Yervoy 5 mg/ml concentrate for solution for infusion: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

YERVOY 5 mg/ml concentrate for solution for infusion

ipilimumab

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

Keep this leaflet, as you may need to read it again.
If you have any questions, ask your doctor.
If you experience any adverse reactions, consult your doctor, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

What YERVOY is and what it is used for
What you need to know before using YERVOY
How to use YERVOY
Possible side effects
How to store YERVOY
Contents of the pack and other information

1. What YERVOY is and what it is used for

YERVOY contains the active substance ipilimumab, a protein that helps your immune system attack and destroy cancer cells through your immune cells.

Ipilimumab is used alone only to treat advanced melanoma (a type of skin cancer) in adults and adolescents aged 12 years and older.

Ipilimumab in combination with nivolumab is used to treat:

advanced melanoma (a type of skin cancer) in adults and adolescents aged 12 years and older
advanced renal cell carcinoma (advanced kidney cancer) in adults
malignant pleural mesothelioma (a type of cancer affecting the lining of the lungs) in adults
advanced colorectal cancer (cancer of the colon or rectum) in adults
advanced esophageal cancer (cancer of the tube connecting the mouth to the stomach) in adults
unresectable or advanced hepatocellular carcinoma (liver cancer) in adults.

Ipilimumab in combination with nivolumab and chemotherapy is used to treat advanced non-small cell lung cancer (a type of lung cancer) in adults.

Since YERVOY may be given in combination with other anticancer medicines, it is important that you also read the package leaflet for these other medicines. If you have any questions about these medicines, please consult your doctor.

2. What you need to know before using YERVOY

Do not receive YERVOY

if you are allergic to ipilimumab or to any of the other components of this medicine (listed in section 6, "Contents of the container and other information"). Consult your doctor if you are unsure.

Warnings and precautions

Talk to your doctor before starting YERVOY, as it may cause:

Heart problems, such as changes in heart rhythm or rate, or abnormal heart rhythm.
Inflammation of the intestine (colitis), which may worsen and lead to bleeding or intestinal perforation. Signs and symptoms of colitis may include diarrhea (watery, loose, or soft stools), an increase in the number of bowel movements compared to usual, blood in the stool, or darker-colored stools, as well as abdominal pain or increased abdominal tenderness.
Lung problems, such as difficulty breathing or cough. These may be signs of lung inflammation (pneumonitis or interstitial lung disease).
Liver inflammation (hepatitis), which may lead to liver failure. Signs and symptoms of hepatitis may include yellowing of the eyes or skin (jaundice), pain in the right side of the abdomen, or fatigue.
Skin inflammation, which may lead to a severe skin reaction (known as toxic epidermal necrolysis; Stevens-Johnson syndrome; or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome)). Signs and symptoms of a severe skin reaction may include rash with or without itching, skin peeling, dry skin, fever, fatigue, facial swelling, or swollen lymph nodes, increased eosinophils (a type of white blood cell), and effects on the liver, kidneys, or lungs. Please note that DRESS syndrome may develop weeks or months after your last dose.
Nerve inflammation, which may cause paralysis. Symptoms of nerve problems may include muscle weakness, numbness or tingling in the hands or feet, loss of consciousness, or difficulty waking up.
Inflammation or problems with your kidneys. Signs and symptoms may include abnormal kidney function tests or reduced urine volume.
Inflammation or problems with hormone-producing glands (especially the pituitary gland, adrenal glands, and thyroid), which could affect how these glands function. Signs and symptoms of gland dysfunction may include headaches, blurred or double vision, fatigue, decreased sex drive, or changes in behavior.
Type 1 diabetes, including diabetic ketoacidosis (acid in the blood caused by diabetes).
Muscle inflammation, such as myocarditis (inflammation of the heart muscle), myositis (inflammation of the muscles), and rhabdomyolysis (stiffness in muscles and joints, muscle spasms). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe fatigue.
Eye inflammation. Signs and symptoms may include red eyes, eye pain, vision problems, blurred vision, or temporary loss of vision.
Hemophagocytic lymphohistiocytosis. A rare condition in which the immune system produces too many infection-fighting cells, called histiocytes and lymphocytes. Symptoms may include enlargement of the liver and/or spleen, rash, swollen lymph nodes, breathing problems, easy bruising, kidney abnormalities, and heart problems.
Organ transplant rejection.

