OPDUALAG 240 mg/80 mg concentrate for infusion solution

Introduction

Package Leaflet: Information for the User

Opdualag240mg/80mg concentrate for solution for infusion

nivolumab/relatlimab

This medicine is subject to additional monitoring, which will allow for quick identification of new safety information. You can help by reporting any side effects you may get. The last section of section 4 will tell you how to report side effects.

Read all of this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• It is important that you carry the patient information card with you at all times
• If you have any further questions, ask your doctor.
• If you get any side effects, talk to your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What is Opdualag and what is it used for
2. What you need to know before you use Opdualag
3. How to use Opdualag
4. Possible side effects
5. Storing Opdualag
6. Contents of the pack and other information

1. What is Opdualag and what is it used for

Opdualag is a cancer medicine used to treat advanced melanoma (a type of skin cancer that can spread to other parts of the body). It can be used in adults and adolescents from 12 years of age.

Opdualag contains two active substances: nivolumab and relatlimab. Both active substances are monoclonal antibodies, proteins designed to recognize and bind to a specific target substance in the body. Nivolumab binds to a target protein called PD-1. Relatlimab binds to a target protein called LAG-3.

PD-1 and LAG-3 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 binding to the two proteins, nivolumab and relatlimab block their actions and prevent the inhibition of T cells. This helps to increase the activity of T cells against melanoma cancer cells.

2. What you need to know before you are given Opdualag

You should not be given Opdualag

• if you are allergic to nivolumab, relatlimab or any of the other ingredients of this medicine (listed in section 6). If you are unsure, consult your doctor.

Warnings and precautions

Talk to your doctor before you receive Opdualag, as it may cause:

• problems in your lungs such as difficulty breathing or coughing. These can be signs of inflammation of the lungs (pneumonitis or interstitial lung disease)
• diarrhea (watery, loose or soft stools) or inflammation of the intestines (colitis), with symptoms such as stomach pain and presence of mucus or blood in the stool
• inflammation of the liver (hepatitis). 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
• inflammation or problems with your kidneys. Signs and symptoms may include abnormal kidney function tests or decreased amount of urine
• problems with your hormone-producing glands (including the pituitary, thyroid and adrenal glands) that can affect the functioning of these glands. Signs and symptoms that these glands are not working properly may include fatigue (extreme tiredness), weight changes or headache and visual disturbances
• diabetes, including a serious, potentially life-threatening problem due to acid in the blood produced by diabetes (diabetic ketoacidosis). Symptoms may include feeling more hungry or thirsty than usual, needing to urinate more often, weight loss, feeling tired or having trouble thinking clearly, sweet or fruity breath, a sweet or metallic taste in your mouth or a different smell in your urine or sweat, feeling sick or being sick, stomach pain and deep or rapid breathing
• inflammation of the skin that can lead to a severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). Signs and symptoms of severe skin reactions may include rash, itching and peeling of the skin (potentially life-threatening)
• inflammation of the heart muscle (myocarditis). Signs and symptoms may include chest pain, irregular or rapid heartbeat, fatigue, swelling of the ankles or difficulty breathing
• hemophagocytic lymphohistiocytosis. A rare disease in which your immune system produces too many cells to fight infections, otherwise normal, called histiocytes and lymphocytes. Symptoms may include enlargement of the liver and/or spleen, skin rash, inflammation of the lymph nodes, respiratory problems, tendency to bruise, kidney abnormalities and heart problems
• rejection of solid organ transplants
• graft-versus-host disease after bone marrow transplantation (in which the transplanted cells from a donor attack your own body cells). If you have had one of these transplants, your doctor will consider whether you should receive treatment with Opdualag. Graft-versus-host disease can be severe and life-threatening
• infusion reactions, which can include difficulty breathing, itching or rash, dizziness or fever

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

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

Note that these signs and symptoms sometimes occur late and 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 tests during your treatment.

Check with your doctor or nurse before you receive Opdualag if:

• you have an active autoimmune disease (a disorder in which the body attacks its own cells)
• you have ocular melanoma
• you have been told that your cancer has spread to your brain
• you have been taking medicines that suppress your immune system

Children and adolescents

Opdualag should not be used in children under 12 years of age.

