NULOJIX 250 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet:information for the user

NULOJIX 250mg powder for concentrate for solution for infusion

belatacept

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.
• If you have any further questions, ask your doctor or pharmacist.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What is NULOJIX and what is it used for

NULOJIX contains the active substance belatacept which belongs to a group of medicines called immunosuppressants. These are medicines that reduce the activity of the immune system, the body's natural defenses.

NULOJIX is used in adults to prevent the immune system from attacking their transplanted kidney and causing transplant rejection. It is used with other immunosuppressive medicines, such as mycophenolic acid and corticosteroids.

2. What you need to know before you start using NULOJIX

Do not use NULOJIX

• If you are allergicto belatacept or any of the other ingredients of this medicine (listed in section 6). Cases of allergic reactions associated with the use of belatacept have been reported in clinical trials.
• If you have not been exposed to the Epstein-Barr virus(EBV) or are not sure if you have been exposed, you should not receive treatment with NULOJIX. EBV is the virus that causes infectious mononucleosis. If you have never been exposed to this virus, your risk of developing a cancer called post-transplant lymphoproliferative disorder (PTLD) is higher. If you are not sure if you have been infected with the virus before, consult your doctor.

Warnings and precautions

Post-transplant lymphoproliferative disorder

Treatment with NULOJIX increases the risk of developing a cancer called post-transplant lymphoproliferative disorder (PTLD). With NULOJIX, this cancer occurs more frequently in the brain and can be fatal. The risk of developing PTLD is higher in the following cases:

• If you have not been exposed to EBV before your transplant
• If you have an infection with a virus called cytomegalovirus (CMV)
• If you have received treatment for acute rejection, for example, antithymocyte globulin to reduce T-lymphocytes. T-lymphocytes are responsible for maintaining the body's ability to resist diseases and infections. They can cause rejection of the transplanted kidney.
• If you are not sure about any of these situations, consult your doctor.

Severe infections

During treatment with NULOJIX, you can develop severe infections that can be life-threatening.

NULOJIX weakens the body's ability to fight infections. Severe infections can be

• Tuberculosis
• Cytomegalovirus (CMV), a virus that can cause severe infections in the blood and tissues
• Herpes zoster
• Other herpes virus infections.

Cases of a rare brain infection called progressive multifocal leukoencephalopathy (PML) have been reported in patients who have received NULOJIX. PML often causes severe disability or death.

Tell your family or caregiver about your treatment.You may have symptoms that you are not aware of. Your doctor may need to check your symptoms to rule out PML, PTLD, or other infections. For a list of symptoms, see section 4 "Possible side effects".

Skin cancer

Limit your exposure to sunlight and ultraviolet (UV) light while using NULOJIX. Wear protective clothing and use sunscreen with a high protection factor. People who receive treatment with NULOJIX have a higher risk of developing certain types of cancer, especially skin cancer.

Blood clots in the transplanted kidney

Depending on the type of kidney transplant you have received, you may have a higher risk of having blood clots in your transplanted kidney.

Use in conversion from another type of immunosuppressive treatment

If your doctor changes your maintenance treatment to an immunosuppressive treatment with NULOJIX, they will monitor your kidney function more frequently during a period of time after the change to monitor rejection.

Use in liver transplants

The use of NULOJIX is not recommended if you have had a liver transplant.

Use with other immunosuppressive medicines

NULOJIX is usually given with steroids. A reduction in steroid intake that is too rapid can increase the risk of your body rejecting the transplanted kidney. Please take the exact dose of steroid prescribed by your doctor.

Children and adolescents

NULOJIX has not been studied in children and adolescents under 18 years of age, therefore it is not recommended in this age group.

Use of NULOJIX with other medicines

Tell your doctor or pharmacist if you are using or have recently used other medicines, including those obtained without a prescription.

While using NULOJIX, consult your doctor or pharmacist before using any other medicine.

The use of live vaccines should be avoided while using NULOJIX. If you need a vaccine, inform your doctor. Your doctor will advise you what to do.

Pregnancy and breastfeeding

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

If you become pregnant while using NULOJIX, inform your doctor.