Contact your doctor immediately if you experience any of these signs or symptoms, or if they worsen. Do not attempt to treat your symptoms with other medicines. Your doctor may give you other medications to prevent more serious complications and reduce your symptoms, delay your next YERVOY dose, or stop your YERVOY treatment completely.

Please note that these signs and symptoms sometimes occur late and may develop weeks or months after the last dose. Before treatment, your doctor will assess your general health. You will also have blood tests during treatment.

Talk to your doctor or nurse before receiving YERVOY

if you have an autoimmune disease (a condition in which the body attacks its own cells);
if you have or have ever had a chronic viral liver infection, including hepatitis B (HBV) or hepatitis C (HCV);
if you have human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
if you have previously experienced a severe skin adverse reaction after prior cancer treatment;
if you have a history of lung inflammation.

Children and adolescents

YERVOY should not be used in children and adolescents under 18 years of age, except in adolescents aged 12 years and older with melanoma.

Other medicines and YERVOY

Before receiving YERVOY, inform your doctor

if you are taking any other medicine that suppresses your immune system, such as corticosteroids. These medicines could interfere with the effect of YERVOY. However, once you are receiving YERVOY, your doctor may prescribe corticosteroids to reduce adverse effects associated with YERVOY.
if you are taking any medicine that affects blood clotting (anticoagulants). These medicines may increase the risk of gastrointestinal or intestinal bleeding, which is a known adverse effect of YERVOY.
if you have recently been prescribed Zelboraf (vemurafenib, another medicine for the treatment of skin cancer). When YERVOY is administered after vemurafenib, the risk of skin-related adverse effects may increase.

Also, inform your doctor if you are taking or have recently taken any other medicines.

Do not take other medicines during your treatment without first consulting your doctor. Based on initial data, the combination of YERVOY (ipilimumab) and vemurafenib is not recommended due to increased liver toxicity.

Pregnancy and breastfeeding

If you are pregnant, planning to become pregnant, or breastfeeding, consult your doctor before using this medicine.

You must not use YERVOY if you are pregnant, unless specifically advised by your doctor. The effects of YERVOY in pregnant women are unknown, but the active substance, ipilimumab, may harm the fetus.

You must use effective contraception while being treated with YERVOY if you are a woman of childbearing potential.
If you become pregnant while using YERVOY, inform your doctor.

It is unknown whether ipilimumab passes into breast milk. However, significant exposure of the infant via breast milk is not expected, and effects on the infant are not anticipated. Ask your doctor whether you can continue breastfeeding during or after treatment with YERVOY.

Driving and using machines

Do not drive, ride a bicycle, or operate machinery after receiving YERVOY unless you are certain you feel well. Feeling tired or weak is a very common adverse effect of YERVOY. This may affect your ability to drive, ride a bicycle, or use machinery.

YERVOY contains sodium

Inform your doctor if you are on a low-sodium (low-salt) diet before receiving YERVOY.

This medicine contains 23 mg of sodium (the main component of table/cooking salt) in each 10 ml vial. This corresponds to 1.15% of the maximum daily sodium intake recommended for an adult.

This medicine contains 92 mg of sodium (the main component of table/cooking salt) in each 40 ml vial. This corresponds to 4.60% of the maximum daily sodium intake recommended for an adult.

3. How to use YERVOY

How YERVOY is administered

Treatment with YERVOY will be given to you in a hospital or clinic under the supervision of an experienced doctor.

When YERVOY is administered alone for the treatment of skin cancer, YERVOY will be given as an intravenous infusion (a drip) into a vein over a period of 30 minutes.

