Package leaflet: Information for the user

NULOJIX 250 mg powder for concentrate for solution for infusion

belatacept
Read this entire leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

What NULOJIX is and what it is used for
What you need to know before using NULOJIX
How to use NULOJIX
Possible side effects
How to store NULOJIX
Contents of the pack and other information

1. What NULOJIX is and what it is used for

NULOJIX contains the active substance belatacept, which belongs to a class of medicines called immunosuppressants. These are medicines that reduce the activity of the immune system, the body's natural defenses.
NULOJIX is used in adult patients to prevent the immune system from attacking the transplanted kidney and causing transplant rejection. It is used in combination with other immunosuppressive medicines, including mycophenolic acid and corticosteroids.

2. What you need to know before using NULOJIX

Do not use NULOJIX

If you are allergic to belatacept or to any of the other ingredients of this medicine (listed in section 6). Allergic reactions associated with the use of belatacept have been reported in clinical studies.
If you have not been exposed to the Epstein-Barr virus (EBV) or are unsure about previous exposure, you must not be treated with NULOJIX. The EBV virus causes glandular fever. If you have not been exposed to this virus, you have a higher risk of developing a type of tumour called post-transplant lymphoproliferative disorder (PTLD). If you are unsure whether you have previously been infected with the virus, please consult your doctor.

Warnings and precautions
Post-transplant lymphoproliferative disorder
Treatment with NULOJIX increases the risk of developing a type of tumour called post-transplant
lymphoproliferative disorder (PTLD). When treated with NULOJIX, PTLD occurs more frequently in
the brain and can lead to death. The risk of developing PTLD is higher in the following cases:

if you were not exposed to EBV before transplantation
if you have an infection with a virus called cytomegalovirus (CMV)
if you have received therapy for the treatment of acute rejection, such as antithymocyte globulin, to reduce T-cells. T-cells are responsible for maintaining the body's ability to resist diseases and infections. They may also cause rejection of the transplanted kidney.
If you are unsure about any of these conditions, consult your doctor.

Serious infections
Serious infections, which may lead to death, can occur during treatment with NULOJIX.
NULOJIX weakens the body's ability to fight infections. Serious infections may include:

Tuberculosis
Cytomegalovirus (CMV), a virus that can cause severe tissue and blood infections
Herpes Zoster (shingles)
Other herpes virus infections.

There have been reports of a rare type of brain infection called progressive multifocal
leukoencephalopathy (PML) occurring in patients treated with NULOJIX. PML often leads to severe
disability or death.
Inform your family members or caregivers about your treatment. Symptoms may occur that you
might not be aware of. Your doctor may need to evaluate symptoms to rule out PML, PTLD, or other
infections. For a list of symptoms, see section 4, “Possible side effects”.
Skin cancer
Limit exposure to sunlight and ultraviolet (UV) light while using NULOJIX.
Wear protective clothing and use sunscreen with a high sun protection factor. Patients using NULOJIX
have an increased risk of developing certain types of cancer, particularly skin cancer.
Blood clots in the transplanted kidney
Depending on the type of transplanted kidney you have received, you may be at higher risk of blood
clots in the transplanted kidney.
Use when switching from another type of maintenance immunosuppressive treatment
If your doctor changes your maintenance treatment to a regimen based on NULOJIX, they may
monitor your kidney function more frequently for a period of time after the switch to monitor for
rejection.
Use in liver transplants
The use of NULOJIX is not recommended if you have received a liver transplant.
Use with other immunosuppressive medicines
NULOJIX is normally administered with steroids. Reducing the steroid dose too quickly may
increase the risk of your body rejecting the transplanted kidney. Take the exact steroid dose as
prescribed by your doctor.
Children and adolescents
NULOJIX has not been studied in children and adolescents under 18 years of age and is therefore not
recommended for use in this patient population.
Other medicines and NULOJIX
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines.
Consult your doctor or pharmacist before taking any other medicine while using NULOJIX.
The use of live vaccines must be avoided while using NULOJIX. Inform your doctor if you need to
receive any vaccinations. Your doctor will advise you accordingly.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning to become pregnant, or are
breastfeeding, consult your doctor before using this medicine.
If you become pregnant while using NULOJIX, inform your doctor.
Do not use NULOJIX during pregnancy unless specifically recommended by your doctor. The effects
of NULOJIX in pregnancy are unknown. While using NULOJIX, you must avoid becoming pregnant.
If you are of childbearing potential, you must use an effective contraceptive method while using
NULOJIX and for up to 8 weeks after the last dose of treatment, as the potential risk to embryonic/
fetal development is unknown. Your doctor will advise you on an appropriate contraceptive method.
You must stop breastfeeding if you are being treated with NULOJIX. It is not known whether
belatacept, the active substance, passes into human milk.
Driving and using machines
Belatacept has a minor influence on the ability to drive or use machines. However, you should not
drive or operate machinery if you feel tired or unwell after treatment with NULOJIX.
NULOJIX contains sodium
Inform your doctor if you are on a low-sodium (low-salt) diet before using NULOJIX.
This medicine contains 0.55 mmol (or 13 mg) of sodium per vial. This is equivalent to 0.64% of the
recommended maximum daily dietary intake of sodium 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 healthcare personnel.
NULOJIX is given by intravenous infusion (as a "drip") over approximately 30 minutes.
The recommended dose is based on body weight (in kg), and will be calculated by healthcare personnel. The dose and frequency of treatment are outlined below.