Do not use NULOJIX if you are pregnant unless your doctor has explicitly recommended it. The effects of NULOJIX on pregnant women are unknown. You should not become pregnant while using NULOJIX. If you are a woman of childbearing age, you must use reliable contraception during treatment with NULOJIX and up to 8 weeks after the last dose of treatment, as the potential risk to embryonic or fetal development is unknown. Your doctor will advise you on the use of a reliable contraceptive.

You should stop breastfeeding if you are receiving treatment with NULOJIX. It is unknown whether belatacept, the active substance, passes into human milk.

Driving and using machines

Belatacept has a minor influence on the ability to drive and use machines. However, you should not drive or use machines if you feel tired or unwell after treatment with NULOJIX.

NULOJIX contains sodium

Tell your doctor if you are on a low-sodium diet before being treated with NULOJIX.

This medicine contains 0.55 mmol (or 13 mg) of sodium per vial. This is equivalent to 0.64% of the maximum recommended daily intake for an adult.

3. How to use NULOJIX

Treatment with NULOJIX will be prescribed and supervised by a kidney transplant specialist.

NULOJIX will be administered to you by a healthcare professional.

It will be given to you by infusion (as a "drip") into a vein over approximately 30 minutes.

The recommended dose is based on body weight (in kg) and will be calculated by a healthcare professional. The dose and frequency of administration are as follows.

At the time of kidney transplant, you may be given NULOJIX in combination with other types of immunosuppressive treatments to help prevent your body from rejecting the transplanted kidney.

Your doctor may decide to change your immunosuppressive treatment to a treatment with NULOJIX during the maintenance phase after your kidney transplant.

At the end of the leaflet, information is provided for the doctor and healthcare professionals on the calculation of doses, preparation, and administration of NULOJIX.

If you are given more NULOJIX than you should

In case this happens, your doctor will monitor you for any signs or symptoms of side effects and treat these symptoms if necessary.

If you miss a dose of NULOJIX

It is very important that you keep all appointments to receive treatment with NULOJIX. If you miss a dose of NULOJIX when it was due, ask your doctor to schedule your next dose.

If you stop treatment with NULOJIX

If you stop treatment with NULOJIX, your body may reject the transplanted kidney. The decision to stop treatment with NULOJIX should be discussed with your doctor, who will usually start another treatment.

If you stop treatment with NULOJIX for a long period of time, without taking any other medicine to prevent rejection, and then restart it, it is unknown whether belatacept will have the same effect as before.

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. Nevertheless, NULOJIX may cause serious adverse effects that may require treatment.

Inform your doctor or caregiver about your treatment, as you may suffer from symptoms that you may not be aware of yourself.

Inform your doctor immediately if you or your family notice any of the symptoms listed below:

Nervous system symptoms may include memory loss; difficulties speaking and communicating; mood or behavior changes; confusion or inability to control muscles; weakness on one side of the body; vision changes; or headache.

Infection symptoms may include fever; unexplained weight loss; swollen lymph nodes; cold symptoms such as runny nose or sore throat; cough with sputum; blood in sputum; ear pain; red cuts or scratches with pus; heat and suppuration.

Kidney or bladder symptoms may include discomfort in the transplanted kidney area; difficulty urinating; changes in the amount of urine produced; blood in urine; pain or burning while urinating.

Gastrointestinal symptoms may include pain when swallowing; painful sores in the mouth; white patches in the mouth or throat; stomach discomfort; stomach pain; vomiting; or diarrhea.

Skin changes may include bruising or unexpected bleeding; skin lesions with irregular borders, or a part of the lesion that does not resemble the other; changes in the size and color of a mole; or a new skin lesion or a new wound or bruise on the skin.

Allergic reactions may include, but are not limited to, rash; skin redness; hives; itching; lip swelling; tongue swelling; facial swelling; whole-body swelling; chest pain; difficulty breathing; wheezing; or dizziness.

