Opdualag

Package leaflet: Information for the user

Opdualag 240 mg/80 mg concentrate for solution for infusion

nivolumab/relatlimab
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

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

Contents of this leaflet:

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

1. What Opdualag is and what it is used for

Opdualag is a medicine used to treat cancer, specifically advanced melanoma (a type of skin tumour that can spread to other parts of the body). It can be used in adults and adolescents aged 12 years and older.
Opdualag contains two active substances: nivolumab and relatlimab. Both active substances are monoclonal antibodies, proteins that can recognise 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 that is part of the immune system, the body's natural defence system). By binding to these two proteins, nivolumab and relatlimab block their actions and prevent them from inhibiting T cells. This helps increase the activity of T cells against melanoma tumour cells.

2. What you should know before being given Opdualag

Do not receive 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 using Opdualag, as it may cause:

• Lung problems such as difficulty breathing or cough. These may be signs of lung inflammation (pneumonitis or interstitial lung disease).
• Diarrhoea (watery, loose, or soft stools) or inflammation of the intestine (colitis), with symptoms such as stomach pain and mucus or blood in the stools.
• Inflammation of the liver (hepatitis). Signs and symptoms of hepatitis may include changes in liver function tests, yellowing of the eyes or skin (jaundice), pain in the right side of the abdomen, or fatigue.
• Inflammation or problems affecting the kidneys. Signs and symptoms may include changes in kidney function tests or reduced urine output.
• Problems in glands that produce hormones (including the pituitary, thyroid, and adrenal glands), which may affect how these glands function. Signs and symptoms indicating improper gland function may include tiredness (extreme fatigue), weight changes, headache, or vision disturbances.
• Diabetes, including a serious, sometimes life-threatening condition caused by acid in the blood due to diabetes (diabetic ketoacidosis). Symptoms may include increased hunger or thirst, more frequent urination, weight loss, feeling tired or difficulty thinking clearly, breath with a sweet or fruity odour, sweet or metallic taste in the mouth, or unusual odour in urine or sweat, feeling unwell or actual illness, stomach pain, and deep or rapid breathing.
• Skin inflammation that may lead to a severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). Signs and symptoms of a severe skin reaction may include redness, itching, and skin peeling (which can be fatal).
• Inflammation of the heart muscle (myocarditis). Signs and symptoms may include chest pain, rapid and/or irregular heartbeat, fatigue, swelling of the ankles, or shortness of breath.
• Hemophagocytic lymphohistiocytosis. A rare condition in which the immune system produces an excessive number of infection-fighting cells called histiocytes and lymphocytes. Symptoms may include: enlargement of the liver and/or spleen, skin rash, swollen lymph nodes, breathing problems, easy bruising, kidney abnormalities, and heart problems.
• Rejection of solid organ transplant.
• Graft-versus-host disease following stem cell transplant (transplanted donor cells attack the recipient's cells). If you have undergone either of these transplants, your doctor will decide whether you should receive Opdualag treatment. Graft-versus-host disease can be serious and may lead to death.
• Infusion reactions, which may include shortness of breath, itching or rash, dizziness, or fever.

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

• prescribe other medicines to prevent complications and reduce symptoms,
• skip your next dose of Opdualag,
• or stop treatment with Opdualag completely. Please note that these signs and symptoms may sometimes be delayed and may develop weeks or months after the last administration. Before treatment, your doctor will check your overall health. During treatment, you will also have blood tests.

Before receiving Opdualag, check with your doctor or nurse if:

• you have active autoimmune disease (a condition in which the body attacks its own cells);
• you have ocular melanoma;
• you have been told that cancer has spread to the brain;
• you have taken a medicine to suppress the immune system.

Opdualag acts on the immune system. It may cause inflammation in certain parts of the body.
The risk of developing these side effects may be higher if you already have an autoimmune disease (a condition in which the body attacks its own cells). Frequent flare-ups of autoimmune disease may also occur, which in most cases are mild.
Children and adolescents
Opdualag must not be given to children under 12 years of age.
Other medicines and Opdualag
Before you are given Opdualag, inform your doctor if you are taking any other medicine that suppresses the immune system, such as corticosteroids, as these medicines may interfere with the effect of Opdualag. However, once you have been treated with Opdualag, your doctor may give you corticosteroids to reduce any possible side effects you may experience during treatment.
Inform your doctor if you are taking, have recently taken, or plan to take any other medicine. Do not take any other medicines during treatment without first talking to your doctor.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor for advice before taking this medicine.
Do not use Opdualag during pregnancy unless your doctor tells you to do so. The effects of Opdualag in pregnant women are unknown, but it is possible that the active substances nivolumab and relatlimab may harm the unborn child.