When YERVOY is administered in combination with nivolumab for the treatment of skin cancer, it will be given as an infusion over a period of 30 minutes every 3 weeks for the first 4 doses (combination phase). After this, nivolumab will be given as an infusion over 30 or 60 minutes, every 2 weeks or every 4 weeks, depending on the dose you are receiving (monotherapy phase).

When YERVOY is administered in combination with nivolumab for the treatment of advanced kidney cancer, it will be given as an infusion over a period of 30 minutes every 3 weeks for the first 4 doses (combination phase). After this, nivolumab will be given as an infusion over 30 or 60 minutes, every 2 weeks or every 4 weeks, depending on the dose you are receiving (monotherapy phase).

When YERVOY is administered in combination with nivolumab for the treatment of advanced colon or rectal cancer in adults, it will be given as an infusion over a period of 30 minutes every 3 weeks for the first 4 doses (combination phase). After this, nivolumab will be given as an infusion over 30 minutes, every 2 weeks or every 4 weeks, depending on the dose you are receiving (monotherapy phase).

When YERVOY is administered in combination with nivolumab for the treatment of malignant pleural mesothelioma or advanced esophageal cancer, it will be given as an infusion over a period of 30 minutes every 6 weeks.

When YERVOY is administered in combination with nivolumab for the treatment of unresectable or advanced liver cancer, you will receive an infusion over 30 minutes every 3 weeks for up to a maximum of 4 doses (combination phase), depending on your treatment. After this, nivolumab will be given as an infusion over 30 minutes, every 2 weeks or every 4 weeks, depending on the dose you are receiving (monotherapy phase).

When YERVOY is administered in combination with nivolumab and chemotherapy for the treatment of advanced non-small cell lung cancer, it will be given as an infusion over a period of 30 minutes every 6 weeks. After completing 2 cycles of chemotherapy, ipilimumab will be administered in combination with nivolumab as an infusion over 30 minutes every 6 weeks.

How much YERVOY is administered

When YERVOY is administered alone for the treatment of skin cancer, the recommended dose is 3 mg of ipilimumab per kilogram of body weight.

The amount of YERVOY you will receive will be calculated based on your body weight. Depending on the dose, part or all of the contents of the YERVOY vial may be diluted with 9 mg/ml (0.9%) sodium chloride injection solution or 50 mg/ml (5%) glucose injection solution before use. More than one vial may be needed to achieve the required dose.

You will be treated with YERVOY once every 3 weeks, for a total of 4 doses. You may notice the appearance of new skin lesions or the growth of existing lesions while being treated with YERVOY. Your doctor will continue to administer YERVOY up to a total of 4 doses, depending on your tolerance to treatment.

When YERVOY is administered in combination with nivolumab for the treatment of skin cancer in adults and adolescents aged 12 years and older, the recommended dose of YERVOY is 3 mg of ipilimumab per kilogram of body weight every 3 weeks for the first 4 doses (combination phase). After this, the recommended dose of nivolumab (monotherapy phase) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks in adults and adolescents aged 12 years and older weighing at least 50 kg, or 3 mg of nivolumab per kilogram of body weight administered every 2 weeks or 6 mg of nivolumab per kilogram of body weight administered every 4 weeks in adolescents aged 12 years and older weighing less than 50 kg.

When YERVOY is administered in combination with nivolumab for the treatment of advanced kidney cancer, the recommended dose of YERVOY is 1 mg of ipilimumab per kilogram of body weight every 3 weeks for the first 4 doses (combination phase). After this, the recommended dose of nivolumab is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks (monotherapy phase).

When YERVOY is administered in combination with nivolumab for the treatment of advanced colon or rectal cancer, the recommended dose of YERVOY is 1 mg of ipilimumab per kilogram of body weight every 3 weeks for the first 4 doses (combination phase). After this, the recommended dose of nivolumab is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks (monotherapy phase), depending on treatment.

When YERVOY is administered in combination with nivolumab for the treatment of malignant pleural mesothelioma or advanced esophageal cancer, the recommended dose of YERVOY is 1 mg of ipilimumab per kilogram of body weight every 6 weeks.

