Cyramza (Ramucirumab)

CYRAMZA^® is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist indicated:

• as a single agent or in combination with paclitaxel, for treatment of adults with advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. (
  1.1 Gastric Cancer

  CYRAMZA^®, as a single agent or in combination with paclitaxel, is indicated for the treatment of adults with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
  )
• in combination with erlotinib, for first-line treatment of adults with metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. (
  1.2 Non-Small Cell Lung Cancer

  CYRAMZA, in combination with erlotinib, is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

  CYRAMZA, in combination with docetaxel, is indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.
  )
• in combination with docetaxel, for treatment of adults with metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. (
  1.2 Non-Small Cell Lung Cancer

  CYRAMZA, in combination with erlotinib, is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

  CYRAMZA, in combination with docetaxel, is indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.
  )
• in combination with FOLFIRI, for the treatment of adults with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. (
  1.3 Colorectal Cancer

  CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil), is indicated for the treatment of adults with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
  )
• as a single agent, for the treatment of adults with hepatocellular carcinoma in patients who have an alpha fetoprotein of ≥400 ng/mL and have been treated with sorafenib. (
  1.4 Hepatocellular Carcinoma

  CYRAMZA, as a single agent, is indicated for the treatment of adults with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.
  )

• For intravenous infusion only. Do not administer as an intravenous push or bolus. (
  2.7 Preparation and Administration

  Preparation

  • Visually inspect vials for particulate matter and discoloration. Discard if particulate matter or discolorations are identified.
  • Calculate the dose and the required volume of CYRAMZA needed for the calculated dose.
  • Withdraw the required volume of CYRAMZA and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL.
    Do not use dextrose containing solutions
    .
  • Do not shake.
    Gently invert the container to ensure adequate mixing.
  • Do not dilute
    with other solutions or co-infuse with other electrolytes or medications.
  • Do not freeze
    . Store diluted solution for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C [77°F]).
  • Discard any unused portion of CYRAMZA.

  Administration

  • Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Discard if particulate matter or discolorations are identified.
  • Do not administer CYRAMZA as an intravenous push or bolus.
  • Administer diluted CYRAMZA solution via infusion pump through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended.
  • Flush the line with sterile 0.9% Sodium Chloride Injection at the end of the infusion.
  )
• Premedicate before each infusion. (
  2.1 Premedication

  • Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride)
    [see Warnings and Precautions ]
    .
  • For patients who have experienced a Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each CYRAMZA infusion
    [see Dosage and Administration ]
    .
  )
• Gastric Cancer
  : Administer CYRAMZA 8 mg/kg every 2 weeks as a single agent or in combination with weekly paclitaxel. (
  2.2 Recommended Dosage for Gastric Cancer

  • The recommended dosage of CYRAMZA, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
  • When given in combination with paclitaxel, administer CYRAMZA prior to administration of paclitaxel.
  • Refer to the prescribing information for paclitaxel for dosage information.
  )
• Non-Small Cell Lung Cancer
  :
  • Administer CYRAMZA 10 mg/kg every 2 weeks with daily erlotinib. (
    2.3 Recommended Dosage for Non-Small Cell Lung Cancer

    EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – CYRAMZA in Combination with Erlotinib

    • The recommended dosage of CYRAMZA is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
    • Refer to the prescribing information for erlotinib for dosage information.

    Disease Progression On Or After Platinum-based Chemotherapy – CYRAMZA in Combination with Docetaxel

    • The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
    • Refer to the prescribing information for docetaxel for dosage information.
    )
  • Administer CYRAMZA 10 mg/kg on Day 1 of a 21-day cycle prior to docetaxel. (
    2.3 Recommended Dosage for Non-Small Cell Lung Cancer

    EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – CYRAMZA in Combination with Erlotinib

    • The recommended dosage of CYRAMZA is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
    • Refer to the prescribing information for erlotinib for dosage information.