Other medicines and Opdualag

Before you receive Opdualag, tell your doctor if you are taking any medicine that suppresses your immune system, such as corticosteroids, as these medicines may interfere with the effect of Opdualag. However, once you are being treated with Opdualag, your doctor may give you corticosteroids to reduce any possible side effects you may have during your treatment.

Tell your doctor if you are taking, have recently taken or are planning to take any other medicines. Do not take any other medicine during your treatment without talking to your doctor first.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.

Do not use Opdualag if you are pregnant, unless your doctor specifically tells you to. The effects of Opdualag on pregnant women are not known, but the active substances, nivolumab and relatlimab, may cause harm to the unborn baby.

• You must use an effective method of contraception while you are being treated with Opdualag and for at least 5 months after the last dose of Opdualag, if you are a woman who could become pregnant.
• If you become pregnant while using Opdualag, tell your doctor.

It is not known whether Opdualag can pass into breast milk and affect a breast-fed baby. Ask your doctor about the benefits and risks of breastfeeding during or after treatment with Opdualag.

Driving and using machines

Opdualag has a minor influence on the ability to drive and use machines; however, be careful when performing these activities until you are sure that Opdualag does not affect you negatively.

Patient information card

You will also find key messages from this leaflet on the patient information card that your doctor has given you. It is important that you carry this patient information card with you at all times and show it to your partner or caregivers.

3. How to use Opdualag

How much Opdualag is given

The recommended dose by infusion in adults and adolescents from 12 years of age is 480 mg of nivolumab and 160 mg of relatlimab every 4 weeks. This dose has been established for adolescent patients who weigh at least 30 kg.

Depending on your dose, the appropriate amount of Opdualag can be diluted before use with sodium chloride injection solution to a concentration of 9 mg/ml (0.9%) or glucose injection solution to a concentration of 50 mg/ml (5%). Opdualag can also be used undiluted.

How Opdualag is given

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

Opdualag will be given to you as an infusion (a drip) into a vein, every 4 weeks. Each infusion takes about 30 minutes to give.

Your doctor will continue to treat you with Opdualag while you are benefiting from it or until the side effects are too severe.

If you miss a dose of Opdualag

It is very important that you attend all your appointments to receive Opdualag. If you miss any, talk to your doctor about when to schedule your next dose.

If you stop treatment with Opdualag

Stopping your treatment may stop the effect of the medicine. Do not stop treatment with Opdualag unless you have discussed it with your doctor.

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

4. Possible side effects

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

Be aware of important symptoms of inflammation(described in section 2 "Warnings and precautions"). Opdualag works on your immune system and can cause inflammation in some parts of your body. Inflammation can cause serious damage to your body and some inflammatory conditions can be life-threatening and require treatment or discontinuation of Opdualag.

The following side effects have been reported with Opdualag:

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

• urinary tract infection (the parts of the body that collect and get rid of urine)
• decrease in the number of red blood cells (which carry oxygen) and white blood cells (lymphocytes, neutrophils and leucocytes, which are important for fighting infections)
• decrease in thyroid gland function (which can cause tiredness or weight gain)
• decrease in appetite
• headache
• difficulty breathing, coughing
• diarrhea (watery, loose or soft stools), vomiting, nausea, stomach pain, constipation
• skin rash (sometimes with blisters), change in skin color in patches (vitiligo), itching
• muscle, bone and joint pain
• feeling tired or weak, fever

Changes in laboratory test results done by your doctor may show:

• abnormal liver function (increased levels in the blood of the liver enzymes alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase)
• abnormal kidney function (increased level in the blood of creatinine)
• decrease in sodium and magnesium and decrease or increase in calcium and potassium

Common (may affect up to 1 in 10 people)