When YERVOY is administered in combination with nivolumab for the treatment of unresectable or advanced liver cancer, the recommended dose of YERVOY is 3 mg of ipilimumab per kilogram of body weight for up to a maximum of 4 doses (combination phase), depending on your treatment. After this, the recommended dose of nivolumab is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks (monotherapy phase), depending on your treatment.

When YERVOY is administered in combination with nivolumab and chemotherapy for the treatment of advanced non-small cell lung cancer, the recommended dose of YERVOY is 1 mg of ipilimumab per kilogram of body weight. It will be administered as an infusion over a period of 30 minutes every 6 weeks.

If you miss a dose of YERVOY

It is very important that you attend all your appointments to receive YERVOY. If you miss an appointment, ask your doctor when to schedule your next dose.

If you interrupt treatment with YERVOY

Interrupting treatment may stop the medicine's effect. Do not interrupt treatment with YERVOY unless you have discussed it with your doctor.

If you have any further questions about your treatment or the use of this medicine, ask your doctor.

When YERVOY is administered in combination with nivolumab or in combination with nivolumab and chemotherapy, nivolumab is administered first, followed by YERVOY, and then chemotherapy.

Please refer to the package leaflet of the other anticancer medicines to understand how these other medicines are used. If you have any questions about these medicines, please consult your doctor.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone gets them. Your doctor will discuss these with you and explain the risks and benefits of your treatment.

Be alert for important symptoms of inflammation

YERVOY acts on the immune system and may cause inflammation in certain parts of the body.

Inflammation can cause serious damage to the body, and some inflammatory conditions could be potentially fatal.

The following adverse effects have been reported in patients who received 3 mg/kg of ipilimumab alone:

Very common (may affect more than 1 in 10 patients)

loss of appetite
diarrhoea (watery, loose or soft stools), vomiting or feeling sick (nausea), constipation, stomach pain
skin rash, itching
pain in the muscles, bones, ligaments, tendons and nerves
feeling tired or weak, reaction at the injection site, fever, oedema (swelling), pain
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Common (may affect up to 1 in 10 patients)

severe bacterial infection of the blood (sepsis), urinary tract infection, respiratory tract infection
tumour pain
a decrease in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood to clot)
reduced function of the thyroid gland, which may cause tiredness or weight gain, reduced function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain
dehydration
confusion, depression
excessive accumulation of fluid in the brain, nerve damage (causing pain, weakness and cramps), dizziness, headache
blurred vision, eye pain
irregular or abnormal heartbeat
low blood pressure, transient reddening of the face and neck, sensation of intense heat with sweating and rapid heartbeat
difficulty breathing (dyspnoea), cough, hay fever
bleeding in the stomach or intestine, inflammation of the intestine (colitis), heartburn, mouth ulcers and herpes (stomatitis)
liver function disturbances
inflammation of the inner surface of a particular organ
inflammation and reddening of the skin, changes in skin colour in patches (vitiligo), hives (itchy, raised rash), hair loss or thinning, excessive night sweating, dry skin
muscle and joint pain (arthralgia), muscle spasms, joint inflammation (arthritis)
kidney function failure
chills, lack of energy
flu-like illness
decrease in body weight
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Uncommon (may affect up to 1 in 100 patients)

