Ramucirumab

Before taking ramucirumab, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to ramucirumab or to any of its ingredients
• have or have had hypertension

• have liver problems
• have had an arterial thromboembolic event
• have or have had gastrointestinal perforation
• if you are going to have surgery
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

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

It is not known if ramucirumab 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 ramucirumab treatment.

• Patients will be given medications such as diphenhydramine before administration of ramucirumab.
• 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 ramucirumab.

Ramucirumab is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Ramucirumab is used to treat stomach cancer, colorectal cancer, or non-small cell lung cancer that has spread to other parts of the body. Ramucirumab may be given alone or in combination with other cancer medicines.

Ramucirumab is usually given after other cancer medicines have been tried without success.

Ramucirumab may also be used for purposes not listed in this medication guide.

You should not use ramucirumab if you are allergic to it, or if you have:

• uncontrolled high blood pressure.

To make sure ramucirumab is safe for you, tell your doctor if you have:

• high blood pressure;

• an unhealed incision from recent surgery;

• a thyroid disorder;

• if you take any NSAIDs (nonsteroidal anti-inflammatory drugs), such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This medicine can harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine. Ramucirumab may affect fertility (your ability to have children).

Use birth control to prevent pregnancy while you are receiving ramucirumab, and for at least 3 months after your treatment ends.

It is not known whether ramucirumab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

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

Gastric Cancer

Used alone or in combination with paclitaxel for the treatment of advanced or metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, that has progressed during or following fluoropyrimidine- or platinum-based chemotherapy1 2 11 (designated an orphan drug by FDA for treatment of this cancer7 ).

Improved overall and progression-free survival demonstrated with ramucirumab compared with placebo; improved overall and progression-free survival and objective response rate demonstrated with ramucirumab-paclitaxel compared with placebo-paclitaxel.1 2 11

Non-small Cell Lung Cancer (NSCLC)

Used in combination with docetaxel for the treatment of metastatic NSCLC that has progressed during or following platinum-based chemotherapy.1 12 Patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive tumors also should have documented disease progression during or following an FDA-labeled anti-EGFR or anti-ALK therapy prior to initiating therapy with ramucirumab.1

Improved overall and progression-free survival and objective response rate demonstrated with ramucirumab-docetaxel compared with placebo-docetaxel.1 12

Colorectal Cancer

Used in combination with fluorouracil, leucovorin (folinic acid), and irinotecan (the combination of fluorouracil, leucovorin, and irinotecan is hereafter referred to as FOLFIRI in this monograph) for the treatment of metastatic colorectal cancer that has progressed during or following combination therapy with oxaliplatin, bevacizumab, and a fluoropyrimidine.1 14

Improved overall and progression-free survival demonstrated with ramucirumab-FOLFIRI compared with placebo-FOLFIRI therapy.1 14

Absorption

Special Populations

Hepatic impairment: No clinically meaningful differences in average steady-state ramucirumab concentrations observed between patients with mild (total bilirubin concentration >1 to 1.5 times the ULN and any AST concentration) or moderate (total bilirubin concentration >1.5 to 3 times the ULN and any AST concentration) hepatic impairment and those with normal hepatic function.1 No formal pharmacokinetic studies in patients with severe (total bilirubin concentration >3 times the ULN and any AST concentration) hepatic impairment.1

Renal impairment: No clinically meaningful differences in average steady-state ramucirumab concentrations observed between patients with mild (Clcr 60–89 mL/minute), moderate (Clcr 30–59 mL/minute), or severe (Clcr 15–29 mL/minute) renal impairment and those with normal renal function.1

Elimination

Half-life

15 days in patients with advanced or metastatic gastric adenocarcinoma receiving 8 mg/kg every 2 weeks.1

23 days in patients with metastatic NSCLC receiving 10 mg/kg every 3 weeks.1

Special Populations

Age, gender, and race do not substantially affect pharmacokinetics of ramucirumab.1 9

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Dilute total dose in NS 250 mL prior to administration (the manufacturer recommends a final volume of 250 mL). Do not use dextrose containing solutions. Invert gently to mix thoroughly; do not shake. Discard unused portion of the vial.

As reported with monotherapy. Frequency not always defined.

Cardiovascular: Hypertension (16%; grades 3/4: 8%), arterial thrombosis (including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia; 2%)

Central nervous system: Headache (9%)

Dermatologic: Skin rash (4%)

Endocrine & metabolic: Hyponatremia (6%)

Gastrointestinal: Diarrhea (14%), intestinal obstruction (2%)

Genitourinary: Proteinuria (8% to 17%; grade ≥3: 1%)

Hematologic & oncologic: Decreased red blood cells (requiring transfusion; 11%), neutropenia (5%), anemia (4%), hemorrhage (2% to 4%)

Immunologic: Antibody development (3%; neutralizing: 1%)

Respiratory: Epistaxis (5%)

Miscellaneous: Infusion related reaction (≤16%; reactions minimized with premedications)

<1% and frequency not defined (Limited to important or life-threatening): Gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome

Applies to ramucirumab: intravenous solution

Along with its needed effects, ramucirumab may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking ramucirumab:

• Back pain or spasms
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• chills
• confusion
• convulsions
• decreased urine output
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• feeling unusually cold
• headache
• increased thirst
• muscle pain or cramps
• nausea or vomiting
• nervousness
• pounding in the ears
• redness of the face, neck, arms, and occasionally, upper chest
• shakiness in the legs, arms, hands, or feet
• shivering
• sweating
• swelling of the face, ankles, or hands
• trembling or shaking of the hands or feet
• unusual tiredness or weakness

• Abdominal or stomach pain, cramping, or burning
• bleeding gums
• bloody nose
• cough
• coughing up blood
• difficulty with breathing or swallowing
• dizziness
• fever
• inability to speak
• increased menstrual flow or vaginal bleeding
• low blood pressure or pulse
• lower back or side pain
• nosebleeds
• pain in the chest, groin, or legs, especially calves of the legs
• pain or discomfort in the arms, jaw, back, or neck
• painful or difficult urination
• pale skin
• paralysis
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• severe constipation
• severe headaches of sudden onset
• severe numbness, especially on one side of the face or body
• slurred speech
• sore throat
• sudden loss of coordination
• sudden onset of shortness of breath for no apparent reason
• sudden onset of slurred speech
• sudden vision changes
• sweating
• temporary blindness
• ulcers, sores, or white spots in the mouth
• unconsciousness
• unusual bleeding or bruising
• vomiting of material that looks like coffee grounds, severe and continuing

Some side effects of ramucirumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea

8 mg/kg IV over 60 minutes every 2 weeks

Comments:
--This drug should be administered prior to administration of FOLFIRI.

-Continue use until disease progression or unacceptable toxicity.
-Do not administer this drug as an IV push or bolus.
-Prior to each drug infusion, all patients should be premedicated with an IV histamine H1 antagonist (e.g., diphenhydramine).
-Patients who have developed a Grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen prior to each drug infusion.

Use: This drug, 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.

US BOXED WARNING:
-Ramucirumab increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.
-Permanently discontinue use in patients who experience severe bleeding.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.