Package leaflet: Information for the user

OPDIVO 10 mg/mL concentrate for solution for infusion

nivolumab
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
It is important that you carry your patient card with you during treatment.
If you have any questions, ask your doctor.
If you get any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

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

1. What OPDIVO is and what it is used for

OPDIVO is a medicine used to treat:

advanced melanoma (a type of skin cancer) in adults and adolescents aged 12 years and older
melanoma after complete resection in adults and adolescents aged 12 years and older (treatment after surgical removal is called adjuvant therapy)
advanced non-small cell lung cancer (a type of lung cancer) in adults
non-small cell lung cancer (a type of lung cancer) before resection in adults (treatment before surgical removal is called neoadjuvant therapy)
non-small cell lung cancer (a type of lung cancer) before and after resection in adults (treatment before surgical removal is called neoadjuvant therapy; treatment after surgical removal is called adjuvant therapy)
malignant pleural mesothelioma (a type of cancer affecting the lining of the lung) in adults
advanced renal cell carcinoma (advanced kidney cancer) in adults
classical Hodgkin lymphoma that has relapsed or has not responded to previous therapies, including autologous stem cell transplant (a transplant of one's own blood-producing stem cells) in adults
classical Hodgkin lymphoma that has relapsed or has not responded to a prior therapy in children aged 5 years and older, adolescents, and adults up to 30 years of age
advanced head and neck cancer in adults
advanced urothelial carcinoma (bladder and urinary tract cancer) in adults
urothelial carcinoma after complete resection in adults
advanced colorectal carcinoma (colon or rectal cancer) in adults
advanced oesophageal carcinoma (cancer of the oesophagus) in adults
oesophageal cancer or gastro-oesophageal junction cancer with residual pathological disease after chemoradiotherapy followed by surgery in adults
advanced adenocarcinoma of the stomach, gastro-oesophageal junction, or oesophagus (cancer of the stomach or oesophagus) in adults
unresectable or advanced hepatocellular carcinoma (liver cancer) in adults.

It contains the active substance nivolumab, which is a monoclonal antibody, a type of protein
designed to recognize and bind to a specific target substance in the body.
Nivolumab binds to a target protein called programmed death-1 receptor (PD-1), which
can inhibit the activity of T cells (a type of white blood cell that is part of the immune system, the
body's natural defence system). By binding to PD-1, nivolumab blocks its action and
prevents it from inhibiting T cell activity; this helps enhance T cell activity against tumour cells in melanoma, lung, kidney, lymphoid, head and neck, bladder, colon, rectum,
stomach, oesophagus, or gastro-oesophageal junction cancers.
OPDIVO may be given 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 should know before using OPDIVO

OPDIVO must not be administered to you if:

you are allergic to nivolumab 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 OPDIVO, as it may cause:

Heart problems, such as changes in heart rhythm or heart rate, or irregular heart rhythms.
Lung problems, such as difficulty breathing or cough. These may be signs of lung inflammation (pneumonitis or interstitial lung disease).
Diarrhoea (watery, loose, or soft stools) or any symptoms of intestinal inflammation (colitis), such as stomach pain and mucus or blood in the stools.
Liver inflammation (hepatitis). Signs and symptoms of hepatitis may include changes in liver function tests, yellowing of the eyes or skin (jaundice), pain in the right side of the abdomen, or fatigue.
Kidney inflammation or kidney problems. Signs and symptoms may include changes in kidney function tests or reduced urine output.
Problems with hormone-producing glands (including the pituitary gland, thyroid, parathyroid glands, and adrenal glands), which may affect how these glands function. Signs and symptoms indicating improper gland function may include tiredness (extreme fatigue), weight changes or headache, low blood calcium levels, and vision problems.
Diabetes, including a serious, sometimes life-threatening condition caused by acid in the blood due to diabetes (diabetic ketoacidosis). Symptoms may include increased hunger or thirst, more frequent urination, weight loss, feeling tired or confused, breath with a sweet or fruity smell, sweet or metallic taste in the mouth, or unusual odour of urine or sweat, nausea or vomiting, stomach pain, and deep or rapid breathing.
Skin inflammation, which may lead to a severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). Signs and symptoms of a severe skin reaction may include redness, itching, and skin peeling (which can be fatal).
Muscle inflammation, such as myocarditis (inflammation of the heart muscle), myositis (muscle inflammation), and rhabdomyolysis (muscle and joint stiffness, muscle spasms). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe fatigue.
Rejection of solid organ transplant.
Graft-versus-host disease. Hemophagocytic lymphohistiocytosis. A rare condition in which the immune system produces an abnormally high 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.

Contact 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 complications and reduce symptoms,
delay your next dose of OPDIVO,
or stop your treatment with OPDIVO completely.

Please note that these signs and symptoms may sometimes be delayed and may develop weeks or months after your last dose. Before treatment, your doctor will assess your overall health. During treatment, you will also undergo blood tests.

Before OPDIVO is administered to you, check with your doctor or nurse if:

you have an autoimmune disease (a condition in which the body attacks its own cells);
you have ocular melanoma;
you have previously received ipilimumab, another medicine used to treat melanoma, and experienced serious side effects from that medicine;
you have been told that cancer has spread to your brain;
you have previously had lung inflammation;
you have taken medicines to suppress the immune system;
you have a type of lymphoma called nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

OPDIVO acts on the immune system. It may cause inflammation in certain parts of the body. The risk of these side effects may be higher if you already have an autoimmune disease (a condition in which the body attacks its own cells). Frequent flare-ups of autoimmune disease may also occur, which in most cases are mild.

Complications of allogeneic stem cell transplantation (using donor stem cells) after treatment with OPDIVO. These complications can be serious and may lead to death. If you undergo allogeneic stem cell transplantation, your healthcare team will monitor you for signs of complications.

Children and adolescents
OPDIVO must not be given to children and adolescents under 18 years of age, except for adolescents aged 12 years and older with melanoma, and children aged 5 years and older and adolescents with classical Hodgkin lymphoma.

Other medicines and OPDIVO
Before OPDIVO is administered, inform your doctor if you are taking any other medicines that suppress the immune system, such as corticosteroids, as these medicines may interfere with the effect of OPDIVO. However, once you have started treatment with OPDIVO, your doctor may give you corticosteroids to reduce any potential side effects that may occur during treatment, and this will not affect the medicine’s efficacy.

Inform your doctor if you are taking or have recently taken any other medicines. Do not take any other medicines during treatment without first discussing with your doctor.

Pregnancy and breastfeeding
Inform your doctor if you are pregnant, suspect you may be pregnant, are planning to become pregnant, or are breastfeeding.

Do not use OPDIVO if you are pregnant, unless your doctor specifically tells you to. The effects of OPDIVO in pregnant women are unknown, but the active substance nivolumab may harm the unborn baby.

If you are a woman of childbearing potential who could become pregnant, you must use an effective method of contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.
If you become pregnant during treatment with OPDIVO, inform your doctor.

It is not known whether OPDIVO passes into breast milk. A risk to the breastfed infant cannot be excluded. Ask your doctor whether you can breastfeed during or after treatment with OPDIVO.

Driving and using machines
OPDIVO alone or in combination with ipilimumab or other anti-cancer medicines may have a minor influence on the ability to drive and use machines. However, exercise caution when performing these activities until you are certain that OPDIVO does not have any adverse effects on you.

OPDIVO contains sodium
If you are on a low-sodium diet (low in salt), inform your doctor before receiving OPDIVO. This medicine contains 2.5 mg of sodium (a main component of table salt) per mL of concentrate. OPDIVO contains 10 mg of sodium per 4 mL vial, 25 mg of sodium per 10 mL vial, 30 mg of sodium per 12 mL vial, or 60 mg of sodium per 24 mL vial, respectively equivalent to 0.5%, 1.25%, 1.5%, or 3% of the maximum daily recommended dietary intake for an adult.