severe bacterial infection of the blood (septic shock), inflammation around the brain or spinal cord, inflammation of the stomach and intestines, inflammation of the intestinal wall (causing fever, vomiting and stomach pain), lung infection (pneumonia)
symptoms due to cancer in the body such as high levels of calcium and cholesterol in the blood, and low blood sugar levels (paraneoplastic syndrome)
increase in eosinophils (a type of white blood cell)
allergic reaction
decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), overactivity of the thyroid gland, which may cause rapid heartbeat, sweating and weight loss, dysfunction of glands producing sex hormones
reduced function of the adrenal glands caused by decreased function of the hypothalamus (part of the brain)
a group of metabolic complications occurring after cancer treatment, characterised by high levels of potassium and phosphate in the blood and low levels of calcium in the blood (tumour lysis syndrome)
changes in mental health, decreased sexual drive
severe and possibly fatal nerve inflammation causing pain, weakness or paralysis of the limbs (Guillain-Barré syndrome), fainting, inflammation of nerves within the brain, difficulty coordinating movements (ataxia), agitation, brief involuntary muscle contractions, difficulty speaking
eye inflammation (conjunctivitis), bleeding in the eye, inflammation of the coloured part of the eye, reduced vision, sensation of a foreign body in the eyes, swollen and watery eyes, eye swelling, eyelid inflammation
inflammation of blood vessels, blood vessel disease, restricted blood supply to the limbs, low blood pressure upon standing
extreme difficulty breathing, fluid accumulation in the lungs, lung inflammation
intestinal perforation, inflammation of the small intestine, inflammation of the intestine or pancreas (pancreatitis), peptic ulcer, oesophagitis, intestinal obstruction, inflammation of the anus and rectal wall (characterised by bloody stools and urgent need to defecate)
liver failure, liver inflammation, enlarged liver, yellowing of the skin or eyes (jaundice)
severe and possibly fatal skin peeling (toxic epidermal necrolysis)
muscle inflammation, causing pain or stiffness in the hip and shoulder
kidney inflammation, or central nervous system inflammation
multi-organ inflammation
inflammation of skeletal muscle
muscle weakness
kidney disease
absence of menstrual periods
multi-organ failure, infusion-related reaction
changes in hair colour
bladder inflammation; signs and symptoms may include frequent and/or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Rare (may affect up to 1 in 1,000 patients)

inflammatory disease of blood vessels (usually arteries in the head)
swelling of the thyroid gland (thyroiditis)
skin disease characterised by dry, red patches covered with scales (psoriasis)
skin inflammation and reddening (erythema multiforme)
a type of severe skin reaction characterised by rash accompanied by one or more of the following: fever, facial or lymph node swelling, increased eosinophils (a type of white blood cell), effects on the liver, kidneys or lungs (a reaction called DRESS syndrome)
an inflammatory disorder (very likely autoimmune in origin) affecting the eyes, skin, and membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome), separation of the membrane at the back of the eye (serous retinal detachment)
symptoms of type 1 diabetes or diabetic ketoacidosis including increased hunger or thirst, more frequent urination, weight loss, feeling tired, malaise, stomach pain, rapid deep breathing, confusion, unusual drowsiness, sweet-smelling breath, sweet or metallic taste in the mouth, or unusual odour in urine or sweat
muscle weakness and fatigue without atrophy (myasthenia gravis)
Absence or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency)
Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea and bloating after consuming foods containing gluten)
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Very rare (may affect up to 1 in 10,000 patients)

severe, potentially life-threatening allergic reactions
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Additionally, the following uncommon adverse effects (may affect up to 1 in 100 patients) have been reported in patients who received different doses of YERVOY other than 3 mg/kg in clinical trials:

triad of symptoms (meningism): neck stiffness, intolerance to bright light, headache, flu-like malaise
inflammation of the heart muscle, heart muscle weakness, fluid around the heart
liver or pancreas inflammation, granulomatous nodules formed by inflammatory cells in various organs of the body
intra-abdominal infection
painful skin lesions on arms, legs and face (erythema nodosum)
increased pituitary gland function
decreased parathyroid gland function
eye inflammation, eye muscle inflammation
hearing loss
poor blood circulation causing numbness or paleness in the toes and fingers
tissue damage in hands and feet causing redness, swelling and blisters
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Other adverse effects have been reported with unknown frequency (cannot be estimated from available data):

organ transplant rejection
a type of blistering skin disease (called pemphigoid)
a condition in which the immune system produces excessive cells fighting infections called histiocytes and lymphocytes, which may cause various symptoms (called haemophagocytic lymphohistiocytosis). Symptoms may include enlargement of the liver and/or spleen, skin rash, swollen lymph nodes, breathing problems, easy bruising, kidney abnormalities and heart problems
pain, numbness, tingling or weakness in arms or legs; bladder or bowel problems, including need to urinate more frequently, urinary incontinence, difficulty urinating and constipation (myelitis)
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Changes in laboratory test results

