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CYRAMZA (ramucirumab) injection
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CYRAMZA safely and effectively. See full prescribing information for CYRAMZA.
CYRAMZA (ramucirumab) injection, for intravenous use
Initial U.S. Approval: 2014
WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING
See full prescribing information for complete boxed warning.
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Hemorrhage: CYRAMZA increased the risk of hemorrhage, and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. (2.3, 5.1)
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Gastrointestinal Perforation: Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. (2.3, 5.5)
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Impaired Wound Healing: Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications (2.3, 5.6)
RECENT MAJOR CHANGES
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Indications and Usage |
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Gastric Cancer (1.1) |
11/2014 |
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Non-Small Cell Lung Cancer (1.2) |
12/2014 |
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Colorectal Cancer (1.3) |
04/2015 |
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Dosage and Administration: |
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Recommended Dose and Schedule (2.1) |
04/2015 |
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Dose Modifications (2.3) |
12/2014 |
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Warnings and Precautions: |
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Hemorrhage (5.1) |
04/2015 |
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Hypertension (5.3) |
12/2014 |
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Gastrointestinal Perforations (5.5) |
04/2015 |
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Impaired Wound Healing (5.6) |
04/2015 |
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Proteinuria Including Nephrotic Syndrome (5.9) |
04/2015 |
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Thyroid Dysfunction (5.10) |
04/2015 |
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Embryofetal Toxicity (5.11) |
04/2015 |
INDICATIONS AND USAGE
CYRAMZA® is a human vascular endothelial growth factor receptor 2 antagonist indicated
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as a single agent or in combination with paclitaxel, for treatment of advanced gastric or gastro-esophageal junction adenocarcinoma, with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. (1.1)
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in combination with docetaxel, for treatment of 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)
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in combination with FOLFIRI, for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. (1.3)
DOSAGE AND ADMINISTRATION
For intravenous infusion only. Do not administer as an intravenous push or bolus. (2)
Gastric Cancer
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The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks. (2.1, 2.2, 2.3)
Non-Small Cell Lung Cancer
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Administer CYRAMZA at 10 mg/kg intravenously on day 1 of a 21-day cycle prior to docetaxel infusion. (2.1, 2.2, 2.3)
Colorectal Cancer
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Administer CYRAMZA at 8 mg/kg intravenously every 2 weeks, prior to FOLFIRI administration. (2.1, 2.2, 2.3)
DOSAGE FORMS AND STRENGTHS
Injection:
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100 mg/10 mL (10 mg per mL) solution, single-dose vial (3)
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500 mg/50 mL (10 mg per mL) solution, single-dose vial (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
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Arterial Thromboembolic Events (ATEs): Serious, sometimes fatal ATEs have been reported in clinical trials. Discontinue CYRAMZA for severe ATEs. (5.2)
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Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend CYRAMZA for severe hypertension. Discontinue CYRAMZA for hypertension that cannot be medically controlled. (5.3)
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Infusion-Related Reactions: Monitor for signs and symptoms during infusion. (5.4)
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Impaired Wound Healing: Withhold CYRAMZA prior to surgery. (5.6)
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Clinical Deterioration in Patients with Cirrhosis: New onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. (5.7)
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Reversible Posterior Leukoencephalopathy Syndrome: Discontinue CYRAMZA. (5.8)
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Proteinuria Including Nephrotic Syndrome: Monitor proteinuria. Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g/24 hours or for nephrotic syndrome. (5.9)
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Thyroid Dysfunction: Monitor thyroid function during treatment with CYRAMZA. (5.10)
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Embryofetal Risk: Can cause fetal harm. (5.11)
ADVERSE REACTIONS
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The most common adverse reactions observed in single-agent CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. (6.1)
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The most common adverse reactions observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. (6.1)
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The most common adverse reactions observed in patients treated with CYRAMZA plus docetaxel at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. (6.1)
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The most common adverse reactions observed in patients treated with CYRAMZA plus FOLFIRI at a rate of ≥30% and ≥2% higher than placebo plus FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
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Lactation: Breastfeeding is not advised. (8.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 5/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Gastric Cancer
CYRAMZA® as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
1.2 Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) 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.
1.3 Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
2 DOSAGE AND ADMINISTRATION
Do not administer CYRAMZA as an intravenous push or bolus.
2.1 Recommended Dose and Schedule
Gastric Cancer
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The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
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When given in combination, administer CYRAMZA prior to administration of paclitaxel.
Non-Small Cell Lung Cancer
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The recommended dose 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. Continue CYRAMZA until disease progression or unacceptable toxicity.
Colorectal Cancer
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The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue CYRAMZA until disease progression or unacceptable toxicity.
2.2 Premedication
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Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride).
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For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion [see Dosage and Administration (2.3)].
2.3 Dose Modifications
Infusion-Related Reactions (IRR)
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Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs.
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Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)].
Hypertension
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Interrupt CYRAMZA for severe hypertension until controlled with medical management.
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Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy [see Warnings and Precautions (5.3)].
Proteinuria
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Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see Table 1) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose (see Table 1) once the urine protein level returns to <2 g/24 hours.
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Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].
Wound Healing Complications
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Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed [see Warnings and Precautions (5.6)].
Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding
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Permanently discontinue CYRAMZA [see Warnings and Precautions (5.1, 5.2, 5.5)].
For toxicities related to paclitaxel, docetaxel, or the components of FOLFIRI, refer to the current prescribing information.
2.4 Preparation for Administration
Inspect vial contents for particulate matter and discoloration prior to dilution [see Description (11)]. Discard the vial, if particulate matter or discolorations are identified. 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.
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Calculate the dose and the required volume of CYRAMZA needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL solution of CYRAMZA.
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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.
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Gently invert the container to ensure adequate mixing.
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DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications.
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Store diluted infusion 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]).
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Discard vial with any unused portion of CYRAMZA.
2.5 Administration
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Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution.
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Administer diluted CYRAMZA infusion via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.
3 DOSAGE FORMS AND STRENGTHS
Injection:
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100 mg/10 mL (10 mg per mL) solution, single-dose vial
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500 mg/50 mL (10 mg per mL) solution, single-dose vial
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 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 d |
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