Yervoy

Black Box Warnings

Severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation may involve any organ system

The most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy

Other immune-mediated adverse reactions include ocular manifestations include autoimmune central neuropathy (encephalitis), neurosensory hypoacusis, myositis, polymyositis, ocular myositis, and sarcoidosis

These reactions typically manifest during treatment but may occur weeks to months after discontinuation

If severe immune-mediated reactions occur, permanently discontinue and initiate systemic high-dose corticosteroid therapy

Assess signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries, including liver function

Contraindications

No known contraindications

Cautions

May cause immune-mediated adverse reactions including enterocolitis, hepatitis, dermatitis, neuropathies, endocrinopathies, ocular, and other significant or severe immune-mediated manifestations; may require initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent

Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg/day prednisone or equivalent

Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions

Evaluate liver function tests before each dose; permanently discontinue with Grade 3-4 hepatotoxicity

Monitor thyroid function tests and clinical chemistries prior to each dose

Evaluate at each visit for signs and symptoms of endocrinopathy and institute hormone replacement therapy as needed

Binding antibodies against ipilimumab may develop

Based on its mechanism of action and data from animal studies, can cause fetal harm when administered to a pregnant woman (see Pregnancy); advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ipilimumab

Pregnancy

A Pregnancy Safety Surveillance Study has been established to collect information about pregnancies in women who have received therapy;. healthcare providers are encouraged to enroll patients or have their patients enroll directly by calling 1-844-593-7869

Based on data from animal studies and its mechanism of action, can cause fetal harm when administered to a pregnant woman

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

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus

Animal studies

• In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner
• The effects are likely to be greater during the second and third trimesters of pregnancy

Lactation

Unknown whether distributed in human breast milk

Advise women to discontinue nursing during treatment and for 3 months after the final dose

In monkeys, ipilimumab was present in milk

There are no data to assess the effects on milk production

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Yervoy can cause serious side effects in many parts of your body which can lead to death. These side effects are most likely to begin during treatment; however, side effects can show up months after your last infusion.

These side effects may include:

1. Inflammation of the intestines (colitis) that can cause tears or holes (perforation) in the intestines. Signs and symptoms of colitis may include:
   • diarrhea (loose stools) or more bowel movements than usual
   • blood in your stools or dark, tarry, sticky stools
   • stomach pain (abdominal pain) or tenderness
2. Inflammation of the liver (hepatitis) that can lead to liver failure. Signs and symptoms of hepatitis may include:
   • yellowing of your skin or the whites of your eyes
   • dark urine (tea colored)
   • nausea or vomiting
   • pain on the right side of your stomach
   • bleeding or bruise more easily than normal
3. Inflammation of the skin that can lead to severe skin reaction (toxic epidermal necrolysis). Signs and symptoms of severe skin reactions may include:
   • skin rash with or without itching
   • sores in your mouth
   • your skin blisters and/or peels
4. Inflammation of the nerves that can lead to paralysis. Symptoms of nerve problems may include:
   • unusual weakness of legs, arms, or face
   • numbness or tingling in hands or feet
5. Inflammation of hormone glands (especially the pituitary, adrenal, and thyroid glands) that may affect how these glands work. Signs and symptoms that your glands are not working properly may include:
   • persistent or unusual headaches
   • unusual sluggishness, feeling cold all the time, or weight gain
   • changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness
   • dizziness or fainting
6. Inflammation of the eyes. Symptoms may include:
   • blurry vision, double vision, or other vision problems
   • eye pain or redness

Call your healthcare provider if you have any of these signs or symptoms or they get worse. Do not try to treat symptoms yourself.

Getting medical treatment right away may keep the problem from becoming more serious. Your oncologist may decide to delay or stop.

Before you are given Yervoy, tell your healthcare provider about all your health problems if you:

• have an active condition where your immune system attacks your body (autoimmune disease), such as ulcerative colitis, Crohn’s disease, lupus, or sarcoidosis
• had an organ transplant, such as a kidney transplant
• have liver damage from diseases or drugs
• have any other medical conditions
• are pregnant or plan to become pregnant. Yervoy may cause stillbirth, premature delivery, and/or death of your unborn baby
• are breastfeeding

Tell your healthcare provider about all the medicines you take, including all prescription and non-prescription medicines, steroids or other medicines that lower your immune response, vitamins, and herbal supplements.

Know the medicines you take. Keep a list to show your doctors and pharmacists each time you get a new medicine.