OPDIVO contains polysorbate 80 (E433)
This medicine contains 0.94 mg of polysorbate 80 per 4 mL vial; 2.14 mg of polysorbate 80 per 10 mL vial; 2.6 mg of polysorbate 80 per 12 mL vial; and 5.0 mg of polysorbate 80 per 24 mL vial. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

Key messages from this leaflet can also be found in the patient card provided to you by your doctor. It is important that you carry this card with you and show it to your partner or caregiver.

3. How to use OPDIVO

How much OPDIVO is administered
When OPDIVO is administered alone, the recommended dose is either 240 mg given every 2 weeks or 480 mg given every 4 weeks, depending on the indication.
When OPDIVO is administered alone for the treatment of skin cancer in adolescents aged 12 years and older and weighing at least 50 kg, the recommended dose is 240 mg given every 2 weeks or 480 mg given every 4 weeks. For adolescents aged 12 years and older and weighing less than 50 kg, the recommended dose is 3 mg of nivolumab per kilogram of body weight given every 2 weeks or 6 mg of nivolumab per kilogram of body weight given every 4 weeks.
When OPDIVO is administered in combination with ipilimumab for the treatment of skin cancer in adults and adolescents aged 12 years and older, the recommended dose of OPDIVO is 1 mg of nivolumab per kilogram of body weight for the first 4 doses (combination phase). Subsequently, the recommended dose of OPDIVO (monotherapy phase) is 240 mg given every 2 weeks or 480 mg given 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 given every 2 weeks or 6 mg of nivolumab per kilogram of body weight given every 4 weeks for adolescents aged 12 years and older and weighing less than 50 kg.
When OPDIVO is administered in combination with ipilimumab for the treatment of advanced kidney cancer, the recommended dose of OPDIVO is 3 mg of nivolumab per kilogram of body weight for the first 4 doses (combination phase). Subsequently, the recommended dose of OPDIVO is 240 mg given every 2 weeks or 480 mg given every 4 weeks (monotherapy phase).
When OPDIVO is administered in combination with ipilimumab for the treatment of advanced colon or rectal cancer, the recommended dose of OPDIVO is 3 mg of nivolumab per kilogram of body weight or 240 mg for the first 4 doses (combination phase), depending on the treatment. Subsequently, the recommended dose of OPDIVO is 240 mg given every 2 weeks or 480 mg given every 4 weeks (monotherapy phase), depending on the treatment.
When OPDIVO is administered in combination with ipilimumab for the treatment of malignant pleural mesothelioma, the recommended dose of OPDIVO is 360 mg every 3 weeks.
When OPDIVO is administered in combination with ipilimumab for the treatment of advanced esophageal cancer, the recommended dose of OPDIVO is 3 mg of nivolumab per kilogram of body weight every 2 weeks or 360 mg every 3 weeks.
When OPDIVO is administered in combination with ipilimumab for the treatment of unresectable or advanced liver cancer, the recommended dose of OPDIVO is 1 mg of nivolumab per kilogram of body weight for up to 4 doses (combination phase), depending on the treatment. Subsequently, the recommended dose of OPDIVO is 240 mg every 2 weeks or 480 mg every 4 weeks (monotherapy phase), depending on the treatment.
When OPDIVO is administered in combination with chemotherapy for neoadjuvant treatment of non-small cell lung cancer, the recommended dose of OPDIVO is 360 mg every 3 weeks.
When OPDIVO is administered in combination with chemotherapy for neoadjuvant and adjuvant treatment of non-small cell lung cancer, the recommended dose of OPDIVO is 360 mg every 3 weeks before resection and 480 mg every 4 weeks after surgical removal.
When OPDIVO is administered in combination with chemotherapy for the treatment of advanced esophageal cancer, the recommended dose of OPDIVO is 240 mg every 2 weeks or 480 mg every 4 weeks.
When OPDIVO is administered in combination with chemotherapy for the treatment of advanced adenocarcinoma of the stomach, gastroesophageal junction, or esophagus, the recommended dose of OPDIVO is 360 mg every 3 weeks or 240 mg every 2 weeks.
When OPDIVO is administered in combination with chemotherapy for the treatment of urothelial carcinoma, the recommended dose of OPDIVO is 360 mg every 3 weeks for up to 6 cycles, followed by nivolumab monotherapy administered intravenously at a dose of 240 mg every 2 weeks or 480 mg every 4 weeks.
When OPDIVO is administered in combination with ipilimumab and chemotherapy for the treatment of advanced non-small cell lung cancer, the recommended dose of OPDIVO is 360 mg every 3 weeks. After completion of 2 cycles of chemotherapy, OPDIVO is administered in combination with ipilimumab, and the recommended dose of OPDIVO is 360 mg every 3 weeks.
When OPDIVO is administered in combination with cabozantinib for the treatment of advanced kidney cancer, the recommended dose of OPDIVO is 240 mg given every 2 weeks or 480 mg given every 4 weeks.
When OPDIVO is administered in combination with brentuximab vedotin for the treatment of relapsed or refractory classical Hodgkin lymphoma, the recommended dose of OPDIVO is 3 mg/kg every 3 weeks for 4–6 cycles.
Depending on the dose, the appropriate amount of OPDIVO will be diluted before use with either a 9 mg/mL (0.9%) sodium chloride injection solution or a 50 mg/mL (5%) glucose injection solution. More than one vial of OPDIVO may be required to achieve the required dose.

How OPDIVO is administered
OPDIVO will be administered to you in a hospital or clinic setting under the supervision of an experienced physician.
OPDIVO will be administered by intravenous infusion (a drip into a vein) lasting 30 or 60 minutes, every 2 weeks or every 4 weeks, depending on the dose you are receiving.
Your doctor will continue administering OPDIVO as long as you benefit from it or until the treatment is no longer tolerated.
When OPDIVO is administered in combination with ipilimumab for the treatment of skin cancer, advanced kidney cancer, advanced colon or rectal cancer, or 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. Subsequently, you will receive an infusion lasting 30 or 60 minutes every 2 weeks or every 4 weeks, depending on the dose you are receiving (monotherapy phase).
When OPDIVO is administered in combination with ipilimumab for the treatment of malignant pleural mesothelioma, you will receive an infusion lasting 30 minutes every 3 weeks.
When OPDIVO is administered in combination with ipilimumab for the treatment of advanced esophageal cancer, you will receive an infusion lasting 30 minutes every 2 or 3 weeks, depending on the dose you are receiving.
When OPDIVO is administered in combination with chemotherapy for neoadjuvant treatment of non-small cell lung cancer, you will receive an infusion lasting 30 minutes every 3 weeks. When OPDIVO is administered after surgical removal for adjuvant treatment of non-small cell lung cancer, you will receive an infusion lasting 30 minutes every 4 weeks.
When OPDIVO is administered in combination with chemotherapy for the treatment of advanced esophageal cancer, you will receive an infusion lasting 30 minutes every 2 or 4 weeks, depending on the dose you are receiving.
When OPDIVO is administered in combination with chemotherapy for the treatment of advanced adenocarcinoma of the stomach, gastroesophageal junction, or esophagus, you will receive an infusion lasting 30 minutes every 3 weeks or every 2 weeks, depending on the dose you are receiving.
When OPDIVO is administered in combination with chemotherapy for the treatment of urothelial carcinoma, you will receive an infusion lasting 30 minutes every 2, 3, or 4 weeks, depending on the dose you are receiving.
When OPDIVO is administered in combination with ipilimumab and chemotherapy for the treatment of advanced non-small cell lung cancer, you will receive an infusion lasting 30 minutes every 3 weeks.
When OPDIVO is administered in combination with cabozantinib, you will receive an infusion lasting 30 minutes or 60 minutes every 2 weeks or 4 weeks, depending on the dose you are receiving.
When OPDIVO is administered in combination with brentuximab vedotin for the treatment of relapsed or refractory classical Hodgkin lymphoma, it will be administered by 30-minute infusion every 3 weeks. For Cycle 1, on Day 1 you will receive brentuximab vedotin and on Day 8 you will receive OPDIVO. For Cycles 2–6, you will receive brentuximab vedotin first, followed by OPDIVO at least 30 minutes after completion of the brentuximab vedotin infusion, on the same day.