Very Common Adverse Effects(may affect more than 1 in 10 people) are:

• Cystitis or kidney infection, upper respiratory tract infection, CMV infection (can cause serious blood and tissue infections), fever, cough, bronchitis
• Difficulty breathing
• Constipation, diarrhea, nausea, vomiting, abdominal pain
• High blood pressure, low blood pressure
• Headache, difficulty falling asleep, feeling nervous or anxious, swollen hands and feet
• Pain in the joints, back, or limbs
• Pain when urinating, blood in urine

Lab tests may reveal:

• Decreased red blood cell count or anemia, decreased white blood cell count
• Increased creatinine levels in blood (blood test to measure kidney function), increased protein levels in urine
• Changes in blood levels of different salts and electrolytes
• Increased cholesterol and triglyceride levels (blood fats)
• High blood sugar levels

Common Adverse Effects(may affect up to 1 in 10 people) are:

• Skin cancer and non-cancerous skin lesions
• Dangerous drop in blood pressure that, if left untreated, can cause collapse, coma, or death
• Stroke
• Necrotic tissue due to lack of blood supply
• Hepatitis (cytolytic hepatitis)
• Kidney damage
• Fluid in the lungs, wheezing, chest pain or angina, enlarged heart (lower part of the heart)
• Blood or tissue infections, respiratory infections, pneumonia, flu, sinusitis, runny nose, sore throat, mouth and throat pain, herpes virus infections, mouth sores, thrush, kidney infection, fungal skin infections, fungal nail infections, and other fungal infections, skin infection, soft tissue infection, wound infection, localized infection, slow healing, hematoma with blood, lymph fluid accumulation around the transplanted kidney
• Fast heart rate, slow heart rate, abnormal and irregular heartbeat, weak heart
• Diabetes
• Dehydration
• Gastritis (inflammation of the stomach and intestines, usually caused by a virus)
• Stomach discomfort
• Strange sensation of tingling, numbness, or weakness in arms and legs
• Skin rash, itching
• Muscle pain, muscle weakness, bone pain, joint inflammation, abnormal cartilage between the bones of the spine, sudden inability to bend joints, muscle spasms, arthritis
• Kidney artery blockage, kidney enlargement due to blockage of urine flow from the kidney, urine reflux from the bladder to the renal ducts, inability to retain urine, incomplete emptying of the bladder, nocturia, sugar in urine
• Weight gain, weight loss
• Cataracts, increased blood congestion in the eye, blurred vision
• Tremors or shaking, dizziness, fainting or loss of consciousness, ear pain, ringing, or other persistent sounds in the ears
• Acne, hair loss, abnormal skin changes, excessive sweating, night sweats
• Muscle weakness or gaps in the abdominal muscles and skin evagination over the scarred area, stomach wall hernia
• Depression, fatigue, feeling tired, somnolence, or lack of energy, general feeling of discomfort, difficulty breathing while lying down, nosebleeds
• Typical appearance of a person with high steroid levels, such as moon face, curved back, obesity in the upper body
• Abnormal fluid retention
• Lab tests may reveal:
• Low platelet count in blood and excess white and red blood cells
• Changes in blood levels of carbon dioxide, fluid retention, low protein levels in blood
• Abnormal liver function tests, increased parathyroid hormone levels in blood
• Increased C-reactive protein levels in blood, indicating inflammation
• Decreased antibody levels (proteins that fight infections) in blood

Uncommon Adverse Effects(may affect up to 1 in 100 people) are:

• Lung cancer, rectal cancer, breast cancer, a type of bone, muscle, or fat tissue cancer, skin and intestinal tract tumors caused by the herpes virus in patients with a weakened immune system, prostate cancer, cervical cancer, throat cancer, lymph node cancer, bone marrow cancer, kidney or renal duct or bladder cancer
• Fungal brain infection, brain inflammation, severe brain inflammation called PML (progressive multifocal leukoencephalopathy)
• Abnormal brain inflammation, increased intracranial pressure and brain pressure, seizures, weakness causing loss of movement or one side of the body, nerve damage, inability to move facial muscles
• Any brain disease that causes headache, fever, hallucinations, confusion, speech and body movement disorders
• Poor blood circulation to the heart, blockage of heartbeats, abnormal aortic heart valve, abnormally fast heart rate
• Sudden breathing problems causing lung damage, increased blood pressure in the lungs, lung inflammation, coughing up blood, abnormalities in the lungs and airways, fluid in the sac surrounding the lungs, temporary cessation of breathing during sleep, abnormal speech sounds
• Genital herpes
• Colon inflammation (large intestine) caused by cytomegalovirus, pancreatitis, stomach ulcers, small intestine ulcers, large intestine ulcers, small intestine obstruction, black tarry stools, rectal bleeding, abnormal stool color
• Bacterial infections, inflammation or infection of the heart lining, tuberculosis, bone infection, lymph node inflammation, chronic dilation of the airways with frequent lung infections
• Strongyloides worm infection, Giardia parasite diarrhea infections
• Kidney disease caused by a virus (polyomavirus-associated nephropathy), kidney inflammation, kidney scarring, retraction of the small kidney ducts, bladder inflammation with hemorrhage
• Blood clot in the renal artery
• Guillain-Barré syndrome (a disease that causes muscle weakness or paralysis)
• EBV-associated lymphoproliferative disease
• Blood clotting in the veins, inflamed veins, periodic leg cramps
• Abnormal arteries, artery scarring, artery clotting, artery narrowing, temporary redness of the face/skin, facial swelling
• Gallstones, liver cavity filled with fluid, fatty liver
• Skin disease with red, scaly skin patches, abnormal hair growth, excessive hair breakage, nail breakage, penile ulcers
• Abnormal mineral balance in the body causing bone problems, bone inflammation, abnormal bone weakening causing bone problems, joint lining inflammation, rare bone disease
• Testicular inflammation, abnormally prolonged penile erection, abnormal cervical cells, breast lump, testicular pain, genital ulcers in women, vaginal wall thinning, infertility or inability to become pregnant, scrotal swelling
• Seasonal allergies
• Lack of appetite, loss of taste, decreased hearing
• Abnormal dreams, mood changes, lack of ability to concentrate and stay still, difficulty understanding or thinking, memory loss, migraine, irritability
• Numbness or weakness due to uncontrolled diabetes, inability to keep legs still
• Swelling of the back of the eye causing vision changes, inflamed eye, uncomfortable/increased sensitivity to light, eyelid swelling
• Cracks in the corner of the mouth, inflamed gums, salivary gland pain
• Increased sexual desire
• Burning sensation
• Infusion reaction, scar tissue, inflammation, disease relapse, feeling of heat, ulcers
• Insufficient urine production
• Transplanted organ failure, problems during or after a transfusion, wound edge separation before healing, bone fractures, complete tendon tear or separation, low blood pressure during or after a procedure, high blood pressure during or after a procedure, hematomas/blood accumulation in soft tissues after a procedure, procedure-related pain, procedure-related headache, soft tissue bruising
• Lab tests may reveal:
• Excessively low red blood cell count, excessively low white blood cell count, red blood cell destruction, blood clotting problems, diabetic acidosis, lack of acid in the blood
• Inadequate hormone production by the adrenal glands
• Low vitamin D levels
• Increased pancreatic enzyme levels in blood, increased troponin levels in blood, increased prostate-specific antigen (PSA) levels, high uric acid levels in blood, decreased CD-4 lymphocyte count, low blood sugar

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of NULOJIX

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date shown on the vial label and on the carton after EXP. The expiration date is the last day of the month indicated.

This medicine will be stored in the facility where the healthcare professional administers it.

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

Keep in the original packaging to protect from light.

After reconstitution, the reconstituted solution must be transferred immediately from the vial to the infusion bag or bottle.

After dilution, and from a microbiological point of view, the product must be used immediately. If not used immediately, the infusion solution must be stored in a refrigerator (2°C - 8°C) for a maximum of 24 hours. The infusion solution can be stored for a maximum of 4 hours of the total 24 hours below 25°C. Do not freeze.

NULOJIX infusion must be performed within 24 hours after reconstitution of the powder.

Do not use NULOJIX if you observe particles or color changes in the reconstituted or diluted solution.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Container Content and Additional Information

NULOJIX Composition

• The active ingredient is belatacept. Each vial contains 250 mg of belatacept. After reconstitution, each ml of concentrate contains 25 mg of belatacept.
• The other components are sodium chloride, sodium phosphate monohydrate, sucrose, sodium hydroxide (for pH adjustment), and hydrochloric acid (for pH adjustment). (See section 2)

Product Appearance and Container Content

NULOJIX powder for concentrate for solution for infusion (powder for concentrate) is a white to off-white powder that may be presented in a compact or fragmented form.

Each vial contains 250 mg of belatacept.

Containers of 1 glass vial and 1 syringe or 2 glass vials and 2 syringes.

Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

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 medicinal product 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:

• Aseptic technique will be used for the reconstitution of the vials and for dilution of the solution for administration.
• To reconstitute the vials and add the solution to the infusion, the silicone-free disposable syringe provided will be used. This will prevent the formation of particles.
• Do not shake the vials. This will prevent the formation of foam.
• The infusion solution must be used with a sterile, apyrogenic, low-protein-binding filter (pore size 0.2 μm to 1.2 μm).

Dose Selection and Vial Reconstitution

Calculate the dose and the number of NULOJIX vials needed. Each NULOJIX vial provides 250 mg of belatacept.

• The total dose of belatacept in mg is equal to the patient's weight in kg multiplied by the belatacept dose in mg/kg (6 or 10 mg/kg, see section 3).
• Dose modification of NULOJIX is not recommended for a weight variation of less than 10%.
• The number of vials needed is equal to the belatacept dose in mg divided by 250, rounded up to the next whole number of vials.
• Reconstitute each vial with 10.5 ml of solution.
• The required volume of the reconstituted solution (ml) is equal to the total dose of belatacept in mg divided by 25.

Practical Details for Vial Reconstitution

Under aseptic conditions, reconstitute each vial with 10.5 ml of one of the following solvents (sterile water for injectable preparations, sodium chloride 9 mg/ml (0.9%) solution for injectable preparations, or glucose 5% solution for injectable preparations) using the disposable syringe included in the package (necessary to avoid particle formation) and an 18-21 gauge needle. The syringes are marked in 0.5 ml units; therefore, the calculated dose should be rounded to the nearest 0.5 ml.

Remove the flip-off seal from the vial and clean the top with a cotton swab moistened with alcohol. Insert the syringe needle into the vial through the center of the rubber stopper. Direct the jet of liquid to the glass walls of the vial and not to the powder. Remove the syringe and needle after adding 10.5 ml of reconstitution liquid to the vial.

To minimize foam formation, gently rotate and invert the vial for at least 30 seconds until the powder is completely dissolved. Do not shake. Although some foam may remain on the surface of the reconstituted solution, each vial includes an excess of belatacept to account for potential losses. Therefore, 10 ml of a 25 mg/ml belatacept solution can be withdrawn from each vial.

The reconstituted solution should be clear to slightly opaque and colorless to pale yellow. It must not be used if opaque particles, color changes, or other foreign particles are observed. It is recommended to immediately transfer the reconstituted solution from the vial to the infusion bag or bottle.

Practical Details for Preparation of the Infusion Solution

After reconstitution, dilute the product to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injectable preparations or glucose 5% solution for injectable preparations. Remove from a 100 ml infusion bag or bottle (usually a 100 ml infusion volume will be adequate for most patients and doses, although a 50 ml to 250 ml infusion volume may be used) a volume of sodium chloride 9 mg/ml (0.9%) solution for injectable preparations or glucose 5% solution for injectable preparations equal to the volume of the reconstituted NULOJIX solution (ml equal to the total dose in mg divided by 25) needed to provide the dose and discard the rest. Slowly add the required amount of reconstituted NULOJIX solution from the vial to the infusion bag or bottle using the same disposable syringe used for powder reconstitution. Gently mix the infusion container. The final concentration of belatacept in the infusion should be 2 mg to 10 mg of belatacept per ml of solution.

Any unused portion of the vials must be discarded in accordance with local regulations.

Administration

When reconstitution and dilution are performed under aseptic conditions, the infusion of NULOJIX should be started immediately or completed within 24 hours after reconstitution of the powder. If not used immediately, the infusion solution should be stored in the refrigerator (2°C - 8°C) for a maximum of 24 hours. Do not freeze. The infusion solution can be stored for a maximum of 4 hours out of the 24 hours below 25°C. The infusion must be performed within 24 hours after reconstitution of the powder. Before administration, the infusion solution should be visually inspected for the presence of particles or color changes. If particles or color changes are observed, the infusion should be discarded. The fully diluted solution should be administered over 30 minutes using an infusion set and a sterile, apyrogenic, low-protein-binding filter (pore size 0.2 μm to 1.2 μm). After administration, it is recommended to flush the intravenous line with infusion fluid to ensure administration of the full dose.

NULOJIX must not be administered concomitantly in the same intravenous line as other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of NULOJIX with other medicinal products.

Do not retain the unused portion of the infusion solution for re-use.

Disposal

Disposal of the unused medicinal product and all materials that have come into contact with it will be carried out in accordance with local regulations.