Package Insert: Information for the User

OPDIVO10mg/ml Concentrate for Solution for Infusion

nivolumab

Read this package insert carefully before starting to use this medicine, as it contains important information for you.

• Keep this package insert, as you may need to read it again.
• It is essential that you always have the "Patient Information Leaflet" with you during treatment.
• If you have any questions, consult your doctor.
• If you experience any adverse effects, consult your doctor, even if they are not listed in this package insert. See section4.

OPDIVO is a medication used to treat:

• advanced melanoma (a type of skin cancer) in adults and adolescents 12 years of age and older
• melanoma after complete resection in adults and adolescents 12 years of age and older (adjuvant therapy after surgery)
• 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 (neoadjuvant therapy before surgery)
• malignant pleural mesothelioma (a type of cancer affecting the lung lining) in adults
• advanced renal cell carcinoma (advanced kidney cancer) in adults
• classical Hodgkin lymphoma that has recurred or not responded to previous treatments, including autologous hematopoietic progenitor cell transplantation (a transplant of their own blood-producing cells) in adults
• 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 cancer (colon or rectal cancer) in adults
• advanced esophageal cancer (cancer of the tube connecting the mouth to the stomach) in adults
• esophageal cancer (cancer of the tube connecting the mouth to the stomach) or gastroesophageal junction cancer with pathological residual disease after chemotherapy and radiation followed by surgery in adults
• advanced gastric adenocarcinoma, gastroesophageal junction, or esophageal adenocarcinoma (stomach or esophageal cancer).

It contains nivolumab as the active ingredient, which is a monoclonal antibody, a type of protein designed to recognize and attack a specific target substance found in the body.

Nivolumab attacks and blocks a target protein called programmed death receptor-1 (PD-1), which can inhibit the activity of T cells (a type of white blood cell that forms part of the immune system). By attacking PD-1, nivolumab blocks its action and prevents its inhibition of T cells. This helps to increase their activity against melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, bladder cancer, colon or rectal cancer, stomach cancer, esophageal cancer, or gastroesophageal junction cancer.

OPDIVO can be administered in combination with other anti-cancer medications. It is essential that you also read the prospectus of the other medications. If you have any doubts about these medications, please consult your doctor.

Do not use OPDIVO

• If you areallergicto nivolumab or any of the other components of this medication (listed in section6 "Contents of the pack and additional information"). If in doubtconsult your doctor.

Warnings and precautions

Consult your doctor before starting to use OPDIVO, as it may cause:

• Heart problemssuch as an abnormal heart rhythm or frequency of heartbeats or an abnormal heart rhythm.
• Lung problemssuch as difficulty breathing or coughing. These may be signs of lung inflammation (pneumonitis or interstitial lung disease).
• Dysdiarrhea(watery, loose, or soft stools) or any symptom ofinflammation of the intestines(colitis), such as stomach pain or presence of mucus or blood in the stools.
• Liver inflammation (hepatitis).The signs and symptoms of hepatitis may include abnormal liver function tests, yellowing of the eyes or skin (jaundice), pain in the right upper abdomen or fatigue.
• Inflammation or problems with your kidneys.The signs and symptoms may include abnormal kidney function tests, decreased urine volume.
• Problems with hormone-producing glands(such as the pituitary gland, thyroid gland, parathyroid glands, and adrenal glands) that may affect the functioning of these glands. The signs and symptoms of these glands not functioning properly are extreme fatigue, weight changes, headache, decreased calcium levels in the blood, and visual disturbances.
• Diabetesincluding a serious, sometimes potentially life-threatening condition due to acid in the blood produced by diabetes (diabetic ketoacidosis). The symptoms may include feeling hungrier or thirstier than normal, needing to urinate more frequently, weight loss, fatigue, or difficulty thinking clearly, breath with a sweet or fruity odor, a sweet or metallic taste in the mouth, or a different odor in the urine or sweat, feeling sick or vomiting, stomach pain, and rapid or deep breathing.
• Skin inflammationthat may lead to severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). The signs and symptoms of severe skin reactions may include rash, itching, and peeling of the skin (possibly fatal).
• Muscle inflammationsuch as myocarditis (inflammation of the heart muscle), myositis (inflammation of the muscles), and rhabdomyolysis (stiffness in the muscles and joints, muscle spasms).The signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe fatigue.
• Rejection of solid organ transplants.
• Graves' disease.
• Hemophagocytic lymphohistiocytosis.A rare disease in which the immune system produces too many cells to fight infections, otherwise normal, called histiocytes and lymphocytes. The symptoms may include an enlarged liver or spleen, skin rash, enlarged lymph nodes, respiratory problems, tendency to form bruises, renal abnormalities, and heart problems.