• infections of the upper respiratory tract (nose and upper airways)
• decrease in the number of platelets (the cells that help blood clot), increase in some white blood cells
• decrease in the secretion of hormones produced by the adrenal glands (glands located above the kidneys), inflammation of the pituitary gland located at the base of the brain, increase in thyroid gland function, inflammation of the thyroid gland
• diabetes, low blood sugar levels; weight loss, high levels of the waste product uric acid in the blood, decrease in the levels of the protein albumin in the blood, dehydration
• confusion
• inflammation of the nerves (which can cause numbness, weakness, tingling or burning of the arms and legs), dizziness, changes in taste
• inflammation of the eye (which can cause pain and redness, vision problems or blurred vision), vision problems, dry eyes, excessive tear production
• inflammation of the heart muscle
• inflammation of a vein, which can cause redness, sensitivity and swelling
• inflammation of the lungs (pneumonitis), characterized by coughing and difficulty breathing; nasal congestion (stuffy nose)
• inflammation of the intestine (colitis), inflammation of the pancreas, inflammation of the stomach (gastritis), difficulty swallowing, mouth ulcers and cold sores; dry mouth
• inflammation of the liver (hepatitis)
• loss or unusual weakening of hair (alopecia), isolated areas of skin growth that become red and itchy (lichenoid keratosis), sensitivity to light, dry skin
• joint pain (arthritis), muscle spasms, muscle weakness
• kidney failure (changes in the amount or color of urine, blood in the urine, swelling of the ankles, loss of appetite), high levels of protein in the urine
• swelling (edema), flu-like symptoms, chills
• reactions related to the administration of the medicine

Changes in laboratory test results done by your doctor may show:

• abnormal liver function (higher levels in the blood of the waste product bilirubin, higher levels in the blood of the liver enzyme gamma-glutamyl transferase)
• increase in sodium and magnesium
• increase in troponin levels (a protein that is released into the blood when the heart is damaged)
• increase in the levels of the enzyme that breaks down glucose (lactate dehydrogenase), the enzyme that breaks down fats (lipase) and the enzyme that breaks down starch (amylase)

Uncommon (may affect up to 1 in 100 people)

• inflammation and infection of the hair follicles
• a disorder that causes red blood cells to be destroyed faster than they are produced (hemolytic anemia)
• decrease in the activity of the pituitary gland located at the base of the brain, decrease in the function of the hormone-producing glands
• inflammation of the brain, which can include confusion, fever, memory problems or dizziness (encephalitis), temporary inflammation of the nerves that causes pain, weakness and paralysis of the limbs (Guillain-Barré syndrome), inflammation of the optic nerve that can cause partial or complete loss of vision
• an inflammatory disorder that affects the eyes, skin and membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada disease), red eye
• fluid around the heart
• asthma
• inflammation of the esophagus (the tube between the throat and stomach)
• inflammation of the bile duct
• skin rash and blisters on legs, arms and abdomen (pemphigoid), skin disease with thickened patches of red skin, often with silver scales (psoriasis), hives (itchy, lumpy rash)
• inflammation of the muscles that causes weakness, swelling and pain, disease in which the immune system attacks the glands that produce moisture in the body, such as tears and saliva (Sjögren's syndrome), inflammation of the muscles that causes pain or stiffness, inflammation of the joints (arthritic disease), disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs, such as joints, skin, brain, lungs, kidneys and blood vessels (systemic lupus erythematosus)
• inflammation of the kidney
• absence of sperm in the semen
• fluid around the lungs.

Changes in laboratory test results done by your doctor may show:

• increase in C-reactive protein level
• increase in erythrocyte sedimentation rate

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

• absence or reduction of digestive enzymes produced by the pancreas (exocrine pancreatic insufficiency).
• inflammation of the tissues surrounding the lungs (pleura), the heart (pericardium) and the abdomen (peritoneum).

Other side effects that have been reported with frequency not known (cannot be estimated from the available data)

• celiac disease (characterized by symptoms such as stomach pain, diarrhea and bloating after eating foods that contain gluten).

Reporting of side effects

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

5. Storage of Opdualag

Opdualag will be administered to you in a hospital or clinic and healthcare professionals will be responsible for its storage.

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 is the last day of the month indicated.

