Ramucirumab

Registered South African indications:

• Gastric cancer
• Colorectal cancer
• Non-small cell lung cancer
• Hepatocellular carcinoma

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Tumour cavitation (non-small cell lung carcinoma patients)
• Tumour involvement of major vessels (non-small cell lung cancer patients)

Cautions

• Pregnancy
• Breastfeeding
• Women of childbearing potential
• Renal impairment
• Hepatic impairment
  - Severe liver cirrhosis (Child-Pugh Classes B & C)
  - Cirrhosis with hepatic encephalopathy
  - Clinically significant ascites due to cirrhosis
  - Hepatorenal syndrome
• Elderly
• Conditions that predisposing to bleeding
• Evidence of portal hypertension (hepatocellular carcinoma patients)
• Prior history of oesophageal variceal bleeding (hepatocellular carcinoma patients)
• Patients with squamous histology (non-small cell lung carcinoma)
• Uncontrolled hypertension
• Recent pulmonary bleeding (>2.5ml or bright red blood) (non-small cell lung cancer)
• Risk factors for aneurysm or history thereof (e.g. hypertension)
• Patients under wound care therapy
• Sodium restricted diet (50ml vial)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inf

• Advanced gastric cancer or gastro-oesphageal junction adenocarcinoma (additional agent may be required) 
  - In combination with paclitaxel with disease progression after prior platinum and fluoropyrimidine chemotherapy
  - Monotherapy with disease progression after prior platinum or fluoropyrimidine chemotherapy, for whom treatment with paclitaxel is not appropriate
• Metastatic colorectal cancer (additional agents required)
  - In combination with irinotecan, folinic acid, and 5-fluorouracil with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine
• Metastatic non-small lung cancer (additional agent required)
  - First-line treatment in combination with erlotinib for metastatic non-small cell lung cancer with activating epidermal growth factor receptor mutations
  - In combination with docetaxel with locally advanced or metastatic non-small cell lung cancer with disease progression after platinum-based chemotherapy
• Advanced or unresectable hepatocellular carcinoma
  - Monotherapy in patients with a serum alpha fetoprotein of ≥400ng/ml who have been previously treated with sorafenib

Consult specialist for dosages and regimens

See additional prescribing points

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• There are no data from the use of ramucirumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity
• 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
• Ramucirumab should only be used if the potential benefit to the mother justifies the potential risk during pregnancy and is not recommended during pregnancy and in women of childbearing potential not using contraception
• Women of childbearing potential should be advised to avoid becoming pregnant while on ramucirumab 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

Breastfeeding

• Caution; not recommended 
• It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorption is expected to be low
• As risk to breastfed newborns/infants cannot be excluded, breastfeeding should be discontinued during treatment with ramucirumab and for at least 3 months after the last dose

Fertility

• There is 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

Renal impairment

• Caution; no dose adjustment recommended
  No formal studies with ramucirumab in patients with renal impairment have been conducted. Limited safety data available for patients with CrCl 15-29ml/min

Hepatic impairment

• Caution; no dose adjustment recommended
  No formal studies with ramucirumab in patients with hepatic impairment have been conducted. No data regarding ramucirumab in patients with severe hepatic impairment is available, however, no dose reductions are recommended
  Use in patients with Child-Pugh class B or C severe liver cirrhosis, cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal syndrome only if the potential benefits of treatment outweigh the potential risks of progressive hepatic failure

Elderly

• Caution; no dose adjustment recommended
  There is limited evidence that patients ≥65 years are at an increased risk of adverse events compared to younger patients
  A trend towards less efficacy with increasing age is observed in patients receiving ramucirumab plus docetaxel for the treatment of advanced non-small cell lung cancer with disease progression after platinum-based chemotherapy
  For ramucirumab used in combination with erlotinib for first-line treatment of non-small cell lung cancer with activating EGFR mutations, patients ≥70 years experienced a higher incidence of severe adverse events
  Comorbidities associated with advanced age, performance status and the likely tolerability to chemotherapy should be thoroughly evaluated prior to initiation of treatment in the elderly

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Hepatic encephalopathy
• Fatigue
• Posterior reversible encephalopathy syndrome

Cardiovascular Disorders

• Hypertension
• Arterial thromboembolic events
• Hypertensive cardiomyopathy
• Aneurysms and artery dissections

Respiratory Disorders

• Epistaxis
• Pulmonary haemorrhage
  - Haemoptysis
  - Laryngeal haemorrhage
  - Haemothorax (including fatal outcome)
• Dysphonia

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Intestinal obstruction
• Gastrointestinal perforation
• Stomatitis
• Gastrointestinal haemorrhage events
  - Anal haemorrhage
  - Diarrhoea haemorrhage
  - Gastric haemorrhage
  - Haematemesis
  - Haematochezia
  - Haemorrhoidal haemorrhage
  - Mallory-Weiss syndrome
  - Melaena
  - Oesophageal haemorrhage
  - Rectal haemorrhage
  - Upper gastrointestinal haemorrhage
• Gingival bleeding

Genitourinary Disorders

• Proteinuria
• Nephrotic syndrome

Endocrine and Metabolic Disorders

• Hypokalaemia
• Hyponatraemia
• Hypoalbuminaemia

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Palmar-plantar erthyrodysaesthesia syndrome
• Fistula

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Neutropenia
• Peripheral oedema
• Infusion-related reactions
  - Rigors/tremors
  - Back pain/spasms
  - Chest pain and/or tightness
  - Chills
  - Flushing
  - Dyspnoea
  - Wheezing
  - Hypoxia
  - Paraesthesia
  - Bronchospasm
  - Supraventricular tachycardia
  - Hypotension
• Infections
  - Pneumonia
  - Cellulitis
  - Paronychia
  - Skin infection
  - Urinary tract infection
• Sepsis
• Leukopenia
• Anaemia
• Febrile neutropenia
• Mucosal inflammation
• Haemangioma
• Thrombotic microangiopathy

• Anticoagulants
• Agents that increase the risk of bleeding

• Hepatic function
• Urine protein
• Blood pressure

None routine. Specific cases may require

• Full blood count with differential
• Thyroid function
• Pregnancy test
• Coagulation parameters

Ramucirumab therapy should be permanently discontinued in the event of;

• Severe arterial thromboembolic events
• Gastrointestinal perforations
• Severe bleeding: NCI CTCAE Grade 3 or 4 bleeding
• Spontaneous development of fistula
• Hepatic encephalopathy or hepatorenal syndrome
• Urine protein level is >3g/24hrs or in the event of nephrotic syndrome
• Medically significant hypertension that cannot be controlled safely with antihypertensive therapy

Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF induced angiogenesis. Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand stimulated activation of VEGF Receptor 2 and its downstream signalling components, including p44/p42 mitogen-activated protein kinases, neutralizing ligand-induced proliferation and migration of human endothelial cells.

Injection (per 10ml) 100mg

• Cyramza (Eli Lilly) originator

Injection (per 50ml) 500mg

• Cyramza (Eli Lilly) originator