If you miss an OPDIVO dose
It is very important that you attend all scheduled appointments for OPDIVO administration. If you miss an appointment, ask your doctor when to schedule your next dose.

If you stop treatment with OPDIVO
Stopping treatment may interrupt the effect of the medicine. Do not stop treatment with OPDIVO before discussing it with your doctor.
If you have any questions about your treatment or the use of this medicine, consult your doctor.
When OPDIVO is administered in combination with other anti-cancer medicines, except brentuximab vedotin, you will receive OPDIVO first, followed by the other medicine. When OPDIVO is administered in combination with brentuximab vedotin, for Cycle 1, on Day 1 you will receive brentuximab vedotin and on Day 8 you will receive OPDIVO. For Cycles 2–6, you will receive brentuximab vedotin first, followed by OPDIVO at least 30 minutes after completion of the brentuximab vedotin infusion, on the same day.
Refer to the package leaflet of these other medicines to understand their use. If you have any questions about them, 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. OPDIVO acts on the immune system and can cause inflammation in some parts of the body. Inflammation can cause serious harm and some inflammatory conditions may be life-threatening and require treatment or discontinuation of OPDIVO.

The following side effects have been reported with OPDIVO alone:

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

Infections of the upper respiratory tract
Decrease in the number of red blood cells (which carry oxygen), white blood cells (which are important for fighting infections), or platelets (cells that help blood to clot)
Decreased appetite, high blood sugar levels (hyperglycaemia)
Headache
Shortness of breath (dyspnoea), cough
Diarrhoea (watery, loose or soft stools), vomiting, nausea, stomach pain, constipation
Rash sometimes with blisters or vesicles, itching
Muscle, bone (musculoskeletal pain), and joint pain (arthralgia)
Feeling of tiredness or weakness, fever

Common (may affect up to 1 in 10 people)

Severe lung infection (pulmonary infection), bronchitis
Reactions related to medicine infusion, allergic reaction (including life-threatening allergic reaction)
Reduced thyroid function (which may cause tiredness or weight gain), increased thyroid function (which may cause rapid heartbeat, sweating and weight loss), swelling of the thyroid gland
Dehydration, decreased body weight, low blood sugar levels (hypoglycaemia)
Inflammation of nerves (causing numbness, weakness, tingling or burning pain in arms and legs), dizziness
Blurred vision, dry eyes
Fast heartbeat, irregular heart rhythm
High blood pressure (hypertension)
Inflammation of the lungs (pneumonitis, characterised by episodes of cough and difficulty breathing), fluid around the lungs
Inflammation of the intestine (colitis), mouth ulcers and cold sores (stomatitis), dry mouth
Skin colour changes with patches (vitiligo), dry skin, skin redness, unusual hair loss or thinning
Inflammation of the joints (arthritis)
Kidney failure (including sudden loss of kidney function)
Pain, chest pain, oedema (swelling)

Uncommon (may affect up to 1 in 100 people)

Increase in certain types of white blood cells
Chronic diseases associated with accumulation of inflammatory cells in various organs and tissues, most commonly the lungs (sarcoidosis)
Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), reduced function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, diabetes
Increased levels of acids in the blood (metabolic acidosis)
Nerve damage causing numbness and weakness (polyneuropathy), inflammation of nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy)
Inflammation of the eye (causing pain and redness)
Inflammation of the heart muscle, inflammation of the heart lining and fluid accumulation around the heart (pericardial diseases), changes in heart rhythm or heartbeat frequency
Fluid in the lungs
Inflammation of the pancreas (pancreatitis), inflammation of the stomach (gastritis)
Inflammation of the liver (hepatitis), blockage of bile ducts (cholestasis)
Skin disease with thickened patches of red skin, often with silvery scales (psoriasis), facial skin condition where the nose and cheeks are unusually red (rosacea), severe skin condition causing red spots, often itchy, similar to measles rash, starting on limbs and sometimes on the face and rest of the body (erythema multiforme), urticaria (itchy, raised rash)
Inflammation of muscles causing pain or stiffness (polymyalgia rheumatica)

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

Temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
A disease causing inflammation or enlargement of a lymph node (Kikuchi lymphadenitis)
Acids in the blood produced by diabetes (diabetic ketoacidosis), reduced function of parathyroid glands
Temporary inflammation of nerves causing pain, weakness and paralysis of extremities (Guillain-Barré syndrome), loss of the protective covering of nerves (demyelination),
a condition in which muscles become weak and tire easily (myasthenic syndrome), inflammation of the brain
Inflammation of the optic nerve which may cause complete or partial loss of vision (optic neuritis)
Inflammatory disease of blood vessels
Ulcer of the small intestine
Severe skin peeling that may lead to death (toxic epidermal necrolysis or Stevens-Johnson syndrome)
A disease in which the immune system attacks glands producing body fluids such as tears and saliva (Sjögren's syndrome), muscle pain, tenderness or muscle weakness not caused by exercise (myopathy), inflammation of muscles (myositis), stiffness in muscles and joints, muscle spasm (rhabdomyolysis)
Kidney inflammation, bladder inflammation; signs and symptoms may include frequent and/or painful urination, urgency to urinate, blood in urine, pain or pressure in lower abdomen
Lack or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency)
Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea and abdominal bloating after consuming foods containing gluten)

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

A disease (called haemophagocytic lymphohistiocytosis) in which the immune system overproduces infection-fighting cells called histiocytes and lymphocytes, and which may cause various symptoms
Rejection of solid organ transplant
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)
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)
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)
Changes in any area of the skin and/or genital area associated with dryness, thinning, itching and pain (lichen sclerosus or other types of lichen)

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

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

Infections of the upper respiratory tract
Decrease in the number of red blood cells (which carry oxygen), white blood cells (which are important for fighting infections), or platelets (cells that help blood to clot)
Allergic reaction, reactions related to medicine infusion
Reduced thyroid function (which may cause tiredness or weight gain), increased thyroid function (which may cause rapid heartbeat, sweating and weight loss)
Decreased appetite, decreased body weight, decreased levels of albumin in blood, high (hyperglycaemia) or low (hypoglycaemia) blood sugar levels
Inflammation of nerves (causing numbness, weakness, tingling or burning pain in arms and legs), headache, dizziness, altered sense of taste
High blood pressure (hypertension)
Shortness of breath (dyspnoea), cough, abnormal voice quality (dysphonia)
Diarrhoea (watery, loose or soft stools), constipation, vomiting, nausea, stomach pain, mouth ulcers and cold sores (stomatitis), indigestion (dyspepsia)
Rash sometimes with blisters or vesicles, itching, pain in hands or soles of feet: rash or skin redness, tingling and tenderness causing symmetric redness, swelling and pain mainly on palms of hands and soles of feet (palmar-plantar erythrodysesthesia syndrome)
Joint pain (arthralgia), muscle and bone pain (musculoskeletal pain), muscle spasms
Excess protein in urine
Feeling of tiredness or weakness, fever, oedema (swelling)

Common (may affect up to 1 in 10 people)