You should not start a new medicine before your talk with the healthcare provider who prescribes you Yervoy.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Yervoy falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

Yervoy can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of Yervoy.

Permanently discontinue Yervoy and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose.

In the U.S.

• Yervoy

Available Dosage Forms:

• Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Monoclonal Antibody

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 ipilimumab injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ipilimumab injection in the elderly.

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:

• Adrenal gland problem or
• Allergic skin reactions (eg, dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis), severe or
• Colitis (inflammation of the intestine) or
• Eye or vision problems (eg, episcleritis, iritis, uveitis) or
• Guillain-Barré syndrome or
• Hemolytic anemia or
• Hepatitis (inflammation of the liver) or
• Hyperthyroidism (overactive thyroid) or
• Hypopituitarism (low levels of pituitary hormone) or
• Hypothyroidism (underactive thyroid) or
• Intestinal or bowel perforation (a hole in the bowel) or
• Meningitis (inflammation of the brain) or
• Myasthenia gravis (severe muscle weakness) or
• Nephritis (inflammation of the kidney) or
• Pancreatitis (inflammation of the pancreas) or
• Pericarditis (inflammation of the heart) or
• Peripheral neuropathy (nerve problem in arms and legs) or
• Pneumonitis (inflammation of the lung)—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.
• This medicine may be used with another drug called nivolumab. Some side effects that can happen may happen more often if Yervoy is used with nivolumab, If you are also using nivolumab, talk with your doctor about the risks and side effects that may happen.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• 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 Yervoy and for 3 months after care ends.
• If you get pregnant while taking this medicine or within 3 months after your last dose, call your doctor right away.

   Recommended Dosing for Unresectable or Metastatic Melanoma

The recommended dose of Yervoy is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a maximum of 4 doses. In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose [see Clinical Studies (14.1)].

   Recommended Dosing for Adjuvant Treatment of Melanoma

The recommended dose of Yervoy is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years [see Clinical Studies (14.2)]. In the event of toxicity, doses are omitted, not delayed.

   Recommended Dose Modifications

Table 1:     Recommended Treatment Modifications for Immune-Mediated Adverse Reactions of Yervoy

Target/Organ System	Adverse Reaction (CTCAE v3)	Treatment Modification
Endocrine	Symptomatic endocrinopathy	Withhold Yervoy Resume Yervoy in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day.
	• Symptomatic reactions lasting 6 weeks or longer • Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day	Permanently discontinue Yervoy
Ophthalmologic	Grade 2 through 4 reactions • not improving to Grade 1 within 2 weeks while receiving topical therapy or • requiring systemic treatment	Permanently discontinue Yervoy
All Other	Grade 2	Withhold Yervoy Resume Yervoy in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day.
	• Grade 2 reactions lasting 6 weeks or longer • Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day • Grade 3 or 4	Permanently discontinue Yervoy

   Preparation and Administration

• Do not shake product. • Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles. Preparation of Solution • Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion. • Withdraw the required volume of Yervoy and transfer into an intravenous bag. • Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion. • Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). • Discard partially used vials or empty vials of Yervoy. Administration Instructions • Do not mix Yervoy with, or administer as an infusion with, other medicinal products. • Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose. • Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.

Injection: 50 mg/10 mL (5 mg/mL)

Injection: 200 mg/40 mL (5 mg/mL)

Yervoy (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.

Yervoy is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution for intravenous infusion, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.

Yervoy is available as follows:

Carton Contents	NDC
One 50 mg vial (5 mg/mL), single-use vial	NDC 0003-2327-11
One 200 mg vial (5 mg/mL), single-use vial	NDC 0003-2328-22

Store Yervoy under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials from light.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Inform patients of the potential risk of immune-mediated adverse reactions [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)].

Embryo-fetal Toxicity

Advise female patients that Yervoy can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Yervoy and for 3 months after the last dose. Advise female patients to contact their healthcare provider with a known or suspected pregnancy. Advise females who may have been exposed to Yervoy during pregnancy to contact Bristol-Myers Squibb at 1-800-721-5072 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].