Induction Phase
Dose: 10 mg/kg

Day of transplant, prior to implantation (Day 1)
Day 5, Day 14, and Day 28
End of week 8 and end of week 12 after transplant

Maintenance Phase
Dose: 6 mg/kg

Every 4 weeks (± 3 days), starting at the end of week 16 after transplant

At the time of kidney transplant, you may be given NULOJIX in combination with other types of immunosuppressive medicines to help prevent your body from rejecting the transplanted kidney.
Your doctor may decide to modify your immunosuppressive treatment regimen with NULOJIX during the maintenance phase after kidney transplantation.
Information for the doctor and healthcare personnel on dose calculation, preparation, and administration of NULOJIX is provided at the end of the package leaflet.

If you use more NULOJIX than you should
If this occurs, your doctor will monitor you closely for any signs or symptoms of adverse reactions and will treat them as necessary.

If you forget to use NULOJIX
It is very important to keep all your scheduled appointments for receiving NULOJIX. If you miss a dose, consult your doctor to determine when the next dose should be administered.

If you stop using NULOJIX
Your body may reject the transplanted kidney if you stop treatment with NULOJIX. The decision to discontinue NULOJIX treatment should be discussed with your doctor, and generally, an alternative therapy should be initiated.
If you stop treatment with NULOJIX for a prolonged period without taking another medicine to prevent rejection, and then restart treatment, it is unknown whether belatacept will have the same effect as before.

If you have any doubts about the use of NULOJIX, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. However, NULOJIX may cause serious side effects, which may require treatment.
Inform your family members or caregivers about your treatment. You may experience symptoms of which you might not be aware.
Contact your doctor immediately if you or a family member notice any of the following symptoms listed below:
Nervous system symptoms may include memory loss; difficulty speaking and communicating; changes in mood or behaviour; confusion or inability to control muscles; weakness on one side of the body; changes in vision; or headache.
Symptoms of infections may include fever; unexplained weight loss; swollen glands; cold-like symptoms such as runny nose or sore throat; cough with sputum; blood in the sputum; earache; red cuts or scratches; warm, oozing pus.
Kidney or bladder symptoms may include tenderness at the site of the transplanted kidney; difficulty urinating; change in the amount of urine produced; blood in the urine; pain or burning sensation while urinating.
Gastrointestinal symptoms may include pain when swallowing; painful mouth ulcers; spots in the mouth or throat; stomach upset; stomach pain; vomiting; or diarrhoea.
Skin changes may include unexpected bruising or bleeding; brown or black skin lesions with irregular borders, or parts of the lesion not resembling each other; changes in size or colour of a mole; or new skin lesion or lump.
Allergic reactions may include, but are not limited to, rash; skin redness; hives; itching; swelling of the lips; swelling of the tongue; facial swelling; swelling throughout the body; chest pain; shortness of breath; wheezing; or dizziness.

Very common side effects (may affect more than 1 in 10 people) are:

Bladder or kidney infection, upper respiratory tract infection, CMV infection (can cause serious blood and tissue infections), fever, cough, bronchitis
Shortness of breath
Constipation, diarrhoea, nausea, vomiting, abdominal pain
High blood pressure, low blood pressure
Headache, difficulty sleeping, feeling nervous or anxious, swelling of hands and feet
Joint pain, back pain, limb pain
Pain when urinating, blood in the urine
Tests may show:
Low blood cell counts or anaemia, low white blood cell counts
Increased blood creatinine levels (a blood test used to measure kidney function), increased protein levels in urine
Changes in blood levels of various salts or electrolytes
Increased cholesterol and triglyceride levels (fats in the blood)
High blood sugar levels

Common side effects (may affect up to 1 in 10 people) are:

