YERVOY

Package leaflet: Information for the user

YERVOY 5 mg/mL concentrate for solution for infusion

ipilimumab
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you get any side effects, talk to your doctor. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet

1. What YERVOY is and what it is used for
2. What you need to know before using YERVOY
3. How to use YERVOY
4. Possible side effects
5. How to store YERVOY
6. 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 the immune system attack and destroy cancer cells through the action of immune cells.
Ipilimumab alone is used for the treatment of advanced melanoma (a type of skin cancer) in adults and adolescents aged 12 years and older.
Ipilimumab in combination with nivolumab is used for the treatment of:

• 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 lung) in adults
• advanced colorectal carcinoma (cancer of the colon or rectum) in adults
• advanced oesophageal carcinoma (cancer of the oesophagus) in adults
• unresectable or advanced hepatocellular carcinoma (cancer of the liver) in adults.

Ipilimumab in combination with nivolumab and chemotherapy is used for the treatment of advanced non-small cell lung cancer (a type of lung cancer) in adults.
Since YERVOY may be administered in combination with other anti-cancer 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 must know before using YERVOY

YERVOY must not be administered to you if

• you are allergic to ipilimumab or to any of the other ingredients of this medicine (listed in section 6 "Contents of the pack and other information"). If you are unsure, talk to your doctor.

Warnings and precautions
Talk to your doctor before using YERVOY, as it may cause:

• Heart problems, such as changes in heart rhythm or heart rate, or heart rhythm abnormalities.
• 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 increased number of bowel movements compared to usual, blood in the stool, or dark-colored stools, abdominal pain or 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, 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)). Signs and symptoms of a severe skin reaction may include rash with or without itching, skin peeling, dry skin, fever, fatigue, swelling of the face or lymph nodes, increased eosinophils (a type of white blood cells), and effects on the liver, kidneys, or lungs. Note that DRESS reactions may develop weeks or months after your last dose.
• Nerve inflammation, which may lead to 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 in the kidneys. Signs and symptoms may include changes in kidney function tests or reduced urine output.
• Inflammation or problems in hormone-producing glands (especially pituitary, adrenal, and thyroid glands), which may affect how these glands function. Signs and symptoms of improper gland function may include headache, double or blurred vision, fatigue, reduced sexual drive, 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 muscles), and rhabdomyolysis (muscle and joint stiffness, muscle spasms). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe fatigue.
• Eye inflammation. Signs and symptoms may include redness of the eyes, eye pain, vision changes, blurred vision, or temporary vision loss.
• Hemophagocytic lymphohistiocytosis. A rare condition in which the immune system produces an excessive number of 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.

Inform your doctor immediately if you experience any of these signs or symptoms, or if they worsen. Do not attempt to treat these symptoms with other medicines. Your doctor may prescribe other medicines to prevent more serious complications and reduce your symptoms, may suspend your next dose of YERVOY, or may discontinue treatment with YERVOY altogether.
Please note that these signs and symptoms may sometimes be delayed and may develop weeks or months after the last administration. Before treatment, your doctor will check your general health status. During treatment, you will also need to undergo blood tests.
Before YERVOY is administered, check with your doctor or nurse

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

Children and adolescents
YERVOY must not be administered to children and adolescents under 18 years of age, except for adolescents aged 12 years and older with melanoma.

Other medicines and YERVOY
Before YERVOY is administered, inform your doctor

• if you are taking any medicine that suppresses the immune system, such as corticosteroids. These medicines may interfere with the effect of YERVOY. However, once you have been treated with YERVOY, your doctor may prescribe corticosteroids to reduce any side effects you may experience.
• if you are taking any medicine that affects blood clotting (anticoagulants). These medicines may increase the risk of bleeding in the stomach or intestines, which is a known side effect of YERVOY.
• if you have recently been prescribed Zelboraf (vemurafenib, another medicine for the treatment of skin cancer). When YERVOY is administered after prior vemurafenib treatment, there may be an increased risk of skin-related side effects.

Also inform your doctor if you are taking or have recently taken any other medicines.
Do not take any other medicine during treatment without first discussing it with your doctor.
Based on preliminary data, the concomitant administration of YERVOY (ipilimumab) and vemurafenib is not recommended due to increased liver toxicity.

