CYRAMZA
Clinical safety rating
cautionComprehensive clinical and safety monograph for CYRAMZA (CYRAMZA).
Comprehensive clinical and safety monograph for CYRAMZA (CYRAMZA).
Gastric or gastroesophageal junction adenocarcinoma, as monotherapy or with paclitaxelNon-small cell lung cancer (NSCLC), in combination with docetaxelMetastatic colorectal cancer, in combination with FOLFIRIHepatocellular carcinoma (HCC), as monotherapyOff-label: Advanced urothelial carcinoma, endometrial cancer
High blood pressure, Diarrhea, Headache, Decreased sodium level in blood, Anemia (low number of red blood cells)
Ramucirumab is a human IgG1 monoclonal antibody that binds to vascular endothelial growth factor receptor 2 (VEGFR-2) and blocks the interaction between VEGFR-2 and its ligands, VEGF-A, VEGF-C, and VEGF-D, thereby inhibiting receptor activation and subsequent angiogenesis.
| Metabolism | Ramucirumab is a monoclonal antibody; metabolism is via catabolism into small peptides and amino acids (nonspecific proteolytic degradation). No major metabolic enzymes involved. |
| Excretion | Ramucirumab is eliminated primarily via proteolytic catabolism; no renal or biliary excretion occurs. Clearance is 0.014 L/h (0.022 L/h with high VEGF), with a mean terminal half-life of 14 days (range 11–17 days) at steady state. |
| Half-life | Terminal elimination half-life is approximately 14 days (range 11–17 days) at steady state, supporting a dosing interval of every 2 weeks. |
| Protein binding | Approximately 95% bound to serum proteins, primarily albumin and immunoglobulins. |
| Volume of Distribution | Volume of distribution at steady state is approximately 5.0–6.0 L, corresponding to 0.07–0.09 L/kg (assuming 70 kg body weight), indicating limited extravascular distribution primarily within plasma volume. |
| Bioavailability | Bioavailability is 100% as ramucirumab is administered only by intravenous infusion; no oral or other form is available. |
| Onset of Action | After intravenous infusion, clinical effects (e.g., tumor response, angiogenesis inhibition) are observed within 2–6 weeks, based on pharmacokinetic steady state and clinical trial results. |
| Duration of Action | Duration of angiogenesis inhibition persists for approximately 2–3 weeks after a single dose, with trough concentrations maintained above therapeutic threshold (20–50 µg/mL) during every-2-week dosing. |
| Molecular Weight | 146609 |
| Action Class | Vascular endothelial growth factor (VEGF) inhibitor |
8 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 2 weeks if used in combination with paclitaxel or FOLFIRI.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (CrCl >=30 mL/min). Not studied in severe renal impairment or dialysis. |
| Liver impairment | No dose adjustment recommended for mild hepatic impairment (Child-Pugh A). For moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, no dosing information available; use with caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No dose adjustment required based on age. Monitor for increased risk of adverse events such as hypertension, hemorrhage, and gastrointestinal perforations. |
| 1st trimester | Avoid use; animal studies show embryo-fetal toxicity including malformations and growth retardation. Human data limited; potential for harm cannot be excluded. |
| 2nd trimester | Avoid use; based on mechanism of action (VEGFR-2 antagonist), may cause fetal harm including impaired angiogenesis and fetal demise. No adequate human studies. |
| 3rd trimester | Avoid use; risk of oligohydramnios, fetal renal impairment, and fetal malformations due to anti-angiogenic effects. Discontinue if pregnancy occurs. |
Clinical note
Comprehensive clinical and safety monograph for CYRAMZA (CYRAMZA).