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

It is not known whether Opdualag passes into breast milk and could affect a breastfed infant. Talk to your doctor about the benefits and risks before breastfeeding during or after treatment with Opdualag.
Driving and using machines
Opdualag may have a minor effect on the ability to drive and use machines; however, use caution when performing these activities until you are certain that Opdualag does not have any negative effects on you.
Patient card
Key messages from this leaflet are also included in the patient card provided to you by your doctor. It is important that you always carry this patient card with you and show it to your partner or caregiver.

3. How to use Opdualag

How much Opdualag is administered
The recommended dose administered by infusion for adults and adolescents aged 12 years and older is 480 mg of nivolumab and 160 mg of relatlimab every 4 weeks. This dose is established for adolescent patients weighing at least 30 kg.
Depending on the dose, the appropriate amount of Opdualag will be diluted, prior to use, with either a 9 mg/mL (0.9%) sodium chloride injectable solution or a 50 mg/mL (5%) glucose injectable solution. Opdualag may also be used undiluted.

How Opdualag is administered
Opdualag will be administered to you in a hospital or clinic setting, under the supervision of an experienced physician.
Opdualag will be given as an intravenous infusion (a slow drip injection) every 4 weeks. Each infusion takes approximately 30 minutes to administer.
Your doctor will continue treating you with Opdualag for as long as you benefit from it or until side effects become too severe.

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

If you interrupt treatment with Opdualag
Interrupting treatment may stop the medicine’s effect. Do not stop treatment with Opdualag without first discussing it with your doctor.
If you have any questions about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Your doctor will discuss these side effects with you and explain the risks and benefits of treatment.
Keep in mind the important symptoms of inflammation (described in section 2, “Warnings and precautions”). Opdualag acts on the immune system and may cause inflammation in certain parts of the body. Inflammation can cause serious harm, and some inflammatory conditions may be life-threatening and require treatment or discontinuation of Opdualag.

The following side effects have been reported with Opdualag:

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

• Urinary tract infection (parts of the body that collect and eliminate urine)
• Decreased number of red blood cells (which carry oxygen) and white blood cells (lymphocytes, neutrophils, and leukocytes, which are important for fighting infections)
• Reduced function of the thyroid gland (which may cause tiredness or weight gain)
• Reduced appetite
• Headache
• Difficulty breathing, cough
• Diarrhoea (watery, liquid, or loose stools), vomiting, nausea, stomach pain, constipation
• Rash (sometimes with blisters), change in skin colour (vitiligo), itching
• Muscle, bone, and joint pain
• Feeling tired or weak, fever

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

• Abnormal liver function (increased levels in blood of the liver enzymes alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase)
• Abnormal kidney function (increased blood creatinine)
• Decreased sodium and magnesium levels, and decreased or increased calcium and potassium levels.

Common (may affect up to 1 in 10 people)

• Upper respiratory tract infections (nose and upper airway)
• Decreased number of platelets (cells that help blood to clot), increased levels of certain types of white blood cells
• Decreased 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, overactive thyroid gland, inflammation of the thyroid gland
• Diabetes, low blood sugar levels, weight loss, high levels of the waste product uric acid in blood, decreased levels of the protein albumin in blood, dehydration
• Confusion
• Nerve inflammation (causing numbness, weakness, tingling sensation, or burning pain in arms and legs), dizziness, change in taste sensation
• Eye inflammation (causing eye pain and redness, vision problems or blurred vision), vision disorders, dry eyes, excessive tear production
• Inflammation of the heart muscle
• Inflammation of a vein, which may cause redness, tenderness, and swelling
• Lung inflammation (pneumonitis), characterized by coughing attacks and difficulty breathing, nasal congestion (stuffy nose)
• Intestinal inflammation (colitis), pancreas inflammation, stomach inflammation (gastritis), difficulty swallowing, mouth ulcers and cold sores, dry mouth
• Liver inflammation (hepatitis)
• Unusual hair loss or thinning (alopecia), isolated areas of skin becoming red, itchy, and thickened (lichenoid keratosis), light sensitivity, dry skin
• Joint pain (arthritis), muscle spasms, muscle weakness
• Kidney failure (changes in amount or colour of urine, blood in urine, swollen ankles, loss of appetite), high levels of protein in urine
• Oedema (swelling), flu-like symptoms, chills
• Reactions related to the administration of the medicine