Inform your doctor immediatelyif you experience any of these signs or symptoms, or if they worsen.Do not try to treat your symptoms with other medications on your own.Your doctor may

• administer other medications to prevent complications and reduce your symptoms,
• stop the administration of the next dose of OPDIVO,
• permanently discontinue your treatment with OPDIVO.

Be aware that these signs and symptomsmay occur lateand may appear weeks or months after receiving your last dose of treatment. Before treatment, your doctor will check your overall health status. Blood tests will also be performed during your treatment.

Check with your doctor before receiving OPDIVO if:

• You have anautoimmune disease(a disorder in which the body attacks its own cells);
• You haveocular melanoma;
• You have previously received ipilimumab, another medication for treating melanoma, and have experiencedsevere adverse effectsas a result of that medication;
• You have been told that yourcancer has spread to your brain;
• You have a history oflung inflammation;
• You have been takingmedications that suppress your immune system.

Complications of hematopoietic progenitor cell transplantation, which use donor hematopoietic progenitor cells (allogenic) after treatment with OPDIVO.These complications may be severe and potentially life-threatening. Your doctor will monitor signs of complications if you have had a hematopoietic progenitor cell transplant.

Children and adolescents

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

Other medications and OPDIVO

Inform your doctor before receiving OPDIVO if you are taking any medication that suppresses your immune system, such as corticosteroids, as these medications may interfere with the effect of OPDIVO. However, once you are on treatment with OPDIVO, your doctor may administer corticosteroids to reduce any possible adverse effects you may experience during treatment, and this will not affect the effect of the medication.

Inform your doctorif you are taking, have taken recently, or may need to take any other medication.Do not take any other medicationduring your treatment without first consulting your doctor.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, or plan to become pregnant,consult your doctor.

Do not use OPDIVO if you are pregnant, unless your doctor tells you specifically. The effects of OPDIVO on pregnant women are unknown, but it is possible that the active ingredient, nivolumab, may cause fetal damage.

• You must use aneffective contraceptive methodwhile receiving treatment with OPDIVO and, at a minimum, for at least 5months after your last dose of OPDIVO, if you are a woman who may become pregnant.
• If you become pregnant while using OPDIVOinform your doctor.

The effects of OPDIVO on breast milk are unknown. The risk to the infant cannot be ruled out.Ask your doctorif you can breastfeed during or after treatment with OPDIVO.

Driving and operating machinery

OPDIVO or OPDIVO in combination with ipilimumab may have a small effect on your ability to drive and operate machinery; however, be cautious when performing these activities until you are sure that OPDIVO does not affect you negatively.

OPDIVO contains sodium

Inform your doctorif you are following a low-sodium diet before receiving OPDIVO. This medication contains2.5mg of sodium per ml of concentrate (main component of table salt) in each ml of concentrate. OPDIVO contains 10mg of sodium per 4ml vial, 25mg of sodium per 10ml vial, 30mg of sodium per 12ml vial, or 60mg of sodium per 24ml vial, which is equivalent to 0.5%, 1.25%, 1.5%, or 3% of the maximum recommended daily sodium intake for an adult.