| Placental transfer | Based on molecular weight (146,609 Da) and mechanism, expected to cross placenta; animal studies confirm fetal exposure via maternal administration. |
| Breastfeeding | Unknown if distributed in human milk; potential for serious adverse reactions in nursing infants (e.g., impaired angiogenesis). Advise against breastfeeding during therapy and for at least 2 months after last dose. |
| Lactation Rating | Avoid |
| Teratogenic Risk | Cyramza (ramucirumab) is a VEGF receptor antagonist. Based on its mechanism of action and animal studies, it can cause fetal harm when administered to pregnant women. In animal reproduction studies, intravenous administration of ramucirumab to pregnant rabbits during organogenesis resulted in embryofetal mortality and reduced fetal weight at exposures less than the recommended human dose. There are no adequate and well-controlled studies in pregnant women. Cyramza is contraindicated in pregnancy. First trimester: High risk of teratogenicity; VEGF inhibition interferes with embryonic vascular development. Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and potential for fetal renal impairment due to anti-angiogenic effects. Avoid use during pregnancy. |
| Fetal Monitoring | Monitor blood pressure every 2 weeks or more frequently if hypertension develops. Monitor urine protein via dipstick or 24-hour urine collection for proteinuria. Assess for signs and symptoms of hemorrhage, including hemoptysis, gastrointestinal bleeding, and intracranial hemorrhage. Monitor thyroid function periodically. In pregnant patients inadvertently exposed, perform serial fetal ultrasound to assess growth and amniotic fluid volume. |
| Fertility Effects | There are no data on the effect of Cyramza on human fertility. Based on animal studies, ramucirumab may impair fertility in females. In female rabbits, administration resulted in increased pre- and post-implantation loss and reduced number of live births. These effects are likely due to VEGF inhibition, which is important for ovarian function and endometrial receptivity. It is recommended to discuss fertility preservation options prior to treatment. |
■ FDA Black Box Warning
Hemorrhage: Severe or fatal hemorrhage, including gastrointestinal hemorrhage, hemoptysis, and intracranial hemorrhage, has occurred. Do not administer in patients with severe bleeding.
| Serious Effects |
None known based on product labeling; however, avoid use in pregnancy and breastfeeding.
| Precautions | Hemorrhage risk: Serious and sometimes fatal hemorrhagic events; permanently discontinue if severe bleeding occurs., Arterial thromboembolic events: Including myocardial infarction and stroke; discontinue if occurs., Gastrointestinal perforation: Fatal cases reported; discontinue if occurs., Impaired wound healing: Interrupt therapy 28 days prior to elective surgery; do not resume until wound fully healed., Hypertension: Monitor blood pressure; treat with antihypertensives; temporarily withhold if severe hypertension occurs., Proteinuria: Monitor urine protein; withhold for >2 g/24h; discontinue if nephrotic syndrome develops., Hypersensitivity/infusion reactions: Permanently discontinue if severe reaction occurs., Thyroid dysfunction: Monitor thyroid function during treatment. |
| Food/Dietary | No specific food interactions are documented. Avoid grapefruit juice if taking concomitant drugs metabolized by CYP3A4 (e.g., simvastatin) due to potential interaction, but no direct interaction with ramucirumab. |
| Clinical Pearls | CYRAMZA (ramucirumab) is a VEGFR-2 antagonist; premedicate with antihistamines and acetaminophen before infusion to reduce infusion-related reactions. Monitor blood pressure closely as hypertension is common; hold for severe hypertension. Avoid use in patients with significant bleeding risk or recent thromboembolic events. Do not administer with platinum-based chemotherapy in NSCLC patients with EGFR or ALK mutations unless progression on targeted therapy. |
| Patient Advice | You may experience high blood pressure; monitor regularly and report symptoms like severe headache or vision changes. · This drug can increase bleeding risk; inform your doctor if you have any unusual bruising or bleeding. · Infusion reactions may occur; you will receive premedication to reduce this risk. · Report any new or worsening shortness of breath, chest pain, or leg swelling as these could be signs of blood clots or heart problems. · Wound healing may be impaired; avoid elective surgery during treatment and inform all healthcare providers you are on this medication. · Effective contraception is required during treatment and for at least 3 months after final dose. |
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