OPDIVO 10 mg/mL concentrate for infusion solution

Introduction

Package Leaflet: Information for the User

OPDIVO10mg/ml concentrate for solution for infusion

nivolumab

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 always carry the "Patient Information Card" with you during treatment.
• If you have any further questions, ask your doctor.
• If you experience side effects, ask your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What OPDIVO is and what it is used for
2. What you need to know before you use OPDIVO
3. How to use OPDIVO
4. Possible side effects
5. Storage of OPDIVO
6. 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 from 12 years of age
• melanoma after complete resection in adults and adolescents from 12 years of age (treatment after surgery 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 (pre-surgical treatment is called neoadjuvant treatment)
• malignant pleural mesothelioma (a type of cancer that affects the lining of the lungs) in adults
• advanced renal cell carcinoma (advanced kidney cancer) in adults
• classical Hodgkin lymphoma that has recurred or has not responded to previous treatments, including an autologous hematopoietic progenitor cell transplant (a transplant of your 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 that connects the mouth to the stomach) in adults
• esophageal cancer (cancer of the tube that connects the mouth to the stomach) or gastroesophageal junction cancer with residual disease after chemoradiotherapy followed by surgery in adults
• advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma (stomach or esophageal cancer)

It contains nivolumab as the active substance, 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 in the blood that is part of the immune system, the body's natural defense). By attacking PD-1, nivolumab blocks its action and prevents the inhibition of its T cells. This helps to increase their activity against melanoma cells, lung cancer cells, kidney cancer cells, lymphoma cells, head and neck cancer cells, bladder cancer cells, colon or rectal cancer cells, stomach cancer cells, esophageal cancer cells, or gastroesophageal junction cancer cells.

OPDIVO can be administered in combination with other anti-cancer medicines. It is important that you also read the package leaflet of the other medicines. If you have any questions about these medicines, please ask your doctor.

2. What you need to know before you use OPDIVO

Do not use OPDIVO

• if you are allergicto nivolumab or to any of the other ingredients of this medicine (listed in section 6 "Contents of the pack and other information"). In case of doubt, consult your doctor.

Warnings and precautions

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

• Heart problemssuch as changes in heart rhythm or frequency or abnormal heart rhythm.
• Lung problemssuch as difficulty breathing or coughing. These can be signs of lung inflammation (pneumonitis or interstitial lung disease).
• Diarrhea(watery, loose, or soft stools) or any symptoms of inflammation of the intestines(colitis), such as stomach pain or presence of mucus or blood in the stool.
• 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 side of the stomach area, or fatigue.
• Kidney inflammation or problems.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 can affect the functioning of these glands. The signs and symptoms that these glands are not working properly are fatigue (extreme tiredness), weight changes, headache, decreased calcium levels in the blood, and visual disturbances.
• Diabetesincluding a serious, potentially life-threatening problem due to acid in the blood produced by diabetes (diabetic ketoacidosis). The symptoms may include feeling more hungry or thirsty than usual, needing to urinate more often, weight loss, fatigue, or difficulty thinking clearly, sweet or fruity breath, a sweet or metallic taste in the mouth, or a different smell in urine or sweat, feeling sick or being sick, stomach pain, and deep or rapid breathing.
• Skin inflammationthat can lead to severe skin reactions (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 life-threatening).
• 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.
• Graft-versus-host 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 enlargement of the liver or spleen, skin rash, enlargement of the lymph nodes, respiratory problems, tendency to bruise, kidney abnormalities, and heart problems.

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

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

Note that these signs and symptoms may occur lateand may appear weeks or months after receiving your last dose of treatment. Before treatment, your doctor will check your overall health. You will also have blood testsduring your treatment.

Check with your doctor before receiving OPDIVO if:

• you have an autoimmune disease(a disorder in which the body attacks its own cells);
• you have ocular melanoma;
• you have previously been given ipilimumab, another medicine to treat melanoma, and have experienced severe side effectsas a result of that medicine;
• you have been told that your cancer has spread to your brain;
• you have a history of lung inflammation;
• you have been taking medicines that suppress your immune system.

Complications of hematopoietic progenitor cell transplants, which use donor hematopoietic progenitor cells (allogeneic) after treatment with OPDIVO.These complications can be serious and can be 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 18 years of age, except in adolescents from 12 years of age with melanoma.

Other medicines and OPDIVO

Before receiving OPDIVO, tell your doctorif you are taking any medicine that suppresses your immune system, such as corticosteroids, as these medicines may interfere with the effect of OPDIVO. However, once you are being treated with OPDIVO, your doctor may give you corticosteroids to reduce any possible side effects you may have during your treatment, and this will not affect the effect of the medicine.

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

Pregnancy and breastfeeding

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

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

• You must use an effective contraceptive methodwhile receiving treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO, in case you are a woman who could become pregnant.
• If you become pregnant while using OPDIVO, tell your doctor.

It is unknown whether OPDIVO passes into breast milk. The risk to the breastfed child cannot be excluded. Ask your doctorif 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, be cautious when performing these activities until you are sure that OPDIVO does not affect you negatively.

OPDIVO contains sodium

Tell your doctorif you are on a low-sodium diet (low-salt diet) before receiving OPDIVO. This medicine contains 2.5 mg of sodium per ml of concentrate (main component of kitchen/table salt) in each 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, which is equivalent to 0.5%, 1.25%, 1.5%, or 3% respectively of the maximum recommended daily intake of sodium for an adult.

You will also find this key message from the package leaflet on the "Patient Information Card", which your doctor will give you. It is important that you always carry this Patient Information Card with you and show it to your partner or caregivers.

3. How to use OPDIVO

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 aged 12 years 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 aged 12 years 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 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 (single-agent phase) is 240 mg administered every 2 weeks or 480 mg administered every 4 weeks in adults and adolescents aged 12 years and older and 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 aged 12 years and older and with a weight 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 administered every 2 weeks or 480 mg administered every 4 weeks (single-agent 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 administered every 2 weeks or 480 mg every 4 weeks (single-agent 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 advanced gastric, gastroesophageal junction, 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 or480 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 kidney cancer, 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 prior to 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%). More than one vial of OPDIVO may be required to obtain the necessary dose.

How OPDIVO is administered

You will receive OPDIVO treatment 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 while 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 kidney cancer, or advanced colon or rectal cancer, you will be administered an infusion over a period of 30 minutes, every 3 weeks for the first 4 doses (combination phase). Subsequently, you will be administered an infusion over a period of 30 or 60 minutes, every 2 or 4 weeks, depending on the dose you are receiving (single-agent phase).

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

When OPDIVO is administered in combination with cabozantinib, you will be administered 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 missed using OPDIVO

It is very important that you attend all your appointments to receive OPDIVO. If you miss any of them, 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 consult 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.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from 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 be life-threatening and may require treatment or withdrawal of OPDIVO.

The following adverse effects have been reported with OPDIVO alone:

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

• Upper respiratory tract infections
• Decrease in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood clotting)
• Decreased appetite, high blood sugar levels (hyperglycemia)
• Headache
• Shortness of breath (dyspnea), cough
• Diarrhea (watery, loose, or soft stools), vomiting, nausea, stomach pain, constipation
• Skin rash, sometimes with blisters, itching
• Pain in muscles, bones (musculoskeletal pain), and joints (arthralgia)
• Feeling of tiredness or weakness, fever

Common (may affect up to 1 in 10 patients)

• Severe lung infection (pneumonia), bronchitis
• Infusion-related reactions, allergic reaction (including life-threatening allergic reaction)
• Decreased function of the thyroid gland (which can cause tiredness or weight gain), increased function of the thyroid gland (which can cause increased heart rate, sweating, and weight loss), swelling of the thyroid gland
• Dehydration, weight loss, low blood sugar levels (hypoglycemia)
• Inflammation of the nerves (causing numbness, weakness, tingling, or burning of the arms and legs), dizziness
• Blurred vision, dry eyes
• Fast heart rate, abnormal heart rhythm
• High blood pressure (hypertension)
• Inflammation of the lungs (pneumonitis), characterized by cough and difficulty breathing, fluid around the lungs
• Inflammation of the intestines (colitis), ulcers in the mouth and herpes (stomatitis), dry mouth
• Change in skin color in patches (including vitiligo), dry skin, redness of the skin, unusual or weakened hair loss
• Inflammation of the joints (arthritis)
• Kidney failure (including sudden loss of kidney function)
• Pain, chest pain, swelling (edema)

Uncommon (may affect up to 1 in 100 patients)

• Elevation of some white blood cell counts
• Chronic diseases associated with the accumulation of inflammatory cells in various organs and tissues, most frequently in the lungs (sarcoidosis)
• 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, diabetes
• Increased level of acid in the blood (metabolic acidosis)
• Nerve damage causing numbness and weakness (polyneuropathy), inflammation of the nerves caused by the body's attack on itself, causing numbness, weakness, tingling, or burning (autoimmune neuropathy)
• Inflammation of the eyes (causing pain and redness)
• Inflammation of the heart muscle, inflammation of the heart lining and fluid accumulation around the heart (pericardial disorders), changes in heart rhythm or frequency
• Fluid 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 red, scaly patches (psoriasis), facial skin condition where the nose and cheeks are abnormally red (rosacea), severe skin condition causing redness, often with itchy patches, similar to measles rash, starting on the limbs and sometimes on the face and rest of the body (erythema multiforme), hives (urticaria)
• Inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica)

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

• Non-infectious, temporary, and reversible inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
• A disease that causes inflammation or enlargement of the lymph nodes (Kikuchi's lymphadenitis)
• Diabetic acidosis, decreased function of the parathyroid glands
• Temporary inflammation of the nerves causing pain, weakness, and paralysis in the limbs (Guillain-Barré syndrome); nerve damage causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve palsy); inflammation of the nerves caused by the body's attack on itself, causing numbness, weakness, tingling, or burning (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenia gravis or syndrome)
• Inflammation in the brain
• Inflammation of the eyes (causing pain and redness)
• Inflammation of the heart muscle, inflammation of the heart lining and fluid accumulation around the heart (pericardial disorders), changes in heart rhythm or frequency
• Fluid 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 red, scaly patches (psoriasis), severe skin condition causing redness, often with itchy patches, similar to measles rash, starting on the limbs and sometimes on the face and rest of the body (erythema multiforme), hives (urticaria)
• Inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica)

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

• A 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)
• Solid 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)
• An inflammatory disorder (most likely of autoimmune origin) that affects the eyes, skin, and ear membranes, brain, and spinal cord (Vogt-Koyanagi-Harada syndrome)
• Pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems, including frequent or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen (myelitis/transverse myelitis)
• Changes in any area of the skin and/or genital area associated with dryness, thinning of the skin, itching, and pain (lichen sclerosis or other lichen disorders)

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

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

• Upper respiratory tract infections
• Decrease in the number of red blood cells (which carry oxygen), white blood cells (important for fighting infections), or platelets (cells that help blood clotting)
• Decreased function of the thyroid gland (which can cause tiredness or weight gain), increased function of the thyroid gland (which can cause increased heart rate, sweating, and weight loss)
• Decreased appetite, weight loss, decreased albumin levels in the blood, high or low blood sugar levels
• Inflammation of the nerves (causing numbness, weakness, tingling, or burning of the arms and legs), headache, dizziness, altered sense of taste
• High blood pressure (hypertension)
• Shortness of breath (dyspnea), cough, abnormal voice sound (dysphonia)
• Diarrhea (watery, loose, or soft stools), constipation, vomiting, nausea, stomach pain, ulcers in the mouth and herpes (stomatitis), indigestion (dyspepsia)
• Skin rash, sometimes with blisters, itching, pain in the hands or soles of the feet; skin rash or redness, tingling, and sensitivity that becomes redness, swelling, and pain mainly on the palm of the hand and the sole of the foot (palmar-plantar erythrodysesthesia syndrome)
• Pain in the joints (arthralgia), pain in the muscles and bones (musculoskeletal pain), muscle spasms
• Excess protein in the urine
• Feeling of tiredness or weakness, fever, swelling (edema)

Common (may affect up to 1 in 10 patients)

• Severe lung infection (pneumonia), bronchitis, eye inflammation (conjunctivitis)
• Elevation of some white blood cell counts, decreased neutrophils with fever
• Allergic reaction, infusion-related reactions
• 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, swelling of the thyroid gland, diabetes
• Dehydration, decreased phosphate levels in the blood
• Feeling of numbness and tingling (paresthesia)
• Hearing a persistent sound in the ear when no sound exists (tinnitus)
• Blurred vision, dry eyes
• Fast heart rate, abnormal heart rhythm, inflammatory disease of the blood vessels
• Blood clot formation inside a blood vessel (thrombosis)
• Inflammation of the lungs (pneumonitis, characterized by cough and difficulty breathing), fluid in the lungs, blood clots, nosebleeds
• Inflammation of the intestines (colitis), inflammation of the pancreas (pancreatitis), dry mouth, inflammation of the stomach (gastritis), oral pain, hemorrhoids (piles)
• Inflammation of the liver
• Change in skin color in patches (including vitiligo), redness of the skin, unusual or weakened hair loss, change in hair color, hives (urticaria), abnormal skin discoloration (hyperpigmentation of the skin), dry skin
• Inflammation of the joints (arthritis), muscle weakness, muscle pain
• Kidney failure (including sudden loss of kidney function)
• Pain, chest pain, chills
• Feeling of not feeling well (malaise)

Uncommon (may affect up to 1 in 100 patients)

• Diabetic acidosis
• Increased levels of acid in the blood
• Temporary inflammation of the nerves causing pain, weakness, and paralysis in the limbs (Guillain-Barré syndrome); nerve damage causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve palsy); inflammation of the nerves caused by the body's attack on itself, causing numbness, weakness, tingling, or burning (autoimmune neuropathy); muscle weakness and fatigue without atrophy (myasthenia gravis or syndrome)
• Inflammation in the brain
• Inflammation of the eyes (causing pain and redness)
• Changes in heart rhythm or frequency, slow heart rate, inflammation of the heart muscle
• Intestinal perforation, duodenum inflammation, sensation of burning or pain in the tongue (glossodynia)
• Severe skin peeling and potentially life-threatening (Stevens-Johnson syndrome), skin disease with red, scaly patches (psoriasis), severe skin condition causing redness, often with itchy patches, similar to measles rash, starting on the 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 of the skin, itching, and pain (lichen sclerosis or other lichen disorders)
• Muscle sensitivity or weakness, not caused by exercise (myopathy), inflammation of the muscles (myositis), stiffness in the muscles and joints, inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica), bone damage in the jaw, abnormal opening between two parts of the body, such as an organ or blood vessel and another structure (fistula)
• Inflammation of the kidneys, inflammation of the bladder, signs and symptoms may include frequent or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen

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

• Non-infectious, temporary, and reversible 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, most frequently in the lungs (sarcoidosis)
• Decreased function of the parathyroid glands
• 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)
• An inflammatory disorder (most likely of autoimmune origin) that affects the eyes, skin, and ear membranes, brain, and spinal cord (Vogt-Koyanagi-Harada syndrome)
• Inflammation of the nerves
• Pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems, including frequent or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen (myelitis/transverse myelitis)
• Severe skin peeling and potentially life-threatening (toxic epidermal necrolysis), changes in any area of the skin and/or genital area associated with dryness, thinning of the skin, itching, and pain (lichen sclerosis)
• Chronic joint disease (spondyloarthritis), disease in which the immune system attacks the glands that produce body hydration, such as tears and saliva (Sjögren's syndrome), muscle spasms (rhabdomyolysis)
• Absence or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency)
• Celiac disease (characterized by symptoms such as stomach pain, diarrhea, and bloating after consuming gluten-containing foods)

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

• A 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)
• Solid organ transplant rejection
• Inflammation of the heart lining and fluid accumulation around the heart (pericardial disorders)

If you experience any of the above adverse effects, 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 blood levels of liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, or alkaline phosphatase, elevated blood levels of the waste product bilirubin)
• Abnormal kidney function tests (elevated 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 thyroid-stimulating hormone
• Increased levels of triglycerides in the blood
• Increased levels of cholesterol in the blood

Reporting of adverse effects

If you experience any adverse effects, consult your doctor,even if they are possible adverse effects not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of 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 vial label after EXP. The expiry date refers to the last day of the month stated.

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

Do not freeze.

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

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

Do not store the unused infusion solution for a new use. Disposal of unused medicine and all materials that have come into contact with it should be done according to local regulations.

6. Package contents and additional information

Composition of OPDIVO

• 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 ingredients are sodium citrate dihydrate, sodium chloride (see section 2 "OPDIVO contains sodium"), mannitol (E421), pentetic acid, polysorbate 80 (E433), sodium hydroxide, hydrochloric acid, and water for injections.

Appearance of OPDIVO and package contents

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

Date of last revision of this leaflet:

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu

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This information is intended only for healthcare professionals:

Preparation and administration of OPDIVO

Preparation should be performed by trained personnel in accordance with good practice rules, particularly with regard to asepsis.

Dose calculation

More than one vial of OPDIVO concentrate may be needed to deliver the total dose to the patient.

Nivolumab as monotherapy

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

Melanoma (advanced or adjuvant treatment) in adolescents. The prescribed dose for adolescents from 12 years of age and with a minimum weight of 50 kg is 240 mg or 480 mg. For adolescents from 12 years of age and with a weight below 50 kg, the prescribed dose is administered in mg/kg. According to this prescribed dose, calculate the total dose to be administered.

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

Nivolumab in combination with ipilimumab

The prescribed dosefor the patient is administered in mg/kg. According to this prescribed dose, calculate the total dose to be administered (see above).

Nivolumab in combination with ipilimumab in malignant pleural mesothelioma

The prescribed dose for a patient is 360 mg 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 (3 mg/kg) or 240 mg 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 (3 mg/kg) or 360 mg regardless of body weight.

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

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

Nivolumab in combination with chemotherapy in advanced esophageal cancer

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

Nivolumab in combination with chemotherapy in gastric, gastroesophageal junction, or esophageal adenocarcinoma

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

Nivolumab in combination with ipilimumab and chemotherapy

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

Nivolumab in combination with cabozantinib

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

Preparation of the infusion

Aseptic handling must be ensuredwhen preparing the infusion.

OPDIVO can be used for intravenous administration:

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

or

• after dilutionaccording to the following instructions:
• the final concentration of the infusion should be between 1 and 10 mg/ml
• the total volume of the infusion should not exceed 160 ml. For patients whose weight is less than 40 kg, the total volume of the infusion should not exceed 4 ml/kg of body weight.

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

STEP1

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

STEP2

• Transfer the concentrate to a sterile evacuated glass vial or intravenous solution container (PVC or polyolefin).
• If applicable, dilute with the precise volume of sodium chloride 9 mg/ml (0.9%) solution for injections or glucose 50 mg/ml (5%) solution for injections. To facilitate preparation, the concentrate can be passed directly into a pre-loaded bag containing the appropriate volume of sodium chloride 9 mg/ml (0.9%) solution for injections or glucose 50 mg/ml (5%) solution for injections.
• Gently mix the infusion by manual rotation. Do not shake.

Administration

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

Administer the OPDIVO infusion intravenously over a period of 30or60minutes depending on the dose and indication.

The OPDIVO infusion should not be infused simultaneously through the same intravenous line with other medicines. Use a separate infusion line for the infusion.

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

The OPDIVO infusion is compatible with:

• PVC containers
• Polyolefin containers
• Glass vials
• PVC infusion sets
• In-line filters with polyethersulfone membranes with pore sizes of 0.2 μm to 1.2 μm.

After administration of the nivolumab dose, flush the line with a sodium chloride 9 mg/ml (0.9%) solution for injections or a glucose 50 mg/ml (5%) solution for injections.

Storage and validity period

Unopened vial

OPDIVO should be stored in a refrigerator(2 °C-8 °C). The vials should be kept in the original packaging to protect them from light. OPDIVO should not be frozen.

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

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

OPDIVO infusion

Chemical and physical stability has been demonstrated from the time of preparation, as described below (times include the administration period):

From a microbiological point of view, the prepared infusion solution, 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 7 days between 2 °C and 8 °C, or 8 hours (of the total 7 days of storage) at room temperature (≤ 25 °C). Aseptic handling must be ensured during the preparation of the infusion.

Disposal

Do not store the unused infusion solution for a new use. Disposal of unused medicine and all materials that have come into contact with it should be done according to local regulations.