You will also find this key message from the leaflet in the "patient information leaflet", which your doctor will give you. It is essential that you always have this patient information leaflet with you and show it to your partner or caregivers.

How much OPDIVO is administered

When OPDIVO is administered alone, the recommended dose is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks, depending on the indication.

When OPDIVO is administered alone for the treatment of skin cancer in adolescents 12 years of age and older and with a minimum weight of 50 kg, the recommended dose is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks. For adolescents 12 years of age and older and with a weight less than 50 kg, the recommended dose is 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.

When OPDIVO is administered in combination with ipilimumab for the treatment of skin cancer in adults and adolescents 12 years of age and older, the recommended dose of OPDIVO is 1 mg of nivolumab per kilogram of body weight during the first 4 doses (combination phase). Subsequently, the recommended dose of OPDIVO (monotherapy phase) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks in adults and adolescents 12 years of age and older and with a minimum weight of 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 12 years of age and older and with a weight less than 50 kg.

When OPDIVO is administered in combination with ipilimumab for the treatment of advanced renal cell carcinoma, the recommended dose of OPDIVO is 3 mg of nivolumab per kilogram of body weight during the first 4 doses (combination phase). Subsequently, the recommended dose of OPDIVO is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks (monotherapy phase).

When OPDIVO is administered in combination with ipilimumab for the treatment of advanced colorectal or rectal cancer, the recommended dose of OPDIVO is 3 mg of nivolumab per kilogram of body weight or 240 mg during the first 4 doses (combination phase), depending on the treatment. Subsequently, the recommended dose of OPDIVO is 240 mg administered every 2 weeks or 480 mg 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 chemotherapy for the 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 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 gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma, 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 of nivolumab every 3 weeks for a maximum of 6 cycles, followed by nivolumab monotherapy administered intravenously, either 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 completing 2 cycles of chemotherapy, OPDIVO is administered in combination with ipilimumab, the recommended dose of OPDIVO is 360 mg every 3 weeks.

When OPDIVO is administered in combination with cabozantinib for the treatment of advanced renal cell carcinoma, the recommended dose of OPDIVO is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks.

Depending on the dose, the appropriate amount of OPDIVO may be diluted before use with a sodium chloride solution for injectable preparations at a concentration of 9 mg/ml (0.9%) or a glucose solution for injectable preparations at a concentration of 50 mg/ml (5%). It may be necessary to use more than one vial of OPDIVO to obtain the required dose.

How to administer OPDIVO

You will receive treatment with OPDIVO in a hospital or clinic under the supervision of an experienced doctor.

OPDIVO will be administered to you as an infusion (a drip) into a vein (intravenously) over a period of 30 or 60 minutes, every 2 or 4 weeks, depending on the dose you receive. Your doctor will continue to administer OPDIVO to you as long as you benefit from it or until you can no longer tolerate the treatment.

When OPDIVO is administered in combination with ipilimumab for the treatment of skin cancer, advanced renal cell carcinoma, or advanced colorectal or rectal cancer, you will receive an infusion over a period of 30 minutes, every 3 weeks during the first 4 doses (combination phase). Subsequently, you will receive an infusion over a period of 30 or 60 minutes, every 2 weeks or 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 over a period of 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 over a period of 30 minutes, every 2 or 3 weeks, depending on the dose you are receiving.

When OPDIVO is administered in combination with chemotherapy for the neoadjuvant treatment of non-small cell lung cancer, you will receive an infusion over a period of 30 minutes every 3 weeks.

When OPDIVO is administered in combination with chemotherapy for the treatment of advanced esophageal cancer, you will receive an infusion over a period of 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 gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma, you will receive an infusion over a period of 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 over a period of 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 over a period of 30 minutes every 3 weeks.

When OPDIVO is administered in combination with cabozantinib, you will receive an infusion over a period of 30 minutes or 60 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving.

If you forget to use OPDIVO

It is very important that you attend all your appointments to receive OPDIVO. If you miss one, ask your doctor when you can schedule your next dose.