Pregnancy and breastfeeding
Inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding.
You must not use YERVOY during pregnancy unless your doctor specifically recommends it. The effects of YERVOY in pregnant women are unknown, but the active substance ipilimumab may cause harm to the unborn child.

• Women of childbearing potential must use an effective method of contraception during treatment with YERVOY.
• If you become pregnant during treatment with YERVOY, inform your doctor.

It is not known whether ipilimumab passes into breast milk. However, significant exposure of the infant to ipilimumab through breast milk is not expected, and it is considered unlikely that there would be effects on breastfed infants. Ask your doctor whether you can breastfeed during or after treatment with YERVOY.

Driving and using machines
Do not drive, ride a bicycle, or operate machinery after receiving YERVOY if you are not sure you feel well. A feeling of fatigue or weakness is a very common side effect of YERVOY. This may affect your ability to drive, ride a bicycle, or operate machinery.

YERVOY contains sodium
If you are on a low-sodium diet (a low-salt diet), inform your doctor before administration of YERVOY.
This medicine contains 23 mg of sodium (the main component of table salt) per 10 mL vial. This corresponds to 1.15% of the maximum daily recommended dietary intake for an adult.
This medicine contains 92 mg of sodium (the main component of table salt) per 40 mL vial. This corresponds to 4.60% of the maximum daily recommended dietary intake for an adult.

3. How to use YERVOY

How YERVOY is administered
YERVOY will be administered in a hospital or clinic under the supervision of an experienced physician.
When YERVOY is given alone for the treatment of skin cancer, it will be administered by intravenous infusion (a drip) over 30 minutes.
When YERVOY is given in combination with nivolumab for the treatment of skin cancer, you will receive an infusion lasting 30 minutes every 3 weeks for the first 4 doses (combination phase). After that, nivolumab will be administered by infusion lasting 30 or 60 minutes every 2 or 4 weeks, depending on the dose you are receiving (monotherapy phase).
When YERVOY is given in combination with nivolumab for the treatment of advanced kidney cancer, you will receive an infusion lasting 30 minutes every 3 weeks for the first 4 doses (combination phase). After that, nivolumab will be administered by infusion lasting 30 or 60 minutes every 2 or 4 weeks, depending on the dose you are receiving (monotherapy phase).
When YERVOY is given in combination with nivolumab for the treatment of advanced colorectal cancer in adults, you will receive an infusion lasting 30 minutes every 3 weeks for the first 4 doses (combination phase). After that, nivolumab will be administered by infusion lasting 30 minutes every 2 or 4 weeks, depending on the dose you are receiving (monotherapy phase).
When YERVOY is given in combination with nivolumab for the treatment of malignant pleural mesothelioma or advanced oesophageal cancer, you will receive an infusion lasting 30 minutes every 6 weeks.
When YERVOY is given in combination with nivolumab for the treatment of unresectable or advanced liver cancer, you will receive an infusion lasting 30 minutes every 3 weeks for up to 4 doses (combination phase), depending on the treatment. After that, nivolumab will be administered by infusion lasting 30 minutes every 2 or 4 weeks, depending on the dose you are receiving (monotherapy phase).
When YERVOY is given in combination with nivolumab and chemotherapy for the treatment of advanced non-small cell lung cancer, you will receive an infusion lasting 30 minutes every 6 weeks. After completion of 2 cycles of chemotherapy, ipilimumab will be administered in combination with nivolumab by infusion lasting 30 minutes every 6 weeks.