Severe lung infection (pulmonary infection), bronchitis, eye inflammation (conjunctivitis)
Increase in certain types of white blood cells, reduction in neutrophils with fever
Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), reduced function (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 phosphate in blood
Sensations such as numbness and tingling (paraesthesia)
Sensation of a persistent sound in the ear when no sound is present (tinnitus)
Blurred vision, dry eye
Fast heartbeat, irregular heart rhythm, inflammatory disease of blood vessels
Formation of a blood clot inside a blood vessel (thrombosis)
Inflammation of the lungs (pneumonitis characterised by episodes of cough and difficulty breathing), fluid around the lungs, blood clots, nosebleeds
Inflammation of the intestine (colitis), inflammation of the pancreas (pancreatitis), dry mouth, inflammation of the stomach (gastritis), oral pain, haemorrhoids (piles)
Inflammation of the liver
Skin colour changes with patches (including vitiligo), skin redness, unusual hair loss or thinning, hair colour change, urticaria (itchy rash), depigmentation or abnormal darkening of the skin (cutaneous hyperpigmentation), dry skin
Inflammation of the joints (arthritis), muscle weakness, muscle pain
Kidney failure (including sudden loss of kidney function)
Pain, chest pain, chills
General feeling of being unwell (malaise)

Uncommon (may affect up to 1 in 100 people)

Acid in the blood produced by diabetes (diabetic ketoacidosis)
Increased levels of acid in the blood
Temporary inflammation of nerves causing pain, weakness and paralysis of extremities (Guillain-Barré syndrome); nerve damage causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve paralysis); inflammation of nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenia gravis or syndrome)
Inflammation of the brain
Inflammation of the eye (causing pain and redness)
Changes in heart rhythm and heartbeat frequency, slow heart rate, inflammation of the heart muscle
Intestinal perforation, inflammation of the duodenum, burning or painful sensation in the tongue (glossodynia)
Severe skin peeling that may lead to death (Stevens-Johnson syndrome), skin disease with thickened patches of red skin, often with silvery scales (psoriasis), severe skin condition causing red spots, often itchy, similar to measles rash, starting on limbs and sometimes on the face and rest of the body
(erythema multiforme), changes in any area of the skin and/or genital area associated with dryness, thinning, itching and pain (other types of lichen)
Muscle tenderness or weakness not caused by exercise (myopathy), inflammation of muscles (myositis), stiffness in muscles and joints, inflammation of muscles causing pain or stiffness (polymyalgia rheumatica), bone damage in the jaw, abnormal opening between two body parts, such as an organ or blood vessel and another structure (fistula)
Kidney inflammation, bladder inflammation; signs and symptoms may include frequent and/or painful urination, urgency to urinate, blood in urine, pain or pressure in lower abdomen

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

Temporary and 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 parathyroid glands
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)
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)
Inflammation of the optic nerve which may cause complete or partial loss of vision (optic neuritis)
Inflammation of nerves
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)
Severe skin peeling that may lead to death (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), disease in which the immune system attacks glands producing body fluids such as tears and saliva (Sjögren's syndrome), muscle spasm (rhabdomyolysis)
Lack or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency)
Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea and abdominal bloating after consuming foods containing gluten)

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

A disease (called haemophagocytic lymphohistiocytosis) in which the immune system overproduces infection-fighting cells called histiocytes and lymphocytes, and which may cause various symptoms
Rejection of solid organ transplant
Inflammation of the heart lining and fluid accumulation around the heart (pericardial diseases)

Contact your doctor immediately if you experience any of the above-listed side effects. Do not attempt to treat these symptoms with other medicines.

Changes in laboratory test results
OPDIVO alone or in combination may cause changes in laboratory test results performed by your doctor, such as:

Abnormal liver function tests (increased blood levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, or alkaline phosphatase; increased blood levels of waste product bilirubin)
Abnormal kidney function tests (increased blood creatinine levels)
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
Increased blood triglyceride levels
Increased blood cholesterol levels

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. Reporting side effects helps provide more information on the safety of this medicine.

5. How to store OPDIVO

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." 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.
The unopened vial may be stored at controlled room temperature up to 25°C under normal light conditions for up to 48 hours.
Do not store 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 OPDIVO contains

The active substance is nivolumab. Each mL of concentrate for solution for infusion contains 10 mg of nivolumab. Each vial contains 40 mg (in 4 mL), 100 mg (in 10 mL), 120 mg (in 12 mL) or 240 mg (in 24 mL) of nivolumab.
The other components are: sodium citrate dihydrate, sodium chloride, mannitol (E421), pentetic acid, polysorbate 80 (E433), sodium hydroxide, hydrochloric acid and water for injections (see section 2 "OPDIVO contains sodium" and "OPDIVO contains polysorbate 80 (E433)").

Description of the appearance of OPDIVO and contents of the pack
OPDIVO concentrate for solution for infusion (sterile concentrate) is a liquid, clear to opalescent, colourless to pale yellow, which may contain a few light particles.
It is available in packs containing 1 vial of 4 mL, 1 vial of 10 mL, 1 vial of 12 mL or 1 vial of 24 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
Swords Laboratories Unlimited Company t/a Bristol-Myers Squibb Cruiserath Biologics
Cruiserath Road, Mulhuddart
Dublin 15, D15 H6EF
Ireland

For further information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
N.V. Bristol-Myers Squibb Belgium S.A. Swixx Biopharma UAB
Tél/Tel: + 32 2 352 76 11 Tel: + 370 52 369140
[email protected] [email protected]

България Luxembourg/Luxemburg
Swixx Biopharma EOOD N.V. Bristol-Myers Squibb Belgium S.A.
Teл.: + 359 2 4942 480 Tél/Tel: + 32 2 352 76 11
[email protected] [email protected]

Česká republika Magyarország
Bristol-Myers Squibb spol. s r.o. Bristol-Myers Squibb Kft.
Tel: + 420 221 016 111 Tel.: + 36 1 301 9797
[email protected] [email protected]

Danmark Malta
Bristol-Myers Squibb Denmark A.M. Mangion Ltd
Tlf: + 45 45 93 05 06 Tel: + 356 23976333
[email protected] [email protected]

Deutschland Nederland
Bristol-Myers Squibb GmbH & Co. KGaA Bristol-Myers Squibb B.V.
Tel: 0800 0752002 (+ 49 89 121 42 350) Tel: + 31 (0)30 300 2222
[email protected] [email protected]

Eesti Norge
Swixx Biopharma OÜ Bristol-Myers Squibb Norway AS
Tel: + 372 640 1030 Tlf: + 47 67 55 53 50
[email protected] [email protected]

Ελλάδα Österreich
Bristol-Myers Squibb A.E. Bristol-Myers Squibb GesmbH
Τηλ: + 30 210 6074300 Tel: + 43 1 60 14 30
[email protected] [email protected]

España Polska
Bristol-Myers Squibb, S.A. Bristol-Myers Squibb Polska Sp. z o.o.
Tel: + 34 91 456 53 00 Tel.: + 48 22 2606400
[email protected] [email protected]

France Portugal
Bristol-Myers Squibb SAS Bristol-Myers Squibb Farmacêutica Portuguesa,
Tél: + 33 (0)1 58 83 84 96 S.A.
[email protected] Tel: + 351 21 440 70 00
[email protected]

Hrvatska România
Swixx Biopharma d.o.o. Bristol-Myers Squibb Marketing Services S.R.L.
Tel: + 385 1 2078 500 Tel: + 40 (0)21 272 16 19
[email protected] [email protected]

Ireland Slovenija
Bristol-Myers Squibb Pharmaceuticals uc Swixx Biopharma d.o.o.
Tel: 1 800 749 749 (+ 353 (0)1 483 3625) Tel: + 386 1 2355 100
[email protected] [email protected]

Ísland Slovenská republika
Vistor ehf. Swixx Biopharma s.r.o.
Sími: + 354 535 7000 Tel: + 421 2 20833 600
[email protected] [email protected]

Italia Suomi/Finland
Bristol-Myers Squibb S.r.l. Oy Bristol-Myers Squibb (Finland) Ab
Tel: + 39 06 50 39 61 Puh/Tel: + 358 9 251 21 230
[email protected] [email protected]

Κύπρος Sverige
Bristol-Myers Squibb A.E. Bristol-Myers Squibb Aktiebolag
Τηλ: 800 92666 (+ 30 210 6074300) Tel: + 46 8 704 71 00
[email protected] [email protected]

Latvija
Swixx Biopharma SIA
Tel: + 371 66164750
[email protected]

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

The following information is intended exclusively for healthcare professionals:

Preparation and administration of OPDIVO
Preparation must be performed by trained personnel following good practice guidelines,
particularly with regard to aseptic technique.
Dose calculation
More than one vial of OPDIVO concentrate may be required to administer the total dose to the patient.
Nivolumab as monotherapy
The prescribed dose for adults is 240 mg or 480 mg depending on the indication, regardless of body weight.
Melanoma (advanced or adjuvant treatment) in adolescents. The prescribed dose for adolescents aged 12 years and older and weighing at least 50 kg is 240 mg or 480 mg. For adolescents aged 12 years and older and weighing less than 50 kg, the prescribed dose is expressed in mg/kg. Based on the prescribed dose, calculate the total dose to be administered.