If you interrupt treatment with OPDIVO

Interrupting your treatment may stop the effect of the medication. Do not interrupt treatment with OPDIVO unless you have discussed it with your doctor.

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

When OPDIVO is administered in combination with other anti-cancer medications, OPDIVO will be administered first, followed by the other medication.

Please refer to the package insert of the other anti-cancer medications to understand the use of these medications. If you have any questions about them, please consult your doctor.

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

Be aware of the importance of inflammation symptoms.OPDIVO acts on your immune system and could cause inflammation in some part of your body. Inflammation could cause serious damage to your body and some inflammatory conditions could pose a life-threatening risk and require treatment or withdrawal of OPDIVO.

The following side effects have been reportedwith OPDIVO alone:

Very common (may affect more than1 in 10patients)

• Upper respiratory tract infections
• Decreased red blood cells (which transport oxygen), white blood cells (important for fighting infections) or platelets (cells that help blood clotting)
• Decreased appetite, high blood sugar levels (hyperglycemia)
• Headache
• Dyspnea (shortness of breath), cough
• Diarrhea (watery, loose, or soft stools), vomiting, nausea, abdominal pain, constipation
• Skin rash, sometimes with blisters, itching
• Muscle and bone pain (musculoskeletal pain), joint pain (arthralgia)
• Feeling tired or weak, fever

Common (may affect up to1 in 10patients)

• Severe lung infection (pneumonia), bronchitis
• Reactions related to the infusion of the medicine, allergic reaction (including potentially life-threatening allergic reaction)
• Decreased thyroid function (which can cause fatigue or weight gain), increased thyroid function (which can cause rapid heart rate, sweating, and weight loss), thyroid gland swelling
• Dehydration, weight loss, low blood sugar levels (hypoglycemia)
• Inflammation of the nerves (which causes numbness, weakness, tingling, or burning in the arms and legs), dizziness
• Blurred vision, dry eyes
• Fast heart rate, abnormal heart rhythm
• High blood pressure
• Lung inflammation (neumonitis), characterized by cough and difficulty breathing, fluid around the lungs
• Intestinal inflammation (colitis), mouth ulcers and herpes (stomatitis), dry mouth
• Change in skin color in patches (vitiligo), dry skin, skin redness, unusual or weakened hair loss
• Joint inflammation (arthritis)
• Renal insufficiency (including sudden loss of renal function)
• Pain, chest pain, edema (swelling)

Uncommon (may affect up to1 in 100patients)

• Elevation of some white blood cells
• Chronic diseases associated with the accumulation of inflammatory cells in various organs and tissues, more frequently in the lungs (sarcoidosis)
• Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), low activity of functioning (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, diabetes
• Metabolic acidosis
• Damaged nerves causing numbness and weakness (polyneuropathy), inflammation of the nerves caused by the body's attack on itself, which causes numbness, weakness, tingling, or burning (autoimmune neuropathy)
• Inflammation of the eyes (which causes pain and redness)
• Changes in heart rhythm or frequency, inflammation of the heart muscle
• Liquid in the lungs
• Inflammation of the pancreas (pancreatitis), inflammation of the stomach (gastritis)
• Inflammation of the liver (hepatitis), obstruction of the bile ducts (cholestasis)
• Skin disease with raised red patches of skin, often with silvery scales (psoriasis), severe skin condition that causes redness, often with itchy patches, similar to measles rash, which starts in the extremities and sometimes on the face and the rest of the body (erythema multiforme), urticaria (hives)
• Joint inflammation (arthritis)
• Renal insufficiency (including sudden loss of renal function)
• Pain, chest pain, edema (swelling)

Rare (may affect up to1 in 10,000patients)

• Temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
• Disease that causes inflammation or enlargement of lymph nodes (Kikuchi lymphadenitis)
• Diabetes-related acid in the blood (diabetic ketoacidosis), decreased parathyroid gland function
• Temporary inflammation of the nerves causing pain, weakness, and paralysis in the limbs (Guillain-Barré syndrome); nerve damage causing numbness and weakness (demylination); a condition in which muscles become weak and tire easily (myasthenic syndrome), inflammation in the brain
• Inflammatory disease of blood vessels
• Ulcers in the small intestine
• Severe skin peeling, potentially life-threatening (toxic epidermal necrolysis or Stevens-Johnson syndrome)
• Disease in which the immune system attacks the glands that produce body moisture, such as tears and saliva (Sjögren's syndrome), muscle pain, sensitivity, or weakness not caused by exercise (myopathy), muscle inflammation (myositis), muscle stiffness and joint stiffness, muscle spasms (rhabdomyolysis)
• Renal inflammation, urinary tract inflammation, symptoms may include frequent or painful urination, urgent need to urinate, blood in the urine, abdominal pain or pressure in the lower abdomen
• Decreased pancreatic enzyme production (exocrine pancreatic insufficiency)
• Celiac disease (characterized by symptoms such as abdominal pain, diarrhea, and bloating after consuming gluten-containing foods)

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

• Disease in which the immune system generates too many cells to fight infections, called histiocytes and lymphocytes, which can cause various symptoms (known as hemophagocytic lymphohistiocytosis)
• Organ transplant rejection
• A group of metabolic complications that occur after cancer treatment, characterized by high levels of potassium and phosphate and low levels of calcium in the blood (tumor lysis syndrome)
• Inflammatory condition (more likely of autoimmune origin) affecting the eyes, skin, and ear membranes, brain, and spinal cord (Vogt-Koyanagi-Harada syndrome)
• Dizziness, numbness, tingling, or weakness in the arms or legs; urinary or intestinal problems, including frequent urination, urinary incontinence, difficulty urinating, and constipation (myelitis/myelitis transverse)
• Changes in any skin area or genital area associated with dryness, thinning of the skin, itching, and pain (lichen sclerosis or other lichen disorders)

The following side effects have been reportedwith OPDIVO in combination with other anti-cancer medicines:

Very common (may affect more than1 in 10patients)

• Upper respiratory tract infections
• Decreased red blood cells (which transport oxygen), white blood cells (important for fighting infections) or platelets (cells that help blood clotting)
• Decreased thyroid function (which can cause fatigue or weight gain), increased thyroid function (which can cause rapid heart rate, sweating, and weight loss)
• Decreased appetite, decreased body weight, decreased albumin levels in the blood, high or low blood sugar levels (hyperglycemia or hypoglycemia)
• Inflammation of the nerves (which causes numbness, weakness, tingling, or burning in the arms and legs), headache, dizziness, altered sense of taste
• High blood pressure
• Dyspnea (shortness of breath), cough, abnormal voice (dysphonia)
• Diarrhea (watery, loose, or soft stools), constipation, vomiting, nausea, abdominal pain, mouth ulcers and herpes (stomatitis), indigestion (dyspepsia)
• Skin rash, sometimes with blisters, itching, skin rash or redness, tingling, and sensitivity that becomes symmetrical redness, swelling, and pain mainly in the palm of the hand and the sole of the foot (erythromelalgia palmar-plantar)
• Joint pain (arthralgia), muscle and bone pain (musculoskeletal pain), muscle spasms
• Proteinuria (excess protein in the urine)
• Feeling tired or weak, fever, edema (swelling)

Common (may affect up to1 in 10patients)