YERVOY may cause changes in laboratory tests performed by your doctor. These include:

variation in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood to clot)
abnormal changes in levels of hormones and liver enzymes in the blood
abnormalities in liver function tests
abnormal levels of calcium, sodium, phosphate or potassium in the blood
presence of blood or proteins in the urine
abnormally high alkalinity of the blood and other body tissues
inability of the kidney to eliminate acids from the blood normally
presence of antibodies in the blood against some of your own cells

The following adverse effects have been reported with ipilimumab in combination with other anti-cancer medicines (the frequency and severity of adverse effects may vary depending on the combination of anti-cancer medicines received):

Very common (may affect more than 1 in 10 patients)

upper respiratory tract infections
decreased activity of the thyroid gland (which may cause tiredness or weight gain)
a decrease in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood to clot)
loss of appetite, high (hyperglycaemia) or low (hypoglycaemia) blood sugar levels
headache
difficulty breathing (dyspnoea), cough
diarrhoea (watery, loose or soft stools), vomiting or feeling sick (nausea), stomach pain, constipation
skin rash, sometimes with blisters, itching
muscle and bone pain (musculoskeletal pain), joint pain (arthralgia)
feeling tired or weak, fever, oedema (swelling)
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Common (may affect up to 1 in 10 patients)

lung infection (pneumonia), bronchitis, eye inflammation (conjunctivitis)
elevated eosinophils (a type of white blood cell)
allergic reaction, infusion-related reactions
increased thyroid gland activity (which may cause increased heart rate, sweating and weight loss), decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), reduced pituitary gland activity (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, thyroid gland swelling, diabetes
dehydration, decreased levels of albumin and phosphates in the blood, decreased body weight
nerve inflammation (causing numbness, weakness, tingling or burning in arms and legs), dizziness
blurred vision, dry eyes
rapid heartbeat, changes in heart rhythm or rate, irregular or abnormal heartbeat
elevated blood pressure (hypertension)
lung inflammation (pneumonitis, characterised by cough and difficulty breathing), fluid around the lungs
intestinal inflammation (colitis), mouth ulcers and herpes (stomatitis), pancreas inflammation (pancreatitis), dry mouth, stomach inflammation (gastritis)
liver inflammation
skin colour changes in patches (vitiligo), skin reddening, unusual hair loss or thinning, hives (itchy, raised rash), dry skin
joint inflammation (arthritis), muscle spasm, muscle weakness
kidney failure (including sudden loss of kidney function)
pain, chest pain, chills
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Uncommon (may affect up to 1 in 100 patients)

decreased neutrophils with fever
acid in the blood caused by diabetes (diabetic ketoacidosis)
increased levels of acid in the blood
brain inflammation; nerve damage causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve paralysis); nerve inflammation caused by the body attacking itself, causing numbness, weakness, tingling or burning (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenia gravis)
eye inflammation causing redness or pain
abnormal irregular heartbeat, heart muscle inflammation, slow heart rate
duodenal inflammation
skin disease with raised red areas, often with silvery scales (psoriasis), severe skin disease causing red spots, often itchy, similar to measles rash, starting in the limbs and sometimes in the face and rest of the body (erythema multiforme), severe and potentially fatal skin peeling (Stevens-Johnson syndrome), changes in any area of the skin and/or genital area associated with dryness, thinning of the skin, itching and pain (or other lichen disorders)
muscle pain, sensitivity or weakness not caused by exercise (myopathy), muscle inflammation (myositis), muscle inflammation causing pain or stiffness (polymyalgia rheumatica)
kidney inflammation
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Rare (may affect up to 1 in 1,000 patients)