Total nivolumab dose in mg = patient's weight in kg × prescribed dose in mg/kg.
Volume of OPDIVO concentrate to prepare the dose (mL) = total nivolumab dose in mg divided by 10 (the concentration of OPDIVO concentrate is 10 mg/mL).

Nivolumab in combination with ipilimumab
The prescribed dose for the patient is indicated in mg/kg. Based on the prescribed dose, calculate the total dose to be administered (see above).
Nivolumab in combination with ipilimumab in malignant pleural mesothelioma
The prescribed dose for the patient is 360 mg regardless of body weight.
Nivolumab in combination with ipilimumab in advanced colorectal carcinoma
The prescribed dose for the patient may be based on body weight (3 mg/kg) or may be 240 mg regardless of body weight.
Nivolumab in combination with ipilimumab in advanced esophageal cancer
The prescribed dose for the patient may be based on body weight (3 mg/kg) or may be 360 mg regardless of body weight.
Nivolumab in combination with ipilimumab in unresectable or advanced hepatocellular carcinoma
The prescribed dose for the patient is based on body weight (1 mg/kg).
Nivolumab in combination with chemotherapy in resectable non-small cell lung cancer
The prescribed dose for the patient is 360 mg regardless of body weight.
Nivolumab in combination with chemotherapy in advanced esophageal cancer
The prescribed dose for the patient is 240 mg or 480 mg regardless of body weight.
Nivolumab in combination with chemotherapy in adenocarcinoma of the stomach, gastroesophageal junction, or esophagus
The prescribed dose for the patient is 360 mg or 240 mg regardless of body weight.
Nivolumab in combination with ipilimumab and chemotherapy
The prescribed dose for the patient is 360 mg regardless of body weight.
Nivolumab in combination with cabozantinib
The prescribed dose for the patient is nivolumab 240 mg or 480 mg regardless of body weight.
Nivolumab in combination with brentuximab vedotin
The prescribed dose for the patient is indicated in mg/kg. Based on the prescribed dose, calculate the total dose to be administered (see above).
Preparation of infusion solution
Ensure aseptic technique is used during preparation of the infusion solution.
OPDIVO may be used for intravenous administration:

without dilution, after transfer into an intravenous infusion container using a dedicated sterile syringe; or
after dilution according to the following instructions:
the final concentration must be between 1 and 10 mg/mL
the total infusion volume must not exceed 160 mL. For patients weighing less than 40 kg, the total infusion volume must not exceed 4 mL per kilogram of patient weight.
To dilute OPDIVO concentrate, use:
9 mg/mL (0.9%) sodium chloride injectable solution; or
50 mg/mL (5%) glucose injectable solution.

STEP 1

Inspect OPDIVO concentrate for any change in color or presence of particles. Do not shake the vial. OPDIVO concentrate is a liquid ranging from clear to opalescent, colorless to pale yellow. Discard the vial if the solution is cloudy, has changed color, or contains particles other than few, translucent to white particles.
Withdraw the required volume of OPDIVO concentrate using a dedicated sterile syringe.

STEP 2

Transfer the concentrate into a sterile, vacuum glass vial or intravenous infusion container (PVC or polyolefin).
If necessary, dilute with the required volume of 9 mg/mL (0.9%) sodium chloride injectable solution or 50 mg/mL (5%) glucose injectable solution. For ease of preparation, the concentrate may be transferred directly into a pre-filled bag containing the appropriate volume of 9 mg/mL (0.9%) sodium chloride injectable solution or 50 mg/mL (5%) glucose injectable solution.
Gently mix the infusion solution by manual rotation. Do not shake.

Administration
OPDIVO infusion must not be administered as a rapid intravenous injection or bolus.
Administer OPDIVO infusion intravenously over 30 or 60 minutes depending on dose and indication.
OPDIVO infusion must not be administered through the same intravenous line concurrently with other substances. Use a separate infusion line.
Use a sterile, non-pyrogenic, low protein-binding infusion set with an in-line filter (pore size from 0.2 μm to 1.2 μm).
OPDIVO infusion is compatible with:

PVC containers
polyolefin containers
glass vials
PVC infusion sets
in-line filters with membranes made of polyethersulfone with pore sizes from 0.2 µm to 1.2 µm.

After administration of the nivolumab dose, flush the line with 9 mg/mL (0.9%) sodium chloride injectable solution or 50 mg/mL (5%) glucose injectable solution.
Storage conditions and shelf life
Unopened vial
OPDIVO must be stored in the refrigerator (2°C - 8°C). Vials should be kept in their original packaging to protect from light. OPDIVO must not be frozen.
The unopened vial may be stored at controlled room temperature up to 25°C under normal lighting conditions for up to 48 hours.
Do not use OPDIVO after the expiry date stated on the carton and label of the vial after "Exp." or "EXP". The expiry date refers to the last day of that month.
OPDIVO infusion
Chemical and physical in-use stability from the time of preparation has been demonstrated as follows (times include the administration period):

Preparation of the infusion solution	In-use chemical and physical stability
Preparation of the infusion solution	Store between 2°C and 8°C, protected from light	Store at room temperature (≤ 25°C) under normal lighting conditions
Undiluted or diluted with an injectable solution of sodium chloride 9 mg/mL (0.9%)	30 days	24 hours (within the total 30-day storage period)
Diluted with an injectable solution of glucose 50 mg/mL (5%)	7 days	8 hours (within the total 7-day storage period)

From a microbiological standpoint, the prepared infusion solution must be used immediately, regardless of the diluent used. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 7 days at a temperature between 2°C and 8°C, or 8 hours (within the total 7-day storage period) at room temperature (≤ 25°C). An aseptic technique must be employed during the preparation of the infusion solution.
Disposal
Do not store unused infusion solution for later use. Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.

Patient Information Leaflet: Information for the user

OPDIVO 600 mg solution for injection

nivolumab
Please read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
It is important that you carry your patient card with you during treatment.
If you have any questions, consult your doctor.
If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor. See section 4.

Contents of this leaflet:

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

1. What OPDIVO is and what it is used for

OPDIVO is a medicine used to treat:

advanced melanoma (a type of skin cancer) in adults
melanoma after complete resection in adults (treatment after surgical removal is called adjuvant therapy)
advanced non-small cell lung cancer (a type of lung cancer) in adults
non-small cell lung cancer (a type of lung cancer) before resection and after resection in adults (treatment before surgical removal is called neoadjuvant therapy; treatment after surgical removal is called adjuvant therapy)
advanced renal cell carcinoma (advanced kidney cancer) in adults
advanced head and neck cancer in adults
advanced urothelial carcinoma (bladder cancer and urinary tract cancer) in adults
urothelial carcinoma after complete resection in adults
advanced colorectal cancer (colon or rectal cancer) in adults
advanced oesophageal cancer (cancer of the oesophagus) in adults
oesophageal cancer or gastro-oesophageal junction cancer with residual pathological disease after chemoradiotherapy followed by surgery in adults
advanced adenocarcinoma of the stomach, gastro-oesophageal junction or oesophagus (stomach or oesophageal cancer) in adults
unresectable or advanced hepatocellular carcinoma (liver cancer) in adults.