• Severe lung infection (pneumonia), bronchitis, conjunctivitis (inflammation of the eye)
• Elevation of some white blood cells, decreased neutrophils with fever
• Allergic reaction, reactions related to the infusion of the medicine
• Decreased secretion of hormones produced by the adrenal glands (glands located above the kidneys), decreased activity (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, thyroid gland swelling, diabetes
• Dehydration, decreased phosphate levels in the blood
• Numbness and tingling (paresthesia)
• Abnormal ear ringing (tinnitus)
• Blurred vision, dry eyes
• Fast heart rate, abnormal heart rhythm, inflammatory disease of blood vessels
• Formation of a blood clot within a blood vessel (thrombosis)
• Lung inflammation (neumonitis, characterized by cough and difficulty breathing), fluid in the lungs, blood clots, nasal bleeding
• Intestinal inflammation (colitis), pancreatitis (inflammation of the pancreas), dry mouth, gastritis (inflammation of the stomach), oral pain, hemorrhoids (piles)
• Liver inflammation
• Change in skin color in patches (including vitiligo), skin redness, hair loss, abnormal hair color, urticaria (hives), abnormal skin pigmentation, dry skin
• Joint inflammation (arthritis), muscle weakness, painful muscles
• Renal insufficiency (including sudden loss of renal function)
• Pain, chest pain, chills
• Feeling unwell (malaise)

Uncommon (may affect up to1 in 100patients)

• Diabetes-related acid in the blood (diabetic ketoacidosis)
• Increased levels of acid in the blood
• Inflammation of the nerves causing pain, weakness, and paralysis in the limbs (Guillain-Barré syndrome); damaged nerves causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve paralysis); inflammation of the nerves caused by the body's attack on itself, which causes numbness, weakness, tingling, or burning (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenic syndrome or syndrome)
• Inflammation in the brain
• Inflammation of the eyes (which causes pain and redness)
• Changes in heart rhythm or frequency, slow heart rate, inflammation of the heart muscle
• Intestinal perforation, duodenal inflammation, tongue pain (glossodynia)
• Severe skin peeling, potentially life-threatening (Stevens-Johnson syndrome), skin disease with raised red patches of skin, often with silvery scales (psoriasis), severe skin condition that causes redness, often with itchy patches, similar to measles rash, which starts in the extremities and sometimes on the face and the rest of the body (erythema multiforme), changes in any skin area or genital area associated with dryness, thinning of the skin, itching, and pain (lichen sclerosis or other lichen disorders)
• Muscle pain, sensitivity, or weakness not caused by exercise (myopathy), muscle inflammation (myositis), muscle stiffness and joint stiffness, inflammation of the 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)
• Renal inflammation, urinary tract inflammation, symptoms may include frequent or painful urination, urgent need to urinate, blood in the urine, abdominal pain or pressure in the lower abdomen

Rare (may affect up to1 in 10,000patients)

• Temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
• Chronic diseases associated with the accumulation of inflammatory cells in various organs and tissues, more frequently in the lungs (sarcoidosis)
• Decreased parathyroid gland function
• A group of metabolic complications that occur after cancer treatment, characterized by high levels of potassium and phosphate and low levels of calcium in the blood (tumor lysis syndrome)
• Inflammatory condition (more likely of autoimmune origin) affecting the eyes, skin, and ear membranes, brain, and spinal cord (Vogt-Koyanagi-Harada syndrome)
• Inflammation of the nerves
• Dizziness, numbness, tingling, or weakness in the arms or legs; urinary or intestinal problems, including frequent urination, urinary incontinence, difficulty urinating, and constipation (myelitis/myelitis transverse)
• Severe skin peeling, potentially life-threatening (toxic epidermal necrolysis), changes in any skin area or genital area associated with dryness, thinning of the skin, itching, and pain (lichen sclerosis)
• Chronic arthritis (spondyloarthropathy), disease in which the immune system attacks the glands that produce body moisture, such as tears and saliva (Sjögren's syndrome), muscle spasms (rhabdomyolysis)
• Decreased pancreatic enzyme production (exocrine pancreatic insufficiency)
• Celiac disease (characterized by symptoms such as abdominal pain, diarrhea, and bloating after consuming gluten-containing foods)

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

• Disease in which the immune system generates too many cells to fight infections, called histiocytes and lymphocytes, which can cause various symptoms (known as hemophagocytic lymphohistiocytosis)
• Organ transplant rejection
• Inflammation of the heart covering and accumulation of fluid around the heart (pericardial disorders)

If you experience any of the side effects described above,inform your doctor immediately.Do not try to treat these symptoms with other medicines on your own.