How much YERVOY is administered
When YERVOY is given alone for the treatment of skin cancer, the recommended dose is 3 mg of ipilimumab per kilogram of body weight.
The amount of YERVOY to be administered will be calculated based on body weight. Depending on the dose, before administration, the contents of the YERVOY vial may be completely or partially diluted with an injectable solution of sodium chloride 9 mg/mL (0.9%) or an injectable solution of glucose 50 mg/mL (5%). More than one vial may be required to achieve the required dose.
Treatment with YERVOY will be administered 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, which may be expected during treatment with YERVOY. Your doctor will continue to administer YERVOY for a total of 4 doses, depending on your tolerance to treatment.
When YERVOY is given 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 that, 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 and 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 for adolescents aged 12 years and older and weighing less than 50 kg.
When YERVOY is given 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 that, the recommended dose of nivolumab is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks (monotherapy phase).
When YERVOY is given in combination with nivolumab for the treatment of advanced colorectal 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 that, the recommended dose of nivolumab is 240 mg administered every 2 weeks or 480 mg every 4 weeks (monotherapy phase), depending on the treatment.
When YERVOY is given in combination with nivolumab for the treatment of malignant pleural mesothelioma or advanced oesophageal cancer, the recommended dose of YERVOY is 1 mg of ipilimumab per kilogram of body weight every 6 weeks.
When YERVOY is given 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 4 doses (combination phase), depending on the treatment. After that, the recommended dose of nivolumab is 240 mg every 2 weeks or 480 mg every 4 weeks (monotherapy phase), depending on the treatment.
When YERVOY is given 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. You will receive an infusion lasting 30 minutes every 6 weeks.

If you miss a dose of YERVOY
It is very important that you attend all your scheduled YERVOY infusions. If you miss an appointment, ask your doctor when to schedule your next infusion.

If you stop YERVOY treatment
Stopping treatment may interrupt the effect of the medicine. Do not stop treatment with YERVOY without first discussing it with your doctor.
If you have any questions about your treatment or the use of this medicine, consult your doctor.
When YERVOY is administered in combination with nivolumab or in combination with nivolumab and chemotherapy, nivolumab must be administered first, followed by YERVOY and then chemotherapy.
Refer to the package leaflet of the other anticancer medicines to understand the use of these other medicines. If you have any questions about these medicines, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Your doctor will discuss these side effects with you and explain the risks and benefits of treatment.
Keep in mind the important symptoms of inflammation
YERVOY acts on the immune system and may cause inflammation in certain parts of the body.
Inflammation can cause serious harm to the body, and some inflammatory conditions may be life-threatening.

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

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

• loss of appetite
• diarrhoea (watery, loose or soft stools), vomiting or feeling unwell (nausea), constipation, stomach ache
• skin redness, itching
• pain in muscles, bones, ligaments, tendons and nerves
• feeling of tiredness or weakness, injection site reactions, fever, oedema (swelling), pain

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Common (may affect up to 1 in 10 people)

• severe bacterial infection of the blood (sepsis), urinary tract infection, respiratory tract infection
• pain at tumour site
• reduction in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood clotting)
• underactive thyroid gland, which may cause tiredness or weight gain, underactivity of the pituitary gland (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain
• dehydration
• confusion, depression
• excessive fluid accumulation in the brain, nerve damage (causing pain, weakness and cramps), dizziness, headache
• blurred vision, eye pain
• irregular or abnormal heartbeat
• low blood pressure, temporary reddening of the face and neck, sensation of intense heat with sweating and rapid heartbeat
• shortness of breath (dyspnoea), cough, hay fever
• gastrointestinal or intestinal bleeding, inflammation of the intestines (colitis), burning sensation in the stomach, mouth ulcers and cold sores (stomatitis)
• abnormalities in liver function
• inflammation of the inner surface lining of a specific organ
• skin inflammation and redness, skin colour changes with patches (vitiligo), hives (itchy skin rash with raised bumps), hair loss or thinning, excessive night sweating, dry skin
• muscle and joint pain (arthralgia), muscle spasms, joint inflammation (arthritis)
• kidney function impairment
• tremor, lack of energy
• flu-like illness
• decrease in body weight

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Uncommon (may affect up to 1 in 100 people)