It contains the active substance nivolumab, which is a monoclonal antibody, a type of protein
designed to recognise and bind to a specific target substance in the body.
Nivolumab binds to a target protein called programmed death-1 receptor (PD-1), which
can inhibit the activity of T cells (a type of white blood cell that is part of the immune system, the
body's natural defence system). By binding to PD-1, nivolumab blocks its action and
prevents it from inhibiting T cell activity; this helps enhance T cell activity against melanoma, lung, kidney, head and neck, bladder, colon, rectum, stomach, oesophagus or gastro-oesophageal junction cancer cells.
OPDIVO may be given in combination with other anti-cancer medicines. It is important that
you also read the package leaflet of these other medicines. If you have any questions about these
medicines, consult your doctor.

2. What you need to know before using OPDIVO

Do not take OPDIVO

if you are allergic to nivolumab 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 OPDIVO, as it may cause:

Heart problems, such as changes in heart rhythm or heart rate, or heart rhythm abnormalities.
Lung problems, such as difficulty breathing or cough. These may be signs of lung inflammation (pneumonitis or interstitial lung disease).
Diarrhoea (watery, loose, or soft stools) or any symptoms of intestinal inflammation (colitis), such as stomach pain, or mucus or blood in the stools.
Liver inflammation (hepatitis). Signs and symptoms of hepatitis may include changes in liver function tests, yellowing of the eyes or skin (jaundice), pain in the right side of the abdomen, or fatigue.
Kidney inflammation or problems. Signs and symptoms may include changes in kidney function tests or reduced urine output.
Problems with hormone-producing glands (including the pituitary gland, thyroid, parathyroid glands, and adrenal glands), which may affect how these glands function. Signs and symptoms indicating improper gland function may include fatigue (extreme tiredness), weight changes, headache, low blood calcium levels, or vision problems.
Diabetes, including a serious, sometimes life-threatening condition caused by acid in the blood due to diabetes (diabetic ketoacidosis). Symptoms may include increased hunger or thirst, more frequent urination, weight loss, feeling tired or difficulty thinking clearly, breath with a sweet or fruity odour, sweet or metallic taste in the mouth, or unusual odour of urine or sweat, nausea or vomiting, stomach pain, and deep or rapid breathing.
Skin inflammation, which may lead to a severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). Signs and symptoms of a severe skin reaction may include redness, itching, and peeling of the skin (which may be fatal).
Muscle inflammation, such as myocarditis (inflammation of the heart muscle), myositis (inflammation of the muscles), and rhabdomyolysis (muscle and joint stiffness, muscle spasms). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe fatigue.
Rejection of solid organ transplant.
Graft-versus-host disease.
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: enlarged liver and/or spleen, rash, swollen lymph nodes, breathing problems, easy bruising, kidney abnormalities, and heart problems.

Contact your doctor immediately if you experience any of these signs or symptoms, or if they worsen. Do not try to treat these symptoms with other medicines. Your doctor may:

prescribe other medicines to prevent complications and reduce symptoms,
delay your next dose of OPDIVO,
or stop treatment with OPDIVO completely.

Please note that these signs and symptoms may sometimes be delayed and may develop weeks or months after the last dose. Before treatment, your doctor will check your general health. During treatment, you will also have blood tests.
Before OPDIVO is given to you, check with your doctor or nurse if:

you have an autoimmune disease (a condition in which the body attacks its own cells);
you have ocular melanoma;
you have previously received ipilimumab, another medicine used to treat melanoma, and experienced serious side effects from that medicine;
you have been told that cancer has spread to the brain;
you have previously had lung inflammation;
you have taken a medicine to suppress the immune system. OPDIVO acts on the immune system. It may cause inflammation in certain parts of the body. The risk of these side effects may be higher if you already have an autoimmune disease (a condition in which the body attacks its own cells). Frequent flare-ups of autoimmune disease may also occur, which in most cases are mild. Complications from allogeneic stem cell transplantation (using donor stem cells) after treatment with OPDIVO. These complications can be severe and may lead to death. If you undergo allogeneic stem cell transplantation, your healthcare team will monitor you for signs of complications.

Children and adolescents
OPDIVO injectable solution must not be administered to children and adolescents under 18 years of age.
Other medicines and OPDIVO
Before OPDIVO is administered, inform your doctor if you are taking any other medicine that suppresses the immune system, such as corticosteroids, as these medicines may interfere with the effect of OPDIVO. However, once you have been treated with OPDIVO, your doctor may give you corticosteroids to reduce any possible side effects you may experience during treatment, and this will not affect the medicine's efficacy.
Tell your doctor if you are taking or have recently taken any other medicines. Do not take any other medicine during treatment without first talking to your doctor.
Pregnancy and breastfeeding
Inform your doctor if you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding.
Do not use OPDIVO during pregnancy unless your doctor tells you to. The effects of OPDIVO in pregnant women are unknown, but the active substance nivolumab may harm the unborn baby.

If you are a woman of childbearing potential who could become pregnant, you must use an effective contraceptive method during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.
If you become pregnant during treatment with OPDIVO, inform your doctor.

It is not known whether OPDIVO passes into breast milk. A risk to the breastfed infant cannot be ruled out.
Ask your doctor whether you can breastfeed during or after treatment with OPDIVO.
Driving and using machines
OPDIVO or OPDIVO in combination with ipilimumab may have a minor influence on the ability to drive and use machines; however, exercise caution when performing these activities until you are sure that OPDIVO does not affect you negatively.
OPDIVO contains polysorbate 80 (E433)
This medicine contains 2.5 mg of polysorbate 80 per 5 mL vial, equivalent to 5 mg/10 mL. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.
Key messages from this leaflet can also be found on the patient card provided to you by your doctor. It is important that you carry this card with you and show it to your partner or caregiver.

3. How to use OPDIVO

How much OPDIVO is given
When OPDIVO is administered alone as an injection under the skin (subcutaneous injection), the recommended dose is 600 mg given every 2 weeks or 1,200 mg given every 4 weeks.
When OPDIVO is administered in combination with ipilimumab for the treatment of skin cancer, the recommended dose of OPDIVO administered as an intravenous infusion is 1 mg of nivolumab per kilogram of body weight for the first 4 doses (combination phase).
Subsequently, the recommended dose of OPDIVO administered as a subcutaneous injection is 600 mg every 2 weeks or 1,200 mg every 4 weeks (monotherapy phase).
When OPDIVO is administered in combination with ipilimumab for the treatment of advanced kidney cancer, the recommended dose of OPDIVO administered as an intravenous infusion is 3 mg of nivolumab per kilogram of body weight for the first 4 doses (combination phase).
Subsequently, the recommended dose of OPDIVO administered as a subcutaneous injection is 600 mg every 2 weeks or 1,200 mg every 4 weeks (monotherapy phase).
When OPDIVO is administered in combination with ipilimumab for the treatment of advanced colon or rectal cancer, the recommended dose of OPDIVO administered as an intravenous infusion is 3 mg of nivolumab per kilogram of body weight or 240 mg for the first 4 doses (combination phase), depending on the treatment regimen. Subsequently, the recommended dose of OPDIVO administered as a subcutaneous injection is 600 mg every 2 weeks or 1,200 mg every 4 weeks (monotherapy phase), depending on the treatment regimen.
When OPDIVO is administered in combination with ipilimumab for the treatment of unresectable or advanced liver cancer, the recommended dose of OPDIVO administered as an intravenous infusion is 1 mg of nivolumab per kilogram of body weight for up to 4 doses (combination phase), depending on the treatment regimen. Subsequently, the recommended dose of OPDIVO administered as a subcutaneous injection is 600 mg every 2 weeks or 1,200 mg every 4 weeks (monotherapy phase), depending on the treatment regimen.
When OPDIVO is administered in combination with chemotherapy for the treatment of advanced oesophageal cancer, the recommended dose of OPDIVO is 600 mg every 2 weeks or 1,200 mg every 4 weeks as a subcutaneous injection.
When OPDIVO is administered in combination with chemotherapy for the treatment of advanced adenocarcinoma of the stomach, gastro-oesophageal junction, or oesophagus, the recommended dose of OPDIVO is 600 mg every 2 weeks as a subcutaneous injection.
When OPDIVO is administered in combination with chemotherapy for neoadjuvant and adjuvant treatment of non-small cell lung cancer, the recommended dose of OPDIVO administered as an intravenous infusion is 360 mg of nivolumab every 3 weeks for 4 cycles (combination phase) before resection. Subsequently, the recommended dose of OPDIVO administered as a subcutaneous injection is 1,200 mg every 4 weeks (monotherapy phase).
When OPDIVO is administered in combination with chemotherapy for the treatment of urothelial carcinoma, the recommended dose of OPDIVO administered as an intravenous infusion is 360 mg of nivolumab every 3 weeks for up to 6 cycles (combination phase). Subsequently, the recommended dose of OPDIVO administered as a subcutaneous injection is 600 mg every 2 weeks or 1,200 mg every 4 weeks (monotherapy phase).
When OPDIVO is administered in combination with cabozantinib for the treatment of advanced kidney cancer, the recommended dose of OPDIVO is 600 mg given every 2 weeks or 1,200 mg given every 4 weeks as a subcutaneous injection.