Changes in laboratory test results

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

• Abnormal liver function tests (elevated levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, or alkaline phosphatase, elevated bilirubin levels in the blood)
• Abnormal kidney function tests (elevated creatinine levels in the blood)
• Elevation of the enzyme that breaks down fats and the enzyme that breaks down carbohydrates
• Elevation or decrease of calcium or potassium levels
• Elevation or decrease of magnesium or sodium levels in the blood
• Elevation of the thyroid-stimulating hormone
• Elevation of triglyceride levels in the blood
• Elevation of cholesterol levels in the blood

Reporting of side effects

If you experience any type of side effect,consult your doctor,even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational reporting system included in theAppendixV. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the packaging and vial label after CAD. The expiration date is the last day of the month indicated.

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

Do not freeze.

Store this medication in the original packaging to protect it from light.

The unopened vial can be stored at room temperature not exceeding 25°C without protection from light for up to 48 hours.

Do not conserve the unused infusion solution for a new use. The disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Composition of OPDIVO

• The active ingredient is nivolumab.

Each milliliter of concentrate for solution for infusion contains10mg of nivolumab.

Each vial contains40mg (in4ml),100mg (in10ml), 120mg (in 12ml) or240mg (in24ml) of nivolumab.

• The other components are sodium citrate dihydrate, sodium chloride (see section2"OPDIVO contains sodium"), mannitol(E421), pentetic acid, polisorbate80 (E433), sodium hydroxide, hydrochloric acid, and water for injection preparations.

Appearance of OPDIVO and contents of the package

OPDIVO concentrate for solution for infusion (sterile concentrate) is a transparent to opalescent, colorless to pale yellow liquid that may contain some (few) particles.

It is available in containers that contain1vial of4ml,1vial of10ml, 1vial of 12ml or1vial of24ml.

Only some sizes of containers may be commercially available.

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

Last review date of this leaflet:

The detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu

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This information is intended solely for healthcare professionals:

Preparation and administration of OPDIVO

The preparation should be carried out by trained personnel in accordance with good practices, especially in terms of asepsis.

Dose calculation

More than one vial of OPDIVO concentrate may be required to administer the total dose to the patient.

Nivolumab monotherapy

The prescribed dose for adults is 240mg or 480mg regardless of body weight, depending on the indication.

Melanoma (advanced or adjuvant treatment) in adolescents. The prescribed dose for adolescents aged 12years or older and with a minimum weight of 50kg is 240mg or 480mg. For adolescents aged 12years or older and with a weight less than 50kg, the prescribed dose is administered in mg/kg. Calculate the total dose to be administered according to the following formula:

• The total dose of nivolumab in mg=the patient's weight in kg×the prescribed dose in mg/kg.
• The volume of OPDIVO concentratefor preparing the dose (ml)=the total dose of nivolumab in mg, divided by 10 (the concentration of OPDIVO concentrate is 10mg/ml).

Nivolumab in combination with ipilimumab

The prescribed dose for the patient is administered in mg/kg. Calculate the total dose to be administered according to the formula above.

Nivolumab in combination with ipilimumab in malignant pleural mesothelioma

The prescribed dose for a patient is 360mg regardless of body weight.

Nivolumab in combination with ipilimumab in advanced colorectal cancer

The prescribed dose for a patient may be based on body weight (3mg/kg) or 240mg regardless of body weight.

Nivolumab in combination with ipilimumab in advanced esophageal cancer

The prescribed dose for a patient may be based on body weight (3mg/kg) or 360mg regardless of body weight.

Nivolumab in combination with chemotherapy in non-small cell lung cancer

The prescribed dose for a patient is 360mg regardless of body weight.

Nivolumab in combination with chemotherapy in advanced esophageal cancer

The prescribed dose for a patient is 240mg or 480mg regardless of body weight.

Nivolumab in combination with chemotherapy in adenocarcinoma of the stomach, gastroesophageal junction, or esophagus

The prescribed dose for a patient is 360mg or 240mg regardless of body weight.

Nivolumab in combination with ipilimumab and chemotherapy

The prescribed dose for a patient is 360mg regardless of body weight.

Nivolumab in combination with cabozantinib

The prescribed dose for a patient is nivolumab 240mg or 480mg regardless of body weight.

Preparation of the infusion

Ensure aseptic handlingwhen preparing the infusion.

OPDIVO can be used for intravenous administration:

• without dilution, after transferring to an infusion container using a sterile syringe;

or

• after dilutionaccording to the following instructions:
• The final concentration of the infusion must range from1 to10mg/ml
• The total volume of the infusion must not exceed 160ml. For patients weighing less than 40kg, the total volume of the infusion must not exceed 4ml/kg.

• OPDIVO concentrate can be diluted with:
• sodium chloride solution for injection at a concentration of 9mg/ml (0.9%); or
• glucose solution for injection at a concentration of 50mg/ml (5%).

STEP1

• Inspect the OPDIVO concentrate for the presence of particles or color changes. Do not agitate the vial. The OPDIVO concentrate is a transparent to opalescent, colorless to pale yellow liquid. Discard the vial if the solution is turbid, discolored, or contains particles other than a few translucent to white particles.
• Extract the required volume of OPDIVO concentrate using a sterile syringe.

STEP2

• Transfer the concentrate to a sterile evacuated glass container or infusion container (PVC or polyolefin).
• If necessary, dilute with the required volume of sodium chloride solution for injection at a concentration of9mg/ml (0.9%) or a glucose solution for injection at a concentration of50mg/ml (5%). To facilitate preparation, the concentrate can be transferred directly to a pre-loaded bag containing the required volume of sodium chloride solution for injection at a concentration of9mg/ml (0.9%) or a glucose solution for injection at a concentration of50mg/ml (5%).
• Mix the infusion gently by manual rotation. Do not agitate.

Administration

The OPDIVO infusion must not be administered as an intravenous bolus injection.

Administer the OPDIVO infusionintravenously over a period of 30or60minutes, depending on the dose and indication.

The OPDIVO infusion must not be administered simultaneously through the same intravenous line with other medicinal products. Use a separate intravenous line for the infusion.

Use a sterile, non-pyrogenic, and low-protein-binding infusion set with a pore size of0.2μm to1.2μm.

The OPDIVO infusion is compatible with:

• PVC containers
• Polyolefin containers
• Glass containers
• PVC infusion sets
• Infusion filters with polyethersulfone membranes with pore sizes of0.2μm to1.2μm.

After administration of the nivolumab dose, purge the line with sodium chloride solution for injection at a concentration of9mg/ml (0.9%) or a glucose solution for injection at a concentration of50mg/ml (5%).

Storage and shelf life

Unopened vial

OPDIVO should bestored in the refrigerator(2°C‑8°C). The vials should be maintained in the original packaging to protect them from light. OPDIVO should not be frozen.

The unopened vial can be stored at room temperature not exceeding 25°C without protection from light for up to 48hours.

Do not use OPDIVO after the expiration date indicated on the packaging and label of the vial after CAD. The expiration date is the last day of the month indicated.

OPDIVO infusion

The chemical and physical stability of the OPDIVO infusion has been demonstrated from the time of preparation, as follows (the times include the administration period):

From a microbiological point of view, the infusion solution prepared, regardless of the diluent used, should be used immediately. If not used immediately, the storage times for use and the conditions prior to use are the responsibility of the user and normally should not exceed 7days between2°Cand8°C, or 8hours (of the total 7days of storage) at room temperature (≤25°C). Ensure aseptic handling during the preparation of the infusion.

Disposal

Do not conserve the unused infusion solution for a new use. The disposal of the unused medicinal product and all materials that have come into contact with it will be carried out in accordance with local regulations.