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

• Abnormal liver function (higher levels of the waste product bilirubin in blood, higher levels of the liver enzyme gamma-glutamyl transferase)
• Increased levels of sodium and magnesium
• Increased levels of troponin (a protein released into the blood when heart damage occurs)
• Increased levels of the enzyme that breaks down glucose (sugar) (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 in hair follicles
• Condition in which red blood cells are destroyed faster than they are produced (haemolytic anaemia)
• Reduced function of the pituitary gland located at the base of the brain, reduced function of glands producing sex hormones
• Brain inflammation which may include confusion, fever, memory problems, or seizures (encephalitis), temporary nerve inflammation causing pain, weakness, and paralysis of limbs (Guillain-Barré syndrome), optic nerve inflammation which may cause partial or complete vision loss
• Condition in which muscles become weak and tire easily (myasthenia gravis)
• Inflammatory disorder affecting the eyes, skin, and membranes of the ears, brain, and spinal cord (Vogt-Koyanagi-Harada disease), red eyes
• Fluid around the heart
• Asthma
• Inflammation of the oesophagus (passage between throat and stomach)
• Inflammation of the bile duct
• Skin rashes and blister formation on the legs, arms, and abdomen (pemphigoid), skin disease with thickened red patches of skin, often with silvery scales (psoriasis), urticaria (itchy, raised rash)
• Muscle inflammation causing weakness, swelling, and pain, disease in which the immune system attacks glands producing body fluids such as tears and saliva (Sjögren's syndrome), muscle inflammation causing pain or stiffness, joint inflammation (painful joint disease), disease in which the immune system attacks its own tissues causing widespread inflammation and tissue damage in affected organs such as joints, skin, brain, lungs, kidneys, and blood vessels (systemic lupus erythematosus)
• Kidney inflammation
• Absence of sperm in semen
• Fluid around the lungs

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

• Increased levels of C-reactive protein
• Increased erythrocyte sedimentation rate.

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

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

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

• Coeliac disease (characterised by symptoms such as stomach pain, diarrhoea, and abdominal bloating after consuming foods containing gluten).

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

5. How to store 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 stated on the carton and on the label of the vial after “Exp.” or “EXP”. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C - 8 °C).
Do not freeze.
Keep the vial in the outer packaging to protect from light.
The unopened vial may be stored at controlled room temperature (up to 25 °C) for up to 72 hours.
Do not store any unused portion of the infusion solution for later reuse.
Unused medicine and waste material arising from this medicine must be disposed of in accordance with local regulations.

6. Package contents and other information

What Opdualag contains

• 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 components are histidine, monohydrochloride monohydrate histidine, sucrose, pentetic acid, polysorbate 80 (E433), and water for injections.

Description of the appearance of Opdualag and contents of the pack
Opdualag concentrate for solution for infusion (sterile concentrate) is a liquid, clear to opalescent, colourless to slightly yellow, essentially free from particles.
It is available in cartons 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

Belgium/Belgique/Belgien Lithuania
N.V. Bristol-Myers Squibb Belgium S.A. Swixx Biopharma UAB
Tél/Tel: + 32 2 352 76 11 Tel: + 370 52 369140
[email protected] [email protected]
Bulgaria Luxembourg/Luxemburg
Swixx Biopharma EOOD N.V. Bristol-Myers Squibb Belgium S.A.
Tel.: + 359 2 4942 480 Tél/Tel: + 32 2 352 76 11
[email protected] [email protected]
Czech Republic Hungary
Bristol-Myers Squibb spol. s r.o. Bristol-Myers Squibb Kft.
Tel: + 420 221 016 111 Tel.: + 36 1 301 9797
[email protected] [email protected]
Denmark Malta
Bristol-Myers Squibb Denmark A.M. Mangion Ltd
Tlf: + 45 45 93 05 06 Tel: + 356 23976333
[email protected] [email protected]
Germany Netherlands
Bristol-Myers Squibb GmbH & Co. KGaA Bristol-Myers Squibb B.V.
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[email protected] [email protected]
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Swixx Biopharma OÜ Bristol-Myers Squibb Norway AS
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Greece Austria
Bristol-Myers Squibb A.E. Bristol-Myers Squibb GesmbH
Tel: + 30 210 6074300 Tel: + 43 1 60 14 30
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Spain Poland
Bristol-Myers Squibb, S.A. Bristol-Myers Squibb Polska Sp. z o.o.
Tel: + 34 91 456 53 00 Tel.: + 48 22 2606400
[email protected] [email protected]
France Portugal
Bristol-Myers Squibb SAS Bristol-Myers Squibb Farmacêutica Portuguesa, S.A.
Tél: + 33 (0)1 58 83 84 96 Tel: + 351 21 440 70 00
[email protected] [email protected]
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Swixx Biopharma d.o.o. Bristol-Myers Squibb Marketing Services S.R.L.
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Ireland Slovenia
Bristol-Myers Squibb Pharmaceuticals Ltd Swixx Biopharma d.o.o.
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Vistor ehf. Swixx Biopharma s.r.o.
Sími: + 354 535 7000 Tel: + 421 2 20833 600
[email protected] [email protected]
Italy Finland
Bristol-Myers Squibb S.r.l. Oy Bristol-Myers Squibb (Finland) Ab
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[email protected] [email protected]
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Latvia United Kingdom (Northern Ireland)
Swixx Biopharma SIA Bristol-Myers Squibb Pharmaceutical Limited
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More detailed information on this medicine is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Opdualag is supplied in a single-dose vial and contains no preservatives. Preparation must be
performed by trained personnel in accordance with good practice standards, particularly with respect to
asepsis.
Opdualag may be used for intravenous administration:

• without dilution, after transfer into an intravenous infusion container using a dedicated sterile syringe; or
• after dilution according to the following instructions:
  • the final infusion concentration must 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 must not exceed 160 mL. For patients weighing less than 40 kg, the total infusion volume must not exceed 4 mL per kilogram of patient body weight.

To dilute Opdualag concentrate, use:

• a 9 mg/mL (0.9%) sodium chloride injectable solution, or
• a 50 mg/mL (5%) glucose injectable solution.

Preparation of infusion solution

• Inspect Opdualag concentrate for any change in color or presence of particles. Do not shake the vial. Opdualag is a solution ranging from clear to opalescent and from colorless to slightly yellow. Discard the vial if the solution is cloudy, has changed color, or contains foreign particles.
• Withdraw the required volume of Opdualag concentrate using a dedicated sterile syringe and transfer the concentrate into a sterile intravenous infusion container (made of ethylene vinyl acetate [EVA], polyvinyl chloride [PVC], or polyolefin). Each vial is filled with 21.3 mL of solution, which includes an overfill of 1.3 mL.
• If necessary, dilute the Opdualag solution with the required volume of 9 mg/mL (0.9%) sodium chloride injectable solution or 50 mg/mL (5%) glucose injectable solution. For ease of preparation, the concentrate may also be transferred directly into a pre-filled bag containing the appropriate volume of 9 mg/mL (0.9%) sodium chloride injectable solution or 50 mg/mL (5%) glucose injectable solution.
• Gently mix the infusion solution by manual rotation. Do not shake.

Administration
Opdualag infusion must not be administered as a rapid intravenous injection or by bolus injection.
Administer Opdualag infusion intravenously over 30 minutes.
It is recommended to use a sterile, non-pyrogenic, low-protein-binding infusion set and an in-line or additional filter with pore size between 0.2 μm and 1.2 μm.
Opdualag infusion is compatible with EVA, PVC, and polyolefin containers, PVC infusion sets, and in-line filters with membranes made of polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) with pore sizes between 0.2 μm and 1.2 μm.
Do not co-administer other medicinal products through the same infusion line.
After administration of the Opdualag dose, flush the line with 9 mg/mL (0.9%) sodium chloride injectable solution or 50 mg/mL (5%) glucose injectable solution.

Storage conditions and shelf life
Closed vial
Opdualag must be stored in a refrigerator (2 °C - 8 °C). Vials should be kept in the original packaging to protect from light. Opdualag must not be frozen.
The unopened vial may be stored at controlled room temperature (up to 25 °C) for up to 72 hours.
Do not use Opdualag after the expiry date stated on the carton and vial label after “Scad.” or “EXP”. The expiry date refers to the last day of that month.

After preparation of the infusion solution
Chemical and physical in-use stability after preparation has been demonstrated as follows (times include the administration period):

From a microbiological standpoint, the prepared infusion solution must be used immediately, regardless of the diluent used. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at a temperature between 2 °C and 8 °C, unless the preparation has taken place under controlled and validated aseptic conditions.
Disposal
Do not store any unused portion of the infusion solution for later reuse. Unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS OF THE
MARKETING AUTHORISATION
Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for nivolumab / relatlimab, the PRAC's scientific conclusions are as follows:
In view of the available data on immune-mediated adverse reactions in patients with pre-existing autoimmune disease from the literature and considering a plausible mechanism of action, the PRAC considers that a causal relationship between nivolumab / relatlimab and immune-mediated adverse reactions in patients with pre-existing autoimmune disease is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing nivolumab / relatlimab should therefore be amended accordingly.
In view of the available data on myasthenia gravis from clinical studies, spontaneous reports and the literature, and considering a plausible mechanism of action, the PRAC considers that a causal relationship between nivolumab / relatlimab and myasthenia gravis is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing nivolumab / relatlimab should therefore be amended accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the respective general conclusions and the reasoning behind the recommendation.
Reasons for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on nivolumab / relatlimab, the CHMP considers that the benefit-risk balance of the medicinal product containing nivolumab / relatlimab remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends variation of the terms of the marketing authorisation.