• 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 (pulmonary infection)
• a group of symptoms caused by the presence of 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), overactive thyroid gland which may cause increased heart rate, sweating and weight loss, deficiency of glands producing sex hormones
• reduced adrenal gland function due to underactivity of the hypothalamus (part of the brain)
• a group of metabolic complications occurring after anti-tumour treatment, characterised by high levels of potassium and phosphate in the blood, and low levels of calcium (tumour lysis syndrome)
• changes in mental health, reduced sexual drive
• severe and potentially fatal nerve inflammation causing pain, weakness or paralysis of limbs (Guillain-Barré syndrome), fainting, inflammation of cranial nerves, difficulty in coordinating movements (ataxia), tremor, brief involuntary muscle contractions, difficulty speaking
• eye inflammation (conjunctivitis), eye bleeding, inflammation of the coloured part of the eye, reduced vision, sensation of foreign body in the eyes, swollen and watery eyes, eye swelling, eyelid inflammation
• inflammation of blood vessels, blood vessel disease, reduced blood supply to limbs, drop in 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 blockage, inflammation of the anus and rectal wall (characterised by blood in stools and frequent urge to defecate)
• liver failure, liver inflammation, liver enlargement, yellowing of the skin or eyes (jaundice)
• severe and potentially fatal skin peeling (toxic epidermal necrolysis)
• muscle inflammation causing pain or stiffness in the hip and shoulder
• kidney or central nervous system inflammation
• multi-organ inflammation
• inflammation of skeletal muscles
• muscle weakness
• kidney disease
• absence of menstrual cycles
• multi-organ dysfunction, infusion-related reaction
• changes in hair colour
• bladder inflammation; signs and symptoms may include frequent and/or painful urination, urgency to urinate, blood in urine, pain or pressure in the lower abdomen

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

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

• inflammatory disease of blood vessels (most commonly affecting arteries in the head)
• swelling of the thyroid gland (thyroiditis)
• skin disease characterised by dry, red patches covered with scales (psoriasis)
• skin inflammation and redness (erythema multiforme)
• a severe type of skin reaction characterised by rash accompanied by one or more of the following: fever, swelling of the face or lymph glands, increase in eosinophils (a type of white blood cell), effects on liver, kidneys or lungs (a reaction known as DRESS)
• an inflammatory disorder (most commonly autoimmune in origin) affecting the eyes, skin, and membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome), detachment of the membrane in the back of the eye (exudative retinal detachment)
• symptoms of type 1 diabetes or diabetic ketoacidosis, including increased hunger or thirst, need to urinate more often, weight loss, feeling tired, feeling unwell, stomach ache, rapid deep breathing, confusion, unusual drowsiness, sweet-smelling breath, a sweet or metallic taste in the mouth, or unusual odour of urine or sweat
• muscle weakness and fatigue without atrophy (myasthenia gravis)
• absence or reduction of digestive enzymes produced by the pancreas (pancreatic exocrine insufficiency)
• coeliac disease (characterised by symptoms such as stomach ache, diarrhoea and abdominal swelling after consuming foods containing gluten)

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

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

• severe allergic reaction, which could potentially be life-threatening

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Additionally, the following uncommon side effects (may affect up to 1 in 100 people) have been reported in patients who received YERVOY doses different from 3 mg/kg in clinical studies:

• triad of symptoms (meningism): neck stiffness, sensitivity to bright light and headache, flu-like malaise
• inflammation of the heart muscle, heart muscle weakness, fluid around the heart
• inflammation of the liver or pancreas, granulomatous nodules (inflammatory cell clusters) in various organs
• infection within the abdomen
• painful skin lesions on arms, legs and face (erythema nodosum)
• overactivity of the pituitary gland
• reduced function of the parathyroid glands
• eye inflammation, inflammation of the eye muscles
• hearing loss
• poor blood circulation causing numbness or paleness in fingers and toes
• tissue damage in hands and feet causing redness, swelling and blisters

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Other side effects reported with unknown frequency (frequency cannot be estimated from the available data):

• organ transplant rejection
• a type of disease characterised by blisters on the skin (called pemphigoid)
• a condition in which the immune system produces excessive numbers of infection-fighting cells 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)

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Changes in laboratory test results
YERVOY may cause changes in laboratory test results performed by your doctor, such as:

• changes in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood clotting)
• abnormal changes in hormone levels 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 protein in the urine
• abnormally increased alkalinity of the blood and other body tissues
• kidneys unable to normally remove acids from the blood
• presence in the blood of antibodies against some of the body's own cells

The following side effects have been reported with ipilimumab in combination with other anticancer medicines (the frequency and severity of side effects may vary with the combination of anticancer medicines received):

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

• upper respiratory tract infection
• reduced thyroid function (which may cause tiredness or weight gain)
• reduction in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood clotting)
• loss of appetite, high (hyperglycaemia) or low (hypoglycaemia) blood sugar levels
• headache
• shortness of breath (dyspnoea), cough
• diarrhoea (watery, loose or soft stools), vomiting or feeling unwell (nausea), stomach ache, constipation
• skin rash sometimes with blisters, itching
• muscle and bone pain (musculoskeletal pain), joint pain (arthralgia)
• feeling of tiredness or weakness, fever, oedema (swelling)

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Common (may affect up to 1 in 10 people)

• lung infection (pulmonary infection), bronchitis, eye inflammation (conjunctivitis)
• increase in eosinophils (a type of white blood cell)
• allergic reaction, infusion-related reactions
• overactive thyroid (which may cause increased heart rate, sweating and weight loss), decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), underactivity (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, swelling of the thyroid gland, diabetes
• dehydration, reduced levels of albumin and phosphate in the blood, decreased body weight
• nerve inflammation (causing numbness, weakness, tingling or burning pain in arms and legs), dizziness
• blurred vision, dry eyes
• rapid heartbeat, changes in heart rhythm or rate, irregular or abnormal heartbeat
• high blood pressure (hypertension)
• lung inflammation (pneumonitis characterised by coughing attacks and difficulty breathing), fluid around the lungs
• intestinal inflammation (colitis), mouth ulcers and cold sores (stomatitis), pancreas inflammation (pancreatitis), dry mouth, stomach inflammation (gastritis)
• liver inflammation
• skin colour changes with patches (vitiligo), skin redness, unusual hair loss or thinning, hives (itchy skin rash with raised bumps), dry skin
• joint inflammation (arthritis), muscle spasms, muscle weakness
• kidney failure (including sudden loss of kidney function)
• pain, chest pain, chills

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Uncommon (may affect up to 1 in 100 people)

• reduction in neutrophils with fever
• acid in the blood caused by diabetes (diabetic ketoacidosis)
• increased acid levels 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, leading to numbness, weakness, tingling or burning pain (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenia gravis)
• eye inflammation causing pain or redness
• irregular or abnormal heart rhythm, heart muscle inflammation, slow heartbeat
• duodenum inflammation
• skin disease with thickened red skin patches, often with silvery scales (psoriasis), severe skin condition causing red spots, often itchy, similar to measles rash, starting on limbs and sometimes spreading to 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, itching and pain (other types of lichen)
• muscle pain, tenderness or weakness not caused by exercise (myopathy), muscle inflammation (myositis), muscle inflammation causing pain or stiffness (polymyalgia rheumatica)
• kidney inflammation

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

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

• 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 commonly the lungs (sarcoidosis)
• reduced function of the parathyroid glands
• temporary nerve inflammation causing pain, weakness and paralysis of limbs (Guillain-Barré syndrome), nerve inflammation
• 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/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, itching and pain (lichen sclerosus)
• chronic joint disease (spondyloarthropathy), a condition in which the immune system attacks glands producing fluids for the body, such as tears and saliva (Sjögren's syndrome), muscle and joint stiffness, muscle spasm (rhabdomyolysis)
• an inflammatory disorder (most commonly autoimmune in origin) affecting the eyes, skin and membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome), detachment of the membrane in the back of the eye (exudative retinal detachment)
• bladder inflammation; signs and symptoms may include frequent and/or painful urination, urgency to urinate, blood in urine, pain or pressure in the lower abdomen
• absence or reduction of digestive enzymes produced by the pancreas (pancreatic exocrine insufficiency)
• coeliac disease (characterised by symptoms such as stomach ache, diarrhoea and abdominal swelling after consuming foods containing gluten)

Inform your doctor immediately if you experience any of these side effects. Do not attempt to treat these symptoms with other medicines.