How OPDIVO is administered
OPDIVO will be administered to you under the supervision of an experienced doctor. More than one vial of OPDIVO may be needed to deliver the required dose.
OPDIVO is administered as a subcutaneous injection into the abdomen or thigh, lasting 3–5 minutes, every 2 weeks or every 4 weeks, depending on the dose you are receiving. Treatment with OPDIVO will continue as long as you benefit from it or until it is no longer tolerated.
When OPDIVO is administered in combination with ipilimumab for the treatment of skin cancer, advanced kidney cancer, advanced colon or rectal cancer, or 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 regimen. Subsequently, you will receive a subcutaneous injection into the abdomen or thigh lasting 3–5 minutes every 2 or 4 weeks, depending on the dose you are receiving (monotherapy phase).
When OPDIVO is administered after surgical removal as a subcutaneous injection into the abdomen or thigh for adjuvant treatment of non-small cell lung cancer, you will receive an injection lasting 3–5 minutes every 4 weeks.
When OPDIVO is administered as a subcutaneous injection into the abdomen or thigh in combination with chemotherapy for the treatment of advanced oesophageal cancer, you will receive an injection lasting 3–5 minutes every 2 or 4 weeks, depending on the dose you are receiving.
When OPDIVO is administered as a subcutaneous injection into the abdomen or thigh in combination with chemotherapy for the treatment of advanced adenocarcinoma of the stomach, gastro-oesophageal junction, or oesophagus, you will receive an injection lasting 3–5 minutes every 2 weeks.
When OPDIVO is administered as a subcutaneous injection into the abdomen or thigh in combination with chemotherapy for the treatment of urothelial carcinoma, you will receive an injection lasting 3–5 minutes every 2 or 4 weeks, depending on the dose you are receiving.
When OPDIVO is administered as a subcutaneous injection into the abdomen or thigh in combination with cabozantinib, you will receive an injection lasting 3–5 minutes every 2 or 4 weeks, depending on the dose you are receiving.

If you miss a dose of OPDIVO
It is very important that you keep all scheduled appointments for OPDIVO administration. If you miss an appointment, consult your doctor to schedule your next dose.

If you stop treatment with OPDIVO
Stopping treatment may interrupt the medicine's effect. Do not stop treatment with OPDIVO 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 OPDIVO is administered in combination with other anti-cancer medicines, you will receive OPDIVO first, followed by the other medicine.
Refer to the package leaflet of these other medicines to understand their use. If you have any questions about them, consult your doctor.

4. Possible side effects

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

The following side effects have been reported with OPDIVO alone:

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

Infections of the upper respiratory tract
Decrease in the number of red blood cells (which carry oxygen), white blood cells (which are important for fighting infections), or platelets (cells that help blood to clot)
Decreased appetite, high blood sugar levels (hyperglycaemia)
Headache
Shortness of breath (dyspnoea), cough
Diarrhoea (watery, loose, or soft stools), vomiting, nausea, stomach pain, constipation
Rash, sometimes with blisters or vesicles, itching
Muscle, bone (musculoskeletal pain), and joint pain (arthralgia)
Feeling of tiredness or weakness, fever

Common (may affect up to 1 in 10 people)

Severe lung infection (pulmonary infection), bronchitis
Reactions related to medicine infusion, allergic reaction (including life-threatening allergic reaction)
Underactive thyroid gland (which may cause tiredness or weight gain), overactive thyroid gland (which may cause increased heart rate, sweating, and weight loss), swelling of the thyroid gland
Dehydration, decreased body weight, low blood sugar levels (hypoglycaemia)
Inflammation of nerves (causing numbness, weakness, tingling, or burning pain in arms and legs), dizziness
Blurred vision, dry eyes
Fast heartbeat, irregular heartbeat
High blood pressure (hypertension)
Inflammation of the lungs (pneumonitis, characterised by coughing fits and difficulty breathing), fluid around the lungs
Inflammation of the intestine (colitis), mouth ulcers and cold sores (stomatitis), dry mouth
Changes in skin colour with patches (vitiligo), dry skin, skin redness, unusual hair loss or thinning
Inflammation of the joints (arthritis)
Kidney failure (including sudden loss of kidney function)
Pain, chest pain, oedema (swelling)
Reaction at injection site

Uncommon (may affect up to 1 in 100 people)

Increase in certain types of white blood cells
Chronic diseases associated with accumulation of inflammatory cells in various organs and tissues, most commonly the lungs (sarcoidosis)
Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), underactive pituitary gland (hypopituitarism) or inflammation of the pituitary gland (hypophysitis) located at the base of the brain, diabetes
Increased levels of acids in the blood (metabolic acidosis)
Nerve damage causing numbness and weakness (polyneuropathy), inflammation of nerves caused by the body attacking itself, causing numbness, weakness, tingling, or burning pain (autoimmune neuropathy)
Inflammation of the eye (causing pain and redness)
Inflammation of the heart muscle, inflammation of the lining of the heart and fluid accumulation around the heart (pericardial diseases), changes in heart rhythm or heartbeat frequency
Fluid in the lungs
Inflammation of the pancreas (pancreatitis), inflammation of the stomach (gastritis)
Inflammation of the liver (hepatitis), blockage of bile ducts (cholestasis)
Skin disease with thickened patches of red skin, often with silvery scales (psoriasis), facial skin condition where the nose and cheeks are unusually red (rosacea), severe skin condition causing red spots, often itchy, similar to measles rash, starting on the limbs and sometimes on the face and rest of the body (erythema multiforme), urticaria (itchy, raised rash)
Inflammation of muscles causing pain or stiffness (polymyalgia rheumatica)

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

Temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
A disease causing inflammation or enlargement of a lymph node (Kikuchi lymphadenitis)
Acids in the blood produced by diabetes (diabetic ketoacidosis), reduced function of the parathyroid glands
Temporary inflammation of nerves causing pain, weakness, and paralysis of limbs (Guillain-Barré syndrome), loss of the protective covering of nerves (demyelination), a condition in which muscles become weak and tire easily (myasthenic syndrome), inflammation of the brain
Inflammation of the optic nerve which may cause complete or partial loss of vision (optic neuritis)
Inflammatory disease of blood vessels
Ulcer of the small intestine
Severe skin peeling which may be fatal (toxic epidermal necrolysis or Stevens-Johnson syndrome)
A disease in which the immune system attacks glands producing body fluids such as tears and saliva (Sjögren's syndrome), muscle pain, tenderness or muscle weakness not caused by exercise (myopathy), inflammation of muscles (myositis), stiffness in muscles and joints, muscle spasm (rhabdomyolysis)
Inflammation of the kidney, inflammation of the bladder; signs and symptoms may include frequent and/or painful urination, urgency to urinate, presence of blood in urine, pain or pressure in lower abdomen
Lack or reduction of digestive enzymes produced by the pancreas (pancreatic exocrine insufficiency)
Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea, and abdominal swelling after consuming foods containing gluten)