    Disease Progression On Or After Platinum-based Chemotherapy – CYRAMZA in Combination with Docetaxel

    • The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
    • Refer to the prescribing information for docetaxel for dosage information.
    )
• Colorectal Cancer
  : Administer CYRAMZA 8 mg/kg every 2 weeks prior to FOLFIRI. (
  2.4 Recommended Dosage for Colorectal Cancer

  • The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
  • Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information.
  )
• Hepatocellular Carcinoma
  : Administer CYRAMZA 8 mg/kg every 2 weeks. (
  2.5 Recommended Dosage for Hepatocellular Carcinoma

  • The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
  )

Injection: 100 mg/10 mL (10 mg/mL) or 500 mg/50 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial

• Lactation
  : Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There is no information on the presence of ramucirumab in human milk or its effects on the breastfed child or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.
  )

• Hemorrhage
  : CYRAMZA increases the risk of hemorrhage and gastrointestinal hemorrhage, including severe and fatal events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. (
  5.1 Hemorrhage

  CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5%

  [see Adverse Reactions ]

  .

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

  Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin, or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown.

  Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding

  [see Dosage and Administration ]

  .
  )
• Gastrointestinal Perforations
  : CYRAMZA increases the risk of gastrointestinal perforation, which can be fatal. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. (
  5.2 Gastrointestinal Perforations

  CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%

  [see Adverse Reactions ]

  .

  Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation

  [see Dosage and Administration ]

  .
  )
• Impaired Wound Healing
  : Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established. (
  5.3 Impaired Wound Healing

  Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2 antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.

  Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established

  [see Dosage and Administration ]

  .
  )
• Arterial Thromboembolic Events (ATEs)
  : Serious and sometimes fatal ATEs can occur with CYRAMZA. Permanently discontinue CYRAMZA in patients who experience an ATE. (
  5.4 Arterial Thromboembolic Events

  Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%

  [see Adverse Reactions ]

  .

  Permanently discontinue CYRAMZA in patients who experience an ATE

  [see Dosage and Administration ]

  .
  )
• Hypertension
  : Monitor blood pressure and treat hypertension. Withhold CYRAMZA for severe hypertension. Permanently discontinue CYRAMZA for hypertension that cannot be controlled with antihypertensive therapy and for hypertensive crisis or hypertensive encephalopathy. (
  5.5 Hypertension

  An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%

  [see Adverse Reactions ]

  . In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.

  Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy

  [see Dosage and Administration ]

  .
  )
• Infusion-Related Reactions (IRR)
  : Monitor for signs and symptoms during infusion. Reduce the infusion rate for Grade 1 or 2 IRR and permanently discontinue for Grade 3 or 4 IRR. (
  5.6 Infusion-Related Reactions

  Infusion-related reactions (IRR), including severe and life-threatening IRR, occurred in CYRAMZA clinical trials. The majority of IRR across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRR 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. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR ranged from <1-9%. Grade 3-5 IRR incidence was <1%

  [see Adverse Reactions ]

  .

  Premedicate prior to each CYRAMZA infusion

  [see Dosage and Administration ]

  . Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR

  [see Dosage and Administration ]

  .
  )
• Worsening of Pre-existing Hepatic Impairment
  : New onset or worsening encephalopathy, ascites or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. (
  5.7 Worsening of Pre-existing Hepatic Impairment

  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.

  Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%)

  [see Adverse Reactions ]

  .
  )
• Posterior Reversible Encephalopathy Syndrome
  : Permanently discontinue CYRAMZA. (
  5.8 Posterior Reversible Encephalopathy Syndrome

  Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients enrolled in six clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.

  Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death

  [see Dosage and Administration ]

  .
  )
• Proteinuria Including Nephrotic Syndrome
  : Monitor for proteinuria. Withhold CYRAMZA for urine protein levels greater than or equal to 2 g per 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 g per 24 hours or nephrotic syndrome. (
  5.9 Proteinuria Including Nephrotic Syndrome

  Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%

  [see Adverse Reactions ]

  .

  Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. 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 ]

  .
  )
• Thyroid Dysfunction
  : Monitor thyroid function during treatment. (
  5.10 Thyroid Dysfunction

  Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism

  [see Adverse Reactions ]

  . Monitor thyroid function during treatment with CYRAMZA.
  )
• Embryo-Fetal Toxicity
  : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.11 Embryo-Fetal Toxicity

  Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal 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 3 months after the last dose

  [see Use in Specific Populations ]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on its mechanism of action

  [see Clinical Pharmacology ]

  , CYRAMZA can cause fetal harm when administered to a pregnant woman. There are no available data on CYRAMZA use in pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise a pregnant woman of the potential risk to a fetus.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Data

  Animal Data

  No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryo-fetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.
  ,
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating CYRAMZA

  [see Use in Specific Populations ]

  .

  Contraception

  Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Females

  Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

  Infertility

  Females

  Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility

  [see Nonclinical Toxicology ]

  .
  )