temporary, reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
chronic diseases associated with accumulation of inflammatory cells in various organs and tissues, most frequently in the lungs (sarcoidosis)
decreased function of the parathyroid gland
temporary nerve inflammation causing pain, weakness and paralysis in the limbs (Guillain-Barré syndrome), nerve inflammation
pain, numbness, tingling or weakness in the arms or legs; bladder or bowel problems, including need to urinate more frequently, urinary incontinence, difficulty urinating and constipation (myelitis/transverse myelitis)
intestinal perforation
severe and potentially fatal skin peeling (toxic epidermal necrolysis), changes in any area of the skin and/or genital area associated with dryness, thinning of the skin, itching and pain (lichen sclerosus)
chronic joint disease (spondyloarthropathy), a condition in which the immune system attacks glands producing body moisture, such as tears and saliva (Sjögren's syndrome), stiffness in muscles and joints, muscle spasms (rhabdomyolysis)
an inflammatory disorder (very likely autoimmune in origin) affecting the eyes, skin and membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome), separation of the membrane at the back of the eye (serous retinal detachment)
bladder inflammation; signs and symptoms may include frequent and/or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen
Absence or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency)
Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea and bloating after consuming foods containing gluten)
Tell your doctor immediately if you experience any of these adverse effects.

Do not attempt to treat your symptoms with other medicines.

Other adverse effects have been reported with unknown frequency (cannot be estimated from available data):

organ transplant rejection
a group of metabolic complications occurring after cancer treatment, characterised by high levels of potassium and phosphate in the blood and low levels of calcium in the blood (tumour lysis syndrome)
inflammation of the heart lining and fluid accumulation around the heart (pericardial disorders)
a condition in which the immune system produces excessive cells fighting infections called histiocytes and lymphocytes, which may cause various symptoms (called haemophagocytic lymphohistiocytosis). Symptoms may include enlargement of the liver and/or spleen, skin rash, swollen lymph nodes, breathing problems, easy bruising, kidney abnormalities and heart problems.

Changes in laboratory test results

YERVOY in combination may cause changes in laboratory tests performed by your doctor. These include:

abnormal liver function tests (increase in blood concentration of liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase or alkaline phosphatase, increase in blood levels of the waste product bilirubin)
abnormal kidney function tests (increase in blood creatinine concentration)
increase in the level of the enzyme that breaks down fats and the enzyme that breaks down starch
increase or decrease in the amount of calcium or potassium
increase or decrease in magnesium or sodium levels in the blood
increase in thyroid-stimulating hormone levels

5. Storage of YERVOY

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the label of the vial after EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator (between 2 °C and 8 °C).

Do not freeze.

Store in the original packaging to protect from light.

Do not store unused solution for potential reuse. Any unused medicine and materials that have come into contact with it must be disposed of in accordance with local regulations.

6. Contents of the pack and other information

Composition of YERVOY

The active substance is ipilimumab.

Each ml of concentrate contains 5 mg of ipilimumab.

Each 10 ml vial contains 50 mg of ipilimumab.

Each 40 ml vial contains 200 mg of ipilimumab.

The other components are tris hydrochloride, sodium chloride (see section 2 "YERVOY contains sodium"), mannitol (E421), pentetic acid, polysorbate 80, sodium hydroxide, hydrochloric acid and water for injections.

Appearance of YERVOY and contents of the pack

YERVOY concentrate for solution for infusion is a liquid ranging from colourless to pale yellow, clear to slightly opalescent, which may contain some (few) particles.

It is available in packs containing 1 glass vial of 10 ml or 1 glass vial of 40 ml.

Only certain pack sizes may be marketed.

Marketing Authorisation Holder

Bristol-Myers Squibb Pharma EEIG
Plaza 254
Blanchardstown Corporate Park 2
Dublin 15, D15 T867
Ireland

Manufacturer

CATALENT ANAGNI S.R.L.
Loc. Fontana del Ceraso snc
Strada Provinciale 12 Casilina, 41
03012 Anagni (FR)
Italy

Swords Laboratories Unlimited Company T/A Bristol-Myers Squibb Cruiserath Biologics
Cruiserath Road, Mulhuddart
Dublin 15, D15 H6EF
Ireland

Date of the most recent revision of this leaflet:

Detailed information on this medicine is available on the European Medicines Agency website: https://www.ema.europa.eu.

