Cyramza

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you are taking.

While there have been no formal drug interaction studies on Cyramza, some medicines may interfere with this treatment.

Cyramza and Grapefruit Juice

You should not eat grapefruit or drink grapefruit juice while receiving Cyramza, as there are known interactions.

Mechanism of Action

Vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D

As a result, ramucirumab inhibits ligand-stimulated activation of VEGF2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells

Absorption

Minimum concentration levels: 50 mcg/mL (range: 6-228 mcg/mL) after 3rd dose; 74 mcg/mL (range: 14-234 mcg/mL) after 6th dose

Pharmacogenomics

NSCLC: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab

Cyramza is a prescription medication used to treat advanced gastric cancer or gastro-esophageal junction adenocarcinoma, as a single-agent after prior fluoropyrimidine or platinum containing chemotherapy. Cyramza is also approved to treat metastatic colorectal cancer when used in combination with a certain chemotherapy regimen. 

Cyramza is also approved for use in combination with docetaxel to treat patients with metastatic non-small cell lung cancer (NSCLC).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Cyramza crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. It is generally not recommended to breastfeed during Cyramza treatment.

• Patients will be given medications such as diphenhydramine before administration of Cyramza.
• For patients who have experienced a Grade 1 or 2 infusion reaction, may be premedicated with dexamethasone (or equivalent) and acetaminophen prior to administration of Cyramza.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with ramucirumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Storage

Parenteral

2–8°C in original carton to protect from light.1 Do not freeze or shake.1

Diluted solution: Room temperature (<25°C) for up to 4 hours or 2–8°C for up to 24 hours after dilution.1 Do not freeze or shake.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• Binds specifically to VEGFR-2 and blocks the interaction of VEGFR-2 with its ligands (VEGFR-A, VEGFR-C, and VEGFR-D), resulting in inhibition of VEGFR-stimulated activation of both VEGFR-2 and downstream signaling pathways.1 8 9

• The VEGFR signaling pathway plays an important role in tumor angiogenesis, tumor growth, and metastatic spread.4 5 6 9

• Binding of ramucirumab to VEGFR-2 blocks ligand-induced phosphorylation and activation of the receptor in vitro.1 4

• Inhibits VEGFR-mediated endothelial cell proliferation and migration in vitro.4

• Inhibits angiogenesis in vivo.1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of ramucirumab injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of ramucirumab injection have not been performed in the geriatric population, no geriatric-specific problems have been documented to date.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood clotting problems (eg, heart attack or stroke) or
• Cirrhosis or
• Hypertension (high blood pressure) or
• Kidney disease or
• Thyroid problems—Use with caution. May make these conditions worse.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Blood clots have happened with Cyramza. Sometimes, blood clots like heart attack and stroke have been deadly. Talk with the doctor.
• High blood pressure has happened with this medicine. Have your blood pressure checked as you have been told by your doctor.
• Some patients have very bad side effects during the infusion. Tell your doctor if you have any bad effects during the infusion.
• Other drugs may be given to help with infusion side effects.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have your urine checked as you have been told by your doctor.
• This medicine may cause liver problems to get worse in people who already have liver problems. Talk with your doctor if you have liver problems .
• A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with Cyramza. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
• This medicine may cause fertility problems. This may affect being able to have children. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking this medicine and for 3 months after care ends.
• If you get pregnant while taking Cyramza or within 3 months after your last dose, call your doctor right away.

Injection:

• 100 mg/10 mL (10 mg per mL) solution, single-dose vial
• 500 mg/50 mL (10 mg per mL) solution, single-dose vial

Hemorrhage

Cyramza increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for Cyramza and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for Cyramza plus paclitaxel and 2.4% for placebo plus paclitaxel.

Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in Cyramza-treated patients with gastric tumors receiving NSAIDs is unknown.

In Study 3, the incidence of severe bleeding was 2.4% for Cyramza plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.

In Study 4, the incidence of severe bleeding was 2.5% for Cyramza plus FOLFIRI and 1.7% for placebo plus FOLFIRI.

Permanently discontinue Cyramza in patients who experience severe bleeding [see Dosage and Administration (2.3)].

Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received Cyramza as a single agent for gastric cancer in Study 1. Permanently discontinue Cyramza in patients who experience a severe ATE [see Dosage and Administration (2.3)].

Hypertension

An increased incidence of severe hypertension occurred in patients receiving Cyramza as a single agent (8%) as compared to placebo (3%), in patients receiving Cyramza plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving Cyramza plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving Cyramza plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%).

Control hypertension prior to initiating treatment with Cyramza. Monitor blood pressure every two weeks or more frequently as indicated during treatment.

Temporarily suspend Cyramza for severe hypertension until medically controlled. Permanently discontinue Cyramza if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.3)].

Infusion-Related Reactions

Prior to the institution of premedication recommendations across clinical trials of Cyramza, IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second Cyramza infusion. Symptoms of IRRs 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.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue Cyramza for Grade 3 or 4 IRRs [see Dosage and Administration (2.3)].

Gastrointestinal Perforations

Cyramza is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received Cyramza as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforation was also increased in patients that received Cyramza plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for Cyramza plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for Cyramza plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue Cyramza in patients who experience a gastrointestinal perforation [see Dosage and Administration (2.3)].

Impaired Wound Healing

Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Cyramza has not been studied in patients with serious or non-healing wounds. Cyramza, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue Cyramza therapy in patients with impaired wound healing.

Withhold Cyramza prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue Cyramza until the wound is fully healed [see Dosage and Administration (2.3)].

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Cyramza. Use Cyramza in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with Cyramza. Confirm the diagnosis of RPLS with MRI and discontinue Cyramza in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

In Study 4, severe proteinuria occurred more frequently in patients treated with Cyramza plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with Cyramza plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI.

Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during Cyramza therapy.

Withhold Cyramza for urine protein levels that are 2 or more grams over 24 hours. Reinitiate Cyramza at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue Cyramza for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome [see Dosage and Administration (2.3)].

Thyroid Dysfunction

Monitor thyroid function during treatment with Cyramza. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the Cyramza plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity

Based on its mechanism of action, Cyramza can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cyramza and for at least 3 months after the last dose of Cyramza [see Use in Specific Populations (8.1, 8.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity.

Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.

Animal Toxicology and/or Pharmacology

Adverse effects in the kidney (glomerulonephritis) occurred in monkeys at doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent).

A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.

How Supplied

Cyramza is supplied in single-dose vials as a sterile, preservative-free solution.

• NDC 0002-7669-01
  100 mg/10 mL (10 mg/mL), individually packaged in a carton
• NDC 0002-7678-01
  500 mg/50 mL (10 mg/mL), individually packaged in a carton

Storage and Handling

Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. DO NOT FREEZE OR SHAKE the vial.