Other side effects reported with unknown frequency (frequency cannot be estimated from the available data):

• organ transplant rejection
• a group of metabolic complications occurring after anti-tumour treatment, characterised by high levels of potassium and phosphate in the blood, and low levels of calcium (tumour lysis syndrome)
• inflammation of the heart lining and fluid accumulation around the heart (pericardial diseases)
• a condition in which the immune system produces excessive numbers of infection-fighting cells 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 test results performed by your doctor, such as:

• abnormalities in liver function tests (increase in blood levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, or alkaline phosphatase; increase in blood levels of the waste product bilirubin)
• abnormalities in kidney function tests (increase in blood creatinine)
• increased levels of the enzyme that breaks down fats and the enzyme that breaks down starch
• increased or decreased levels of calcium or potassium
• increased or decreased levels of magnesium or sodium in the blood
• increased levels of the hormone that stimulates the thyroid

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, contact your doctor. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store 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 label of the vial after “Exp.” or “EXP”. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep in the original packaging to protect from light.
Do not store any unused infusion solution for later use. Unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.

6. Package contents and other information

What YERVOY contains

• 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.

Description of the appearance of YERVOY and contents of the pack
YERVOY concentrate for solution for infusion is from transparent to slightly opalescent, from
colourless to pale yellow, and may contain (few) light particles.
It is available in packs containing 1 glass vial of 10 mL or 1 glass vial of 40 mL.
Not all 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

More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Preparation must be performed by trained personnel following good practice guidelines,
particularly with regard to aseptic technique.
Dose calculation:
Ipilimumab as monotherapy or ipilimumab in combination with nivolumab:
The prescribed dose for the patient is indicated in mg/kg. Based on the prescribed dose, calculate the
total dose to be administered. More than one vial of concentrated YERVOY may be required to deliver the
total dose to the patient.

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

Preparation of the infusion:
Aseptic technique must be carefully maintained during preparation of the infusion.
YERVOY may be used for intravenous administration:

• without dilution, after transfer into an infusion container using a dedicated sterile syringe; or
• after dilution up to 5 times the original concentrate volume (up to 4 parts diluent to 1 part concentrate). The final concentration must be between 1 and 4 mg/mL. To dilute YERVOY concentrate, the following may be used:
• an injectable solution of sodium chloride 9 mg/mL (0.9%); or
• an injectable solution of glucose 50 mg/mL (5%).

STEP 1

• Allow the required number of YERVOY vials to reach room temperature for approximately 5 minutes.
• Inspect the concentrated YERVOY for the presence of particles or discoloration. Concentrated YERVOY is a liquid that ranges from transparent to slightly opalescent, colorless to pale yellow, and may contain (a few) light particles. Do not use if there is an unusual amount of particles or signs of discoloration.
• Withdraw the required volume of concentrated YERVOY using a dedicated sterile syringe.

STEP 2

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

Administration:
YERVOY infusion must not be administered by rapid intravenous injection or as a bolus injection. Administer YERVOY infusion intravenously as a 30-minute infusion.
YERVOY infusion must not be administered simultaneously through the same intravenous line as other medicinal products. Use a separate infusion line.
Use an infusion set with an in-line, sterile, pyrogen-free, low protein-binding filter (pore size from 0.2 μm to 1.2 μm).
YERVOY infusion is compatible with:

• PVC infusion sets
• in-line filters made of polyethersulfone (0.2 μm–1.2 μm) and nylon (0.2 μm)

At the end of the infusion, flush the line with an injectable solution of sodium chloride 9 mg/mL (0.9%)
or an injectable solution of glucose 50 mg/mL (5%).
Storage conditions and shelf life:
Unopened vial
YERVOY must be stored in a refrigerator (2°C–8°C). Vials should be kept in their original packaging to protect the medicinal product from light. YERVOY must not be frozen.
Do not use YERVOY after the expiry date stated on the label and carton after “Exp.” or "EXP". The expiry date refers to the last day of that month.
YERVOY infusion
From a microbiological standpoint, once opened, the medicinal product must be infused or diluted and infused immediately. Chemical and physical in-use stability of the undiluted or diluted infusion solution (between 1 and 4 mg/mL) has been demonstrated for 24 hours at room temperature (20°C–25°C) or when refrigerated (2°C–8°C). If not used immediately, the infusion solution (undiluted or diluted) must be used within 24 hours if stored refrigerated (2°C–8°C) or at room temperature (20°C–25°C). Use under any other conditions and timeframes is the responsibility of the user.
Disposal:
Do not store unused infusion solution for later use. Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.