This information is intended for healthcare professionals only:

Preparation must be performed by trained personnel in accordance with good practices, particularly with regard to asepsis.

Dose calculation:

Ipilimumab as monotherapy or ipilimumab in combination with nivolumab:

The prescribed dose for the patient is expressed in mg/kg. Based on this prescribed dose, calculate the total dose to be administered. More than one vial of YERVOY concentrate may be required to deliver the total dose to the patient.

Each 10 ml vial of YERVOY concentrate contains 50 mg of ipilimumab; each 40 ml vial contains 200 mg of ipilimumab.
Total ipilimumab dose in mg = patient's weight in kg × prescribed dose in mg/kg.
Volume of YERVOY concentrate to prepare the dose (ml) = total dose in mg divided by 5 (the concentration of YERVOY concentrate is 5 mg/ml).

Preparation of the infusion:

Ensure aseptic handling when preparing the infusion.

YERVOY may be used for intravenous administration either:

undiluted, after transfer to an infusion container using an appropriate sterile syringe;

after dilution up to 5 times the original concentrate volume (up to 4 parts diluent per 1 part concentrate). The final concentration should be in the range of 1 to 4 mg/ml. To dilute the YERVOY concentrate, use:
9 mg/ml (0.9%) sodium chloride injection solution; or
50 mg/ml (5%) glucose injection solution.

STEP 1

Allow the appropriate number of YERVOY vials to stand at room temperature for approximately 5 minutes.
Inspect the YERVOY concentrate for particles or discoloration. The YERVOY concentrate is a clear to slightly opalescent liquid, colourless to pale yellow, which may contain some (few) particles. Do not use if there is an unusual amount of particles or signs of discoloration.
Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe.

STEP 2

Transfer the concentrate to a sterile evacuated glass vial or an IV bag (PVC or non-PVC).
If required, dilute with the necessary volume of 9 mg/ml (0.9%) sodium chloride injection solution or 50 mg/ml (5%) glucose injection solution. To facilitate preparation, the concentrate may also be transferred directly into a pre-filled bag containing the appropriate volume of 9 mg/ml (0.9%) sodium chloride injection solution or 50 mg/ml (5%) glucose injection solution. Gently mix the infusion by manual rotation.

Administration:

YERVOY infusion must not be administered as an intravenous bolus injection. Administer YERVOY infusion intravenously over a period of 30 minutes.

YERVOY infusion must not be administered simultaneously through the same intravenous line as other agents. Use a separate line for the infusion.

Use a sterile, non-pyrogenic, low protein-binding infusion set with an in-line filter (pore size 0.2 μm to 1.2 μm).

YERVOY infusion is compatible with:

PVC infusion sets
In-line filters made of polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm)

Flush the line with 9 mg/ml (0.9%) sodium chloride injection solution or 50 mg/ml (5%) glucose injection solution at the end of the infusion.

Storage conditions and shelf life:

Unopened vial

YERVOY must be stored in a refrigerator (between 2 °C and 8 °C). Vials should be kept in the original packaging to protect from light. Do not freeze.

Do not use YERVOY after the expiry date stated on the vial label and packaging following EXP. The expiry date refers to the last day of the month indicated.

YERVOY infusion

From a microbiological standpoint, once opened, the medicinal product should be infused or diluted and infused immediately. Chemical and physical stability has been demonstrated for the undiluted or diluted (1 to 4 mg/ml) infusion solution for 24 hours at room temperature (20 °C to 25 °C) or under refrigeration (2 °C to 8 °C). If not used immediately, the infusion solution (undiluted or diluted) should be used within 24 hours when stored either refrigerated (2 °C to 8 °C) or at room temperature (20 °C to 25 °C). Any other storage times and conditions during use are the responsibility of the user.

Disposal:

Do not store unused solution for potential reuse. Any unused medicine and materials that have come into contact with it must be disposed of in accordance with local regulations.