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

Do not freeze.

Keep the vial in the outer packaging to protect it from light.

The unopened vial can be stored at controlled room temperature (not above 25 °C) for a maximum of 72 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 in accordance with local regulations.

6. Package Contents and Additional Information

Composition of Opdualag

• The active substances are nivolumab and relatlimab.

Each ml of concentrate for solution for infusion contains 12 mg of nivolumab and 4 mg of relatlimab.

A 20 ml vial of concentrate contains 240 mg of nivolumab and 80 mg of relatlimab.

• The other ingredients are histidine, histidine hydrochloride monohydrate, sucrose, pentetic acid, polysorbate 80 (E433), and water for injections.

Appearance and Package Contents of the Product

Opdualag concentrate for solution for infusion (sterile concentrate) is a clear to opalescent, colorless to slightly yellow liquid that is essentially free of particles.

It is available in packs containing one glass vial.

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

You can request more information about this medicine by contacting the local representative of the marketing authorisation holder:

Date of Last Revision of this Leaflet:

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

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This information is intended only for healthcare professionals:

Opdualag is supplied in a single-dose vial and does not contain any preservative. Preparation must be performed by qualified personnel in accordance with good practice, especially with regard to asepsis.

Opdualag can be used for intravenous administration:

• without dilution, after transfer to an infusion container using a suitable sterile syringe; or
• after dilution according to the following instructions:
• • the final infusion concentration should be between 3 mg/ml of nivolumab and 1 mg/ml of relatlimab and 12 mg/ml of nivolumab and 4 mg/ml of relatlimab;
  • the total infusion volume should not exceed 160 ml. For patients weighing less than 40 kg, the total infusion volume should not exceed 4 ml per kg of patient weight.

The Opdualag concentrate can be diluted with:

• sodium chloride injection solution at a concentration of 9 mg/ml (0.9%); or
• glucose injection solution at a concentration of 50 mg/ml (5%).

Infusion Preparation

• Inspect the Opdualag concentrate for particulate matter or color changes. Do not shake the vial. Opdualag is a clear to opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, has changed color, or contains foreign particles.
• Withdraw the required volume of Opdualag concentrate using a suitable sterile syringe and transfer the concentrate to a sterile container for intravenous administration (EVA, PVC, or polyolefin). Each vial contains 21.3 ml of solution, including a 1.3 ml overfill.
• If applicable, dilute the Opdualag solution with the precise volume of sodium chloride injection solution at a concentration of 9 mg/ml (0.9%) or glucose injection solution at a concentration of 50 mg/ml (5%). To facilitate preparation, the concentrate can also be transferred directly to a pre-loaded bag containing the appropriate volume of sodium chloride injection solution at a concentration of 9 mg/ml (0.9%) or glucose injection solution at a concentration of 50 mg/ml (5%).
• Gently mix the infusion by manual rotation. Do not shake.

Administration

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

Administer the Opdualag infusion intravenously over a period of 30 minutes.

The use of an infusion set and an in-line or additional sterile filter, non-pyrogenic and with low protein binding (pore size 0.2 μm to 1.2 μm), is recommended.

The Opdualag infusion is compatible with EVA, PVC, and polyolefin containers, PVC infusion sets, and in-line filters with polyethersulfone (PES), nylon, and polyvinylidene fluoride (PVDF) membranes with pore sizes of 0.2 μm to 1.2 μm.

Do not administer other medications concurrently through the same infusion line.

After administration of the Opdualag dose, flush the line with sodium chloride injection solution at a concentration of 9 mg/ml (0.9%) or glucose injection solution at a concentration of 50 mg/ml (5%).

Storage and Validity Conditions

Unopened Vial

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

The unopened vial can be stored at controlled room temperature (not above 25 °C) for a maximum of 72 hours.

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

After Preparation of the Infusion

Chemical and physical stability in use 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 in-use storage times and conditions are the responsibility of the user and normally should not exceed 24 hours between 2 °C and 8 °C, unless the preparation has been made in controlled and validated aseptic conditions.

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 in accordance with local regulations.