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

A disease (called haemophagocytic lymphohistiocytosis) in which the immune system overproduces cells that fight infections, called histiocytes and lymphocytes, and which may cause various symptoms
Rejection of solid organ transplant
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)
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)
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)
Changes in any area of the skin and/or genital area associated with dryness, thinning, itching, and pain (lichen sclerosus or other types of lichen)

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

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

Infections of the upper respiratory tract
Decrease in the number of red blood cells (which carry oxygen), white blood cells (which are important for fighting infections), or platelets (cells that help blood to clot)
Underactive thyroid gland (which may cause tiredness or weight gain), overactive thyroid gland (which may cause increased heart rate, sweating, and weight loss)
Decreased appetite, decreased body weight, decreased levels of albumin in the blood, high (hyperglycaemia) or low (hypoglycaemia) blood sugar levels
Inflammation of nerves (causing numbness, weakness, tingling, or burning pain in arms and legs), headache, dizziness, altered sense of taste
High blood pressure (hypertension)
Shortness of breath (dyspnoea), cough, abnormal voice tone (dysphonia)
Diarrhoea (watery, loose, or soft stools), constipation, vomiting, nausea, stomach pain, mouth ulcers and cold sores (stomatitis), indigestion (dyspepsia)
Rash, sometimes with blisters or vesicles, itching, pain in hands or soles of feet: rash or skin redness, tingling and tenderness causing symmetric redness, swelling, and pain mainly on the palm of the hand and sole of the foot (hand-foot skin reaction or palmar-plantar erythrodysesthesia syndrome)
Joint pain (arthralgia), muscle and bone pain (musculoskeletal pain), muscle spasms
Excess protein in urine
Feeling of tiredness or weakness, fever, oedema (swelling)

Common (may affect up to 1 in 10 people)

Severe lung infection (pulmonary infection), bronchitis, eye inflammation (conjunctivitis)
Increase in certain types of white blood cells, reduction in neutrophils with fever
Allergic reaction, reactions related to medicine infusion
Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), underactive pituitary gland (hypopituitarism) or inflammation of the pituitary gland (hypophysitis) located at the base of the brain, swelling of the thyroid gland, diabetes
Dehydration, reduced levels of phosphate in the blood
Sensations such as numbness and tingling (paraesthesia)
Sensation of a persistent sound in the ear when no sound is present (tinnitus)
Blurred vision, dry eye
Fast heartbeat, irregular heartbeat, inflammatory disease of blood vessels
Formation of a blood clot inside a blood vessel (thrombosis)
Inflammation of the lungs (pneumonitis characterised by coughing fits and difficulty breathing), fluid around the lungs, blood clots, nosebleeds
Inflammation of the intestine (colitis), inflammation of the pancreas (pancreatitis), dry mouth, inflammation of the stomach (gastritis), oral pain, haemorrhoids (piles)
Inflammation of the liver
Changes in skin colour with patches (including vitiligo), skin redness, unusual hair loss or thinning, change in hair colour, urticaria (itchy rash), depigmentation or abnormal darkening of the skin (cutaneous hyperpigmentation), dry skin
Inflammation of the joints (arthritis), muscle weakness, muscle pain
Kidney failure (including sudden loss of kidney function)
Pain, chest pain, chills
General feeling of being unwell (malaise)

Uncommon (may affect up to 1 in 100 people)

Acids in the blood produced by diabetes (diabetic ketoacidosis)
Increased levels of acid in the blood
Temporary inflammation of nerves causing pain, weakness, and paralysis of limbs (Guillain-Barré syndrome); nerve damage causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve paralysis); inflammation of nerves caused by the body attacking itself, causing numbness, weakness, tingling, or burning pain (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenia gravis or syndrome), inflammation of the brain
Inflammation of the eye (causing pain and redness)
Changes in heart rhythm or heartbeat frequency, slow heartbeat, inflammation of the heart muscle
Intestinal perforation, inflammation of the duodenum, burning sensation or pain in the tongue (glossodynia)
Severe skin peeling which may be fatal (Stevens-Johnson syndrome), skin disease with thickened patches of red skin, often with silvery scales (psoriasis), severe skin condition causing red spots, often itchy, similar to measles rash, starting on limbs and sometimes on face and rest of the body (erythema multiforme), changes in any area of the skin and/or genital area associated with dryness, thinning, itching, and pain (other types of lichen)
Muscle tenderness or weakness not caused by exercise (myopathy), inflammation of muscles (myositis), stiffness in muscles and joints, inflammation of muscles causing pain or stiffness (polymyalgia rheumatica), bone damage in the jaw, abnormal connection between two body parts, such as an organ or blood vessel and another structure (fistula)
Inflammation of the kidney, inflammation of the bladder; signs and symptoms may include frequent and/or painful urination, urgency to urinate, presence of blood in urine, pain or pressure in lower abdomen

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

Temporary and 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
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)
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)
Inflammation of the optic nerve which may cause complete or partial loss of vision (optic neuritis)
Inflammation of nerves
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)
Severe skin peeling which may be fatal (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 disease in which the immune system attacks glands producing body fluids such as tears and saliva (Sjögren's syndrome), muscle spasm (rhabdomyolysis)
Lack or reduction of digestive enzymes produced by the pancreas (pancreatic exocrine insufficiency)
Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea, and abdominal swelling after consuming foods containing gluten)

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

A disease (called haemophagocytic lymphohistiocytosis) in which the immune system overproduces cells that fight infections, called histiocytes and lymphocytes, and which may cause various symptoms
Rejection of solid organ transplant
Inflammation of the lining of the heart and fluid accumulation around the heart (pericardial diseases)

Tell your doctor immediately if you experience any of the side effects listed above. Do not try to treat these symptoms with other medicines.

Changes in test results
OPDIVO alone or in combination may cause changes in test results performed by your doctor, such as:

Abnormal liver function tests (increased levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, or alkaline phosphatase in blood, increased levels of bilirubin waste product in blood)
Abnormal kidney function tests (increased creatinine in blood)
Increased levels of the enzyme that breaks down fats and the enzyme that breaks down starch
Increase or decrease in calcium or potassium levels
Increase or decrease in magnesium or sodium levels in blood
Increase in the hormone that stimulates the thyroid
Increased levels of triglycerides in blood
Increased cholesterol levels in blood

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

5. How to store OPDIVO

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" or "EXP". The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Store in the original packaging to protect the medicine from light.
Do not store any unused injectable solution for later use. Unused medicine and waste materials arising from this medicine must be disposed of in accordance with local regulations.

6. Package contents and other information

What OPDIVO contains

The active substance is nivolumab. Each mL of injectable solution contains 120 mg of nivolumab. Each vial contains 600 mg (in 5 mL) of nivolumab.

The other components are recombinant human hyaluronidase (rHuPH20), histidine, histidine hydrochloride monohydrate, sucrose, pentetic acid, polysorbate 80 (E433), methionine and water for injections (see section 2 "OPDIVO contains polysorbate 80 (E433)").

Description of the appearance of OPDIVO and contents of the pack

OPDIVO injectable solution is a liquid ranging from clear to opalescent, colourless to pale yellow, which may contain a few light particles.

It is available in packs containing 1 glass vial of 5 mL.

Marketing Authorization Holder

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

Manufacturer

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

For further information on this medicinal product, please contact the local representative of the Marketing Authorization Holder: