OPDIVO 600 mg INJECTABLE SOLUTION

Introduction

Package Leaflet: Information for the User

OPDIVO600mg solution for injection

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 is OPDIVO and what is it 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 is OPDIVO and what is it 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 surgery is called adjuvant therapy)
• advanced non-small cell lung cancer (a type of lung cancer) in adults
• advanced renal cell carcinoma (kidney cancer) 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 pathological 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, 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"). If in doubt, consult your doctor.

Warnings and precautions

Consult your doctor before starting treatment with OPDIVO, as it may cause:

• Heart problemssuch as an alteration in the rhythm or frequency of the heartbeat or an 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 the presence of mucus or blood in the stool.
• Liver inflammation (hepatitis).The signs and symptoms of hepatitis can 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 can include abnormal kidney function tests, decreased urine volume.
• Problems with the hormone-producing glands(such as the pituitary, thyroid, parathyroid, and adrenal glands) that can affect the functioning of these glands. The signs and symptoms that these glands are not functioning 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 can 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 a severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). The signs and symptoms of severe skin reactions can 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 can 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, which are otherwise normal, called histiocytes and lymphocytes. The symptoms can include an enlarged liver or spleen, skin rash, enlarged 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 suspend 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.

OPDIVO acts on your immune system. This could cause inflammation in some parts of your body. The risk of these side effects may be greater if you already have an autoimmune disease (a condition in which the body attacks its own cells). You may also experience flare-ups of your autoimmune disease, which in most cases are mild.

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 fatal. Your doctor will monitor signs of complications if you have had a hematopoietic progenitor cell transplant.

Children and adolescents

OPDIVO solution for injection must not be used in children and adolescents under 18 years of age.

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 might take any other medicine. Do not take any other medicineduring your treatment without first consulting your doctor.

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 polysorbate80 (E433)

This medicine contains 2.5 mg of polysorbate 80 in each 5 ml vial, equivalent to 5 mg/10 ml. Polysorbates can cause allergic reactions. Tell your doctor if you have any known allergy.

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 as an injection under the skin (subcutaneous injection), the recommended dose is 600 mg administered every 2 weeks or 1200 mg administered 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 infusion into a vein 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 an injection under the skin is 600 mg administered every 2 weeks or 1200 mg administered every 4 weeks (single-agent phase).

When OPDIVO is administered in combination with ipilimumab for the treatment of advanced kidney cancer, the recommended dose of OPDIVO administered as an infusion into a vein 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 an injection under the skin is 600 mg administered every 2 weeks or 1200 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 administered as an infusion into a vein is 3 mg of nivolumab per kilogram of body weight or 240 mg for the first 4 doses (combination phase), depending on your treatment. Subsequently, the recommended dose of OPDIVO administered as an injection under the skin is 600 mg administered every 2 weeks or 1200 mg administered every 4 weeks (single-agent phase), depending on your treatment.

When OPDIVO is administered in combination with chemotherapy for the treatment of advanced esophageal cancer, the recommended dose of OPDIVO is 600 mg every 2 weeks or 1200 mg every 4 weeks administered as an injection under the skin.

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 600 mg every 2 weeks administered as an injection under the skin.

When OPDIVO is administered in combination with chemotherapy for the treatment of urothelial carcinoma, the recommended dose of OPDIVO administered as an infusion into a vein is 360 mg of nivolumab every 3 weeks for a maximum of 6 cycles (combination phase). Subsequently, the recommended dose of OPDIVO administered as an injection under the skin is 600 mg administered every 2 weeks or1200 mg administered every 4 weeks (single-agent phase).

When OPDIVO is administered in combination with cabozantinib for the treatment of advanced kidney cancer, the recommended dose of OPDIVO is 600 mg administered every 2 weeks or 1200 mg administered every 4 weeks as an injection under the skin.

How OPDIVO is administered

You will receive treatment with OPDIVO under the supervision of an experienced doctor. It may be necessary to use more than one vial of OPDIVO to obtain the required dose.

OPDIVO is administered as an injection under the skin of the abdomen or thigh over a period of 3 to 5 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving. Treatment with OPDIVO will continue while you are benefiting from it or until you can no longer tolerate it.

When OPDIVO is administered in combination with ipilimumab, for the treatment of skin cancer, kidney cancer, or colon or rectal cancer, you will be given an infusion over a period of 30 minutes, every 3 weeks for the first 4 doses (combination phase). Subsequently, you will be given an injection under the skin of the abdomen or thigh over a period of 3 to 5 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving (single-agent phase).

When OPDIVO is administered as an injection under the skin of the abdomen or thigh in combination with chemotherapy for the treatment of esophageal cancer, you will be given an injection over a period of 3 to 5 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving.

When OPDIVO is administered as an injection under the skin of the abdomen or thigh in combination with chemotherapy for the treatment of gastric, gastroesophageal junction, or esophageal adenocarcinoma, you will be given an injection over a period of 3 to 5 minutes, every 2 weeks.

When OPDIVO is administered as an injection under the skin of the abdomen or thigh in combination with chemotherapy for the treatment of urothelial carcinoma, you will be given an injection over a period of 3 to 5 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving.

When OPDIVO is administered as an injection under the skin of the abdomen or thigh in combination with cabozantinib, you will be given an injection over a period of 3 to 5 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving.

If you miss a dose of 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

Stopping your treatment may stop the effect of the medicine. 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 medicine, ask your doctor.

When OPDIVO is administered in combination with other anti-cancer medicines, you will first be given OPDIVO followed by the other medicine.

Please consult the package leaflet of the other anti-cancer medicines to understand the use of these medicines. If you have any questions about them, please ask 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 with 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 the 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
• Reactions related to the infusion of the medicine, allergic reaction (including potentially life-threatening allergic reaction)
• Decrease in the function of the thyroid gland (which can cause tiredness or weight gain), increase in the 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 heartbeat, 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)
• Reaction at the injection site

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)
• Decrease in the secretion of hormones produced by the adrenal glands (glands located above the kidneys), low activity (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, diabetes
• Increased acid levels 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 rate
• 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, often with silvery scales (psoriasis), skin condition of the face 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 extremities 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 (high levels of acid in the blood due to diabetes), 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); a condition where the muscles become weak and tired easily (myasthenic syndrome), inflammation of the brain
• An inflammation of the optic nerve that could cause complete or partial loss of vision (optic neuritis)
• Inflammatory disease of the blood vessels
• Ulcers in the small intestine
• Severe and potentially life-threatening skin peeling (toxic epidermal necrolysis or Stevens-Johnson syndrome)
• A disease where the immune system attacks the glands that produce moisture for the body, such as tears and saliva (Sjögren's syndrome), muscle pain, sensitivity, or weakness not caused by exercise (myopathy), inflammation of the muscles (myositis), stiffness in the muscles and joints, muscle spasms (rhabdomyolysis)
• Kidney inflammation, bladder inflammation, signs and symptoms may include frequent and/or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen
• Absence or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency)
• 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 where the immune system produces too many cells to fight infections, called histiocytes and lymphocytes, which can cause various symptoms (known as hemophagocytic lymphohistiocytosis)
• Rejection of solid organ transplants
• 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 urination, urinary incontinence, difficulty urinating, and constipation (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 lichenoid 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 with blood clotting)
• Decrease in thyroid gland activity (which can cause tiredness or weight gain), increase in thyroid gland activity (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 speech sound (dysphonia)
• Diarrhea (watery, loose, or soft stools), constipation, vomiting, nausea, stomach pain, mouth ulcers 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 symmetrical redness, swelling, and pain mainly on the palms of the hands and soles of the feet (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, decrease in neutrophils with fever
• Allergic reaction, reactions related to the infusion of the medicine
• Decrease in the secretion of hormones produced by the adrenal glands (glands located above the kidneys), decrease in activity (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland located at the base of the brain, swelling of the thyroid gland, diabetes
• Dehydration, decrease in phosphate levels in the blood
• Feeling of numbness and tingling (paresthesia)
• Hearing a persistent sound in the ear when no sound is present (tinnitus)
• Blurred vision, dry eyes
• Fast heartbeat, abnormal heart rhythm, inflammatory disease of the blood vessels
• Formation of a blood clot within 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), mouth 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), 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 being well (malaise)

Uncommon (may affect up to 1 in 100 patients)

• Diabetic acidosis (high levels of acid in the blood due to diabetes)
• Increased acid levels 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 of the brain
• Inflammation of the eyes (causing pain and redness)
• Changes in heart rhythm or rate, slow heartbeat, inflammation of the heart muscle
• Intestinal perforation, inflammation of the duodenum, burning sensation or pain in the tongue (glossodynia)
• Severe and potentially life-threatening skin peeling (Stevens-Johnson syndrome), skin disease with red, scaly patches, often with silvery scales (psoriasis), severe skin condition causing redness, often with itchy patches, similar to measles rash, starting on the extremities 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 lichenoid 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)
• Kidney inflammation, bladder inflammation, signs and symptoms may include frequent and/or painful urination, urgent need to urinate, blood in the urine, pain or pressure in the lower abdomen

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)
• Decrease in the 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)
• An inflammation of the optic nerve that could cause complete or partial loss of vision (optic neuritis)
• Inflammation of the nerves
• Pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems, including frequent urination, urinary incontinence, difficulty urinating, and constipation (myelitis/transverse myelitis)
• Severe and potentially life-threatening skin peeling (toxic epidermal necrolysis), changes in any area of the skin and/or genital area associated with dryness, thinning of the skin, itching, and pain (lichen sclerosis)
• Chronic joint disease (spondyloarthritis), a disease where the immune system attacks the glands that produce moisture for the body, 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 where the immune system produces too many cells to fight infections, called histiocytes and lymphocytes, which can cause various symptoms (known as hemophagocytic lymphohistiocytosis)

• Rejection of solid organ transplants
• Inflammation of the heart lining and fluid accumulation around the heart (pericardial disorders)

If you experience any of the adverse effects described above, inform your doctor immediately.Do not attempt 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 levels of bilirubin in the blood)
• Abnormal kidney function tests (elevated creatinine levels in the blood)
• 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 that do not appear 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 that appears on the packaging and the label on the vial after CAD. The expiry date is the last day of the month indicated.

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

Do not freeze.

Store in the original package to protect it from light.

Do not store the unused injectable solution for 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.

6. Package Contents and Additional Information

Composition of OPDIVO

• The active ingredient is nivolumab.

Each milliliter 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 monohydrochloride, sucrose, pentetic acid, polysorbate 80 (E433), methionine, and water for injectable preparations (see section 2 "OPDIVO contains polysorbate 80 (E433)").

Appearance of OPDIVO and Package Contents

OPDIVO injectable solution is a clear to opalescent liquid, colorless to pale yellow, which may contain a few particles.

It is available in packages 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

Date of Last Revision of this Leaflet:

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

---------------------------------------------------------------------------------------------------------------------------

This information is intended only for healthcare professionals:

To avoid medication errors, it is essential to check the vial labels to ensure that the patient is administered the correct formulation (intravenous or subcutaneous) as prescribed.

Preparation and Administration of OPDIVO

Preparation should be performed by trained personnel in accordance with good practice standards, particularly regarding asepsis.

Dose Calculation

More than one vial of OPDIVO may be necessary to provide the total dose to the patient.

Nivolumab as monotherapy

The prescribed dose for a patient is 600 mg or 1200 mg, regardless of body weight.

Nivolumab in combination with chemotherapy in advanced esophageal cancer

The prescribed dose for a patient is 600 mg or 1200 mg, regardless of body weight.

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

The prescribed dose for a patient is 600 mg, regardless of body weight.

Nivolumab in combination with cabozantinib

The prescribed dose for a patient is nivolumab 600 mg or 1200 mg, regardless of body weight.

Preparation of the Injection

• Inspect the OPDIVO injectable solution vial for any foreign particles or color alterations. Do not shake the vial. OPDIVO injectable solution is a clear to opalescent liquid, colorless to pale yellow. Discard the vial if the solution is cloudy, discolored, or contains particles other than a few translucent to white ones.
• Allow the vial or vials (depending on the prescribed dose) to reach room temperature.
• Extract the necessary volume of OPDIVO injectable solution using a sterile syringe and an appropriate transfer needle.

Administration

OPDIVO injectable solution should not be administered intravenously.

Administer OPDIVO injectable solution subcutaneously with a 23 G-25 G hypodermic needle or a subcutaneous administration device (e.g., butterfly needle) over a period of 3 to 5 minutesinto the subcutaneous tissue of the abdomen or thigh.

Alternate the injection site for consecutive injections. Do not inject into areas where the skin is sensitive, red, or has bruises, scars, or moles. If administration is interrupted, resume at the same injection site or another one.

Do not administer other medications subcutaneously at the same site used for OPDIVO injectable solution.

OPDIVO injectable solution is compatible with:

• Polypropylene
• Polycarbonate
• Polyethylene
• Polyurethane
• Polyvinyl chloride
• Fluorinated ethylene propylene
• Stainless steel

Storage Conditions 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.

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

Syringe Storage

From a microbiological point of view, once transferred from the vial to the syringe, the medication should be used immediately, as it does not contain any antimicrobial preservative or bacteriostatic agents. If not used immediately, OPDIVO injectable solution transferred to the syringe can be stored in a refrigerator at 2 °C to 8 °C and protected from light for a maximum of 7 days and/or at room temperature between 20 °C and 25 °C and with ambient light for a maximum of 8 hours. It should be discarded if the storage time exceeds these limits. Aseptic handling should be ensured during syringe preparation for injection.

Disposal

Do not store the unused injectable solution for 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.