks. EGFR mutation status must be determined with a validated test before starting; erlotinib is dosed according to its own prescribing information.
• NSCLC with docetaxel after platinum-based chemotherapy: 10 mg/kg on day 1 of a 21-day cycle, before docetaxel 75 mg/m² given as an intravenous infusion over about 60 minutes. For East Asian patients, a reduced docetaxel starting dose of 60 mg/m² on day 1 of a 21-day cycle should be considered.
• Hepatocellular carcinoma: 8 mg/kg every 2 weeks. Patients are selected on a serum AFP of 400 ng/mL or more, measured with a validated test before treatment.

Premedication and Infusion Reactions

• Premedication with a histamine H1 antagonist (for example diphenhydramine) is recommended before each infusion.
• After a grade 1 or 2 infusion-related reaction, premedication must be given before all later infusions, and the infusion rate is reduced by 50% for that infusion and all subsequent ones.
• After a second grade 1 or 2 reaction, dexamethasone (or equivalent) is given; for later infusions, premedication is an intravenous H1 antagonist, paracetamol and dexamethasone (or equivalents).
• A grade 3 or 4 infusion-related reaction means stopping ramucirumab immediately and permanently.

Dose Adjustments for Ramucirumab

• Hypertension: blood pressure is monitored before each administration and treated as clinically indicated. Ramucirumab is stopped temporarily for severe hypertension until it is controlled, and permanently if medically significant hypertension cannot be controlled safely.
• Proteinuria: patients are monitored for new or worsening proteinuria. If urine protein is 2+ or more on a dipstick, a 24-hour urine collection is done. Ramucirumab is stopped temporarily if urine protein is 2 g/24 hours or more, and resumed at a reduced dose once it falls below 2 g/24 hours: 8 mg/kg is reduced to 6 mg/kg and then 5 mg/kg; 10 mg/kg is reduced to 8 mg/kg and then 6 mg/kg. A second reduction is made if 2 g/24 hours or more recurs. It is stopped permanently if urine protein exceeds 3 g/24 hours or in nephrotic syndrome.
• Surgery and wound healing: ramucirumab is stopped for at least 4 weeks before elective surgery, and temporarily if wound-healing complications occur, until the wound is fully healed.
• Permanent discontinuation: severe arterial thromboembolic events; gastrointestinal perforation; grade 3 or 4 bleeding; spontaneous fistula; hepatic encephalopathy or hepatorenal syndrome.

Adjusting the Partner Chemotherapy

• Paclitaxel: for grade 4 haematological toxicity or grade 3 paclitaxel-related non-haematological toxicity, reduce the dose by 10 mg/m² for all following cycles, and by a further 10 mg/m² if these persist or recur.
• Docetaxel: withhold during febrile neutropenia, neutrophils below 500 cells/mm³ for more than 1 week, severe or cumulative skin reactions, or other grade 3 or 4 non-haematological toxicity until it resolves. Then reduce by 10 mg/m² for all following cycles, and by 15 mg/m² if it persists or recurs. East Asian patients started at 60 mg/m² stop docetaxel instead.
• FOLFIRI: the components are reduced independently for specific toxicities (diarrhoea, neutropenia, thrombocytopenia, stomatitis, febrile neutropenia), following the SmPC tables.

Special Populations

• Elderly: there is limited evidence that patients aged 65 or over are at higher risk of adverse events than younger patients; no dose reduction is recommended.
• Renal impairment: no formal studies; no dose adjustment is suggested in mild, moderate or severe impairment.
• Hepatic impairment: no formal studies; no dose adjustment is suggested in mild or moderate impairment, and there are no data in severe impairment (see Special Instructions).
• Children and adolescents: safety and efficacy under 18 years have not been established, and there is no relevant use in these indications.

Traceability

To improve traceability of this biological medicine, the name and batch number of the product given must be clearly recorded.

Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events, including myocardial infarction, cardiac arrest, cerebrovascular accident and cerebral ischaemia, have been reported. Ramucirumab is stopped permanently after a severe event.

Gastrointestinal Perforation and Fistula

Ramucirumab is an anti-angiogenic therapy and may increase the risk of gastrointestinal perforation, which has been reported; it is stopped permanently if it occurs. Patients may also be at increased risk of fistula, and ramucirumab is stopped if one develops.

Bleeding

Ramucirumab may increase the risk of severe bleeding and is stopped permanently after grade 3 or 4 bleeding. Blood counts and coagulation parameters are monitored in patients with conditions that predispose to bleeding and in those taking anticoagulants or other medicines that raise bleeding risk. Severe gastrointestinal haemorrhage, including fatal cases, was reported in gastric cancer with paclitaxel and in colorectal cancer with FOLFIRI. In HCC with portal hypertension or earlier oesophageal variceal bleeding, varices should be screened for and treated according to standard care before starting.

In NSCLC, patients with squamous histology are at higher risk of serious pulmonary bleeding. Patients with recent pulmonary bleeding (more than 2.5 mL or bright red blood), tumour cavitation or tumour invasion of major blood vessels were excluded from trials, and ramucirumab is contraindicated in cavitation or major vessel involvement.

Infusion-Related Reactions

Most occur during or after the first or second infusion, so patients are watched during the infusion for signs of hypersensitivity. Symptoms include rigors or tremors, back pain or spasms, chest pain or tightness, chills, flushing, dyspnoea, wheezing, hypoxia and paraesthesia; severe cases involved bronchospasm, supraventricular tachycardia and hypotension. A grade 3 or 4 reaction means stopping immediately and permanently.

Hypertension

Severe hypertension was more frequent than with placebo, usually managed with standard antihypertensive treatment. Patients with uncontrolled hypertension were excluded from the trials, so ramucirumab should not be started until pre-existing hypertension is controlled. Blood pressure is monitored during treatment.

Posterior Reversible Encephalopathy Syndrome

Cases, including fatal ones, have been reported rarely. Symptoms may include seizure, headache, nausea or vomiting, blindness or altered consciousness, with or without hypertension; brain imaging (for example MRI) can confirm the diagnosis. Ramucirumab is stopped in affected patients, and the safety of restarting after recovery is not known.

Aneurysms and Artery Dissections

Inhibitors of the VEGF pathway, in patients with or without hypertension, may promote aneurysms and artery dissections. This risk should be weighed carefully before starting, particularly with risk factors such as hypertension or a history of aneurysm.

Impaired Wound Healing

The effect of ramucirumab has not been evaluated in patients with serious or non-healing wounds. It is withheld for at least 4 weeks before scheduled surgery, and the decision to resume after surgery rests on clinical judgement of adequate wound healing. If wound-healing complications occur, it is stopped until the wound is fully healed.

Liver Disease

Ramucirumab is used with caution in severe liver cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal syndrome, where data are very limited, and only if the potential benefit outweighs the risk of progressive hepatic failure. In HCC, hepatic encephalopathy was reported more often than with placebo; patients are monitored for its signs and ramucirumab is stopped permanently in hepatic encephalopathy or hepatorenal syndrome.

Cardiac Failure

Cardiac failure was numerically more frequent with ramucirumab plus chemotherapy or erlotinib than with chemotherapy or erlotinib alone, but not with ramucirumab alone compared with placebo. After marketing it was seen mostly with paclitaxel. Patients are monitored for signs and symptoms, and suspending treatment should be considered if they appear.

Proteinuria, Stomatitis and Kidney Function

Proteinuria was more frequent than with placebo (see Administration and Dosage for monitoring and dose rules). Stomatitis was more frequent with chemotherapy plus ramucirumab than with chemotherapy plus placebo, and symptomatic treatment should start promptly. Safety data are limited in severe renal impairment (creatinine clearance 15 to 29 mL/min).

Older Patients with NSCLC

With docetaxel, a trend towards less efficacy with increasing age was seen, so comorbidities, performance status and likely tolerance of chemotherapy should be thoroughly evaluated before treating older adults. With erlotinib, patients aged 70 years and over had more grade 3 or higher adverse events and more serious adverse events than those under 70.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant and use effective contraception during treatment and for up to 3 months after the last dose.
• Pregnancy: there are no data in pregnant women and animal studies are insufficient. Because angiogenesis is critical to maintaining pregnancy and to foetal development, inhibiting it may harm the pregnancy, including the foetus. Ramucirumab should be used only if the potential benefit to the mother justifies the risk, and is not recommended in pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether ramucirumab passes into human milk; excretion and oral absorption are expected to be low, but a risk to the infant cannot be excluded. Breastfeeding should be stopped during treatment and for at least 3 months after the last dose.
• Fertility: there are no human data; animal studies suggest female fertility is likely to be compromised during treatment.

Sodium and Polysorbate

A 10 mL vial contains less than 1 mmol (23 mg) of sodium, essentially “sodium free”. A 50 mL vial contains about 85 mg of sodium, roughly 4% of the WHO recommended maximum daily intake of 2 g for an adult. The vials contain about 1 mg (10 mL) or 5 mg (50 mL) of polysorbate 80.

Effect on Driving

Ramucirumab has no or negligible influence on the ability to drive and use machines. Patients with symptoms that affect concentration and reaction should not drive or use machines until the effect subsides.

Store the vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Cyramza is a refrigerated biological medicine, so the cold chain at 2–8 °C is maintained during transport and storage until the infusion is prepared. Vials are Type I glass (10 mL and 50 mL), in packs of 1 or 2 vials of 10 mL or 1 vial of 50 mL; not all pack sizes may be marketed. For storage after dilution, see Shelf Life.

Unopened vial: 3 years. After dilution, the infusion solution contains no antimicrobial preservative. Chemical and physical in-use stability in sodium chloride 9 mg/mL (0.9%) solution for injection has been shown for 24 hours at 2–8 °C or 4 hours at 25 °C. From a microbiological point of view it should be used immediately; if not, the user is responsible for in-use times and conditions, which would normally be no longer than 24 hours at 2–8 °C unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); treatment is started and supervised by physicians experienced in oncology. Ramucirumab is diluted and given by intravenous infusion in hospital or clinic, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C).