Advise patients that there is a Pregnancy Safety Surveillance Study that monitors pregnancy outcomes in women exposed to Yervoy during pregnancy, and they can be enrolled by calling 1-844-593-7869 [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with Yervoy and for 3 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713

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MEDICATION GUIDE Yervoy® (yur-voi) (ipilimumab) injection
What is the most important information I should know about Yervoy? Yervoy can cause serious side effects in many parts of your body which can lead to death. These problems may happen anytime during treatment with Yervoy or after you have completed treatment. Call your healthcare provider right away if you develop any of these signs or symptoms or they get worse. Do not try to treat symptoms yourself. Intestinal problems (colitis) that can cause tears or holes (perforation) in the intestines. Signs and symptoms of colitis may include: • diarrhea (loose stools) or more bowel movements than usual • blood in your stools or dark, tarry, sticky stools • stomach pain (abdominal pain) or tenderness Liver problems (hepatitis) that can lead to liver failure. Signs and symptoms of hepatitis may include:
• yellowing of your skin or the whites of your eyes • dark urine (tea colored) • nausea or vomiting		• pain on the right side of your stomach • bleeding or bruise more easily than normal
Skin problems that can lead to severe skin reaction. Signs and symptoms of severe skin reactions may include:
• skin rash with or without itching	• sores in your mouth		• your skin blisters or peels
Nerve problems that can lead to paralysis. Symptoms of nerve problems may include:
• unusual weakness of legs, arms, or face		• numbness or tingling in hands or feet
Hormone gland problems (especially the pituitary, adrenal, and thyroid glands). Signs and symptoms that your glands are not working properly may include:
• persistent or unusual headaches • unusual sluggishness • feeling cold all the time • weight gain		• changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness • dizziness or fainting
Eye problems. Symptoms may include:
• blurry vision, double vision, or other vision problems		• eye pain or redness
Getting medical treatment right away may keep the problem from becoming more serious. Your healthcare provider will check you for these problems during treatment with Yervoy. Your healthcare provider may treat you with corticosteroid medicines. Your healthcare provider may need to delay or completely stop treatment with Yervoy if you have severe side effects.
What is Yervoy? Yervoy is a prescription medicine used to treat a kind of skin cancer called melanoma. Yervoy may be used: • in adults and children 12 years and older when melanoma has spread or cannot be removed by surgery • to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery It is not known if Yervoy is safe and effective in children less than 12 years of age.
Before you receive Yervoy, tell your healthcare provider about all your medical conditions, including if you: • have immune system problems (autoimmune disease), such as ulcerative colitis, Crohn’s disease, lupus, or sarcoidosis • have had an organ transplant • have liver problems • are pregnant or plan to become pregnant. Yervoy can harm your unborn baby. o Females who are able to become pregnant should use effective birth control during treatment with Yervoy and for 3 months after the last dose of Yervoy. o If you become pregnant or think you are pregnant, tell your healthcare provider right away. You or your healthcare provider should contact Bristol-Myers Squibb at 1-800-721-5072 as soon as you become aware of the pregnancy. o Pregnancy Safety Surveillance Study: Females who become pregnant during treatment with Yervoy are encouraged to enroll in a Pregnancy Safety Surveillance Study. The purpose of this study is to collect information about the health of you and your baby. You or your healthcare provider can enroll you in the Pregnancy Safety Surveillance Study by calling 1-844-593-7869. • are breastfeeding or plan to breastfeed. It is not known if Yervoy passes into your breast milk. o Do not breastfeed during treatment with Yervoy and for 3 months after the last dose of Yervoy. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive Yervoy? • Yervoy is given to you into your vein through an intravenous (IV) line over 90 minutes. • Your healthcare provider will decide how many treatments you will need. • Your healthcare provider will do blood tests before starting and during treatment with Yervoy. • It is important for you to keep all appointments with your healthcare provider. Call your healthcare provider if you miss an appointment. There may be special instructions for you.
What are the possible side effects of Yervoy? Yervoy can cause serious side effects. See “What is the most important information I should know about Yervoy?” The most common side effects of Yervoy include:
• tiredness • diarrhea • itching • rash • nausea • vomiting		• headache • weight loss • fever • decreased appetite • difficulty falling or staying asleep
These are not all of the possible side effects of Yervoy. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bristol-Myers Squibb at 1-800-721-5072.
General information about the safe and effective use of Yervoy. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your healthcare provider or pharmacist for information about Yervoy that is written for healthcare professionals.
What are the ingredients of Yervoy? Active ingredient: ipilimumab Inactive ingredients: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 80, sodium chloride, tris hydrochloride, and Water for Injection, USP Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA For more information, call 1-800-321-1335 U.S. License No. 1713 [print code]

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: July 2017

Yervoy (ipilimumab) is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Yervoy is used to treat melanoma (skin cancer) that cannot be treated with surgery, or that has spread to other parts of the body.

Yervoy is also used to prevent melanoma from coming back after surgery, including lymph node removal.