Cancerous and non-cancerous skin growths
Dangerous drop in blood pressure, which, if uncontrolled, may lead to collapse, coma, and death
Stroke
Tissue necrosis due to interruption of blood supply
Liver inflammation (cytolytic hepatitis)
Kidney damage
Fluid in the lungs, wheezing, chest pain or angina, enlargement of the heart muscle (lower part of the heart)
Blood or tissue infections, respiratory infections, pneumonia, influenza, sinus inflammation, runny nose, sore throat, mouth/throat area pain, herpes virus infections, herpes zoster (shingles), and other viral infections, mouth ulcers, oral thrush, kidney infection, fungal skin infections, fungal nail infections and other fungal infections, skin infection, soft tissue infection, wound infection, infection limited to one area, slow healing, haematoma, accumulation of lymphatic fluid around the transplanted kidney
Increased heart rate, decreased heart rate, irregular or abnormal heartbeat, heart failure
Diabetes
Dehydration
Inflammation of the stomach and intestine, usually caused by a virus
Stomach upset
Unusual sensation of pins and needles, numbness or weakness in arms and legs
Rash, itching
Muscle pain, muscle weakness, bone pain, joint swelling, abnormal cartilage between spinal bones, sudden inability to bend joints, muscle spasms, arthritis
Blockage of renal blood vessels, kidney enlargement due to obstruction of urinary outflow from the kidney, urine reflux from bladder to kidney tubules, inability to retain urine, incomplete bladder emptying, nocturnal urination, sugar in the urine
Weight gain, weight loss
Cataract, increased blood congestion in the eyes, blurred vision
Tremor or shaking, dizziness, weakness or fainting, ear pain, ringing, buzzing or other persistent noises in the ears
Acne, hair loss, abnormal skin changes, excessive sweating, night sweats
Abdominal muscle weakness/depression and bulging of the skin above the incision scar, hernia of the abdominal wall
Depression, fatigue, feeling of tiredness, drowsiness, or lack of energy, general malaise, difficulty breathing when lying down, nosebleeds
Physical appearance typical of high steroid levels, such as moon face, buffalo hump, upper body obesity
Abnormal fluid accumulation
Tests may show:
Decreased platelet count in blood, excess white blood cells, excess red blood cells
Changes in blood levels of carbon dioxide, fluid retention, decreased blood protein levels
Abnormal liver function tests, increased parathyroid hormone levels in blood
Increased levels of protein (C-reactive protein) in blood indicating inflammation
Decreased levels of antibodies (proteins that fight infections) in blood

Uncommon side effects (may affect up to 1 in 100 people) are:

Lung cancer, rectal cancer, breast cancer, a form of cancer in bones, muscles, or fatty tissue, skin and intestinal tract tumour caused by a herpes virus and found in patients with weakened immune systems, prostate cancer, cervical cancer, throat cancer, lymph node cancer, bone marrow cancer, kidney cancer, renal tubule cancer, or bladder cancer
Fungal brain infection, brain inflammation, severe brain infection called PML (Progressive Multifocal Leukoencephalopathy)
Abnormal swelling of the brain, increased intracranial and brain pressure, seizures, weakness causing loss of movement on one side of the body, loss of nerve covering, inability to move facial muscles
Any brain disease causing headache, fever, hallucinations, confusion, abnormal body movements and speech
Poor blood flow to the heart, blocked heart pulsation, abnormal aortic heart valve, abnormally accelerated heart rate
Sudden breathing problems leading to lung damage, increased blood pressure in the lungs, lung inflammation, bloody sputum, abnormalities in lungs and airways, fluid in the sac around the lungs, temporary interruption of breathing during sleep, abnormal speech sound
Genital herpes
Inflammation of the colon (large intestine) caused by cytomegalovirus, pancreatitis, stomach, small intestine or large intestine ulcer, small intestine obstruction, black tarry stools, rectal bleeding, abnormal stool colour
Bacterial infections, inflammation or infection of the inner heart layer, tuberculosis, bone infection, lymph node inflammation, chronic dilation of airways in the lungs with frequent lung infections
Infection with Strongyloides worm, diarrhoeal infection with Giardia parasite
Kidney disease caused by a virus (polyomavirus-associated nephropathy), kidney inflammation, kidney scarring, narrowing of small kidney tubules, bladder inflammation with bleeding
Blood clots in the renal artery
Guillain-Barré syndrome (a condition causing muscle weakness or paralysis)
EBV (Epstein-Barr virus) lymphoproliferative disease
Blood clots in veins, inflamed veins, periodic leg cramps
Abnormal arteries, arterial scarring, clots in arteries, arterial narrowing, temporary facial/ skin redness, facial swelling
Gallstones, fluid-filled sac in the liver, hepatic steatosis
Skin disease with thickened red patches, often with silvery scales, abnormal hair growth, excessive hair fragility, nail fragility, penile ulcer
Abnormal mineral balance in the body causing bone problems, bone inflammation, abnormal bone weakening leading to bone issues, joint lining inflammation, rare bone condition
Testicular inflammation, abnormal prolonged penile erection, abnormal cervical cells, breast mass, testicular pain, ulcer in the female genital area, thinning of the vaginal wall, infertility or inability to conceive, scrotal swelling
Seasonal allergy
Poor appetite, loss of taste, hearing loss
Abnormal dreams, mood changes, abnormal inability to concentrate and stay still, difficulty understanding and thinking, poor memory, migraine, irritability
Numbness or weakness due to inadequate diabetes control, diabetic foot changes, inability to keep legs still
Swelling at the back of the eye causing vision changes, eye inflammation, discomfort/increased light sensitivity, eyelid swelling
Cracked mouth corners, swollen gums, salivary gland pain
Increased sexual desire
Burning sensation
Infusion reaction, scar tissue, inflammation, disease recurrence, feeling of warmth, ulcer
Inadequate urine production
Transplanted organ dysfunction, problems during or after transfusion, wound dehiscence before healing, bone fractures, complete tendon rupture or separation, low blood pressure during or after a procedure, high blood pressure during or after a procedure, soft tissue bruising or blood collection after a procedure, procedure-related pain, headache related to a procedure, soft tissue bruising
Tests may show:
Dangerous drop in red blood cells, dangerous drop in white blood cell count, destruction of red blood cells, blood clotting problems, presence of diabetic acid in blood, lack of acid in blood
Improper hormone production from adrenal glands
Decreased vitamin D levels
Increased pancreatic enzymes in blood, increased troponin levels in blood, increased prostate-specific antigen (PSA), high uric acid levels in blood, decreased CD-4 lymphocyte count, low blood sugar levels

Reporting of side effects
If any of the side effects becomes severe, or if you notice any side effects not listed in this leaflet, inform your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NULOJIX

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 label of the vial and on the
carton after "EXP". The expiry date refers to the last day of the month.
This medicine will be stored in the healthcare facility where it is administered.
Store in a refrigerator (2 °C – 8 °C).
Keep in the original packaging to protect the medicine from light.
After reconstitution, the reconstituted solution must be immediately transferred from the vial to the
infusion bag or bottle.
From a microbiological standpoint, the product should be used immediately after dilution.
If not used immediately, the infusion solution may be stored in a refrigerator (2 °C – 8 °C) for up to 24 hours.
The infusion solution may be kept for a maximum of 4 hours of the total 24 hours at temperatures below 25 °C. Do not freeze.
The NULOJIX infusion must be completed within 24 hours after reconstitution of the powder.
Do not use NULOJIX if you notice particles or any change in colour of the reconstituted or diluted solution.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer require. This will help protect the environment.

6. Package contents and other information

What NULOJIX contains

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

Description of the appearance of NULOJIX and contents of the pack
NULOJIX powder for concentrate for solution for infusion (powder for concentrate) is a powder
ranging from white to almost white, which may appear solid or fragmented.
Each vial contains 250 mg of belatacept.
Pack sizes of 1 glass vial and 1 syringe or 2 glass vials and 2 syringes.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
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

More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.

The following information is intended for healthcare professionals only:

Use aseptic techniques when preparing vials and diluting the solution for administration.
Use the provided single-use, silicone-free syringe to reconstitute the vials and transfer the solution for infusion. This will prevent the formation of aggregates.
Do not shake the vials. This will prevent foam formation.
The infusion solution must be administered with a sterile, non-pyrogenic filter with low protein binding (pore size from 0.2 μm to 1.2 μm).

Dose selection and reconstitution of vials
Calculate the required dose and number of NULOJIX vials. Each NULOJIX vial contains 250 mg of belatacept.

The total belatacept dose 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 adjustments of NULOJIX are not recommended for body weight changes of less than 10%.
Number of vials required equals the total belatacept dose in mg divided by 250, rounded up to the next whole vial.
Reconstitute each vial with 10.5 ml of diluent.
The volume of reconstituted solution required (ml) equals the total belatacept dose in mg divided by 25.

Practical details for reconstitution of vials
Under aseptic conditions, reconstitute each vial with 10.5 ml of one of the following diluents (sterile water for injections, sodium chloride 9 mg/ml (0.9%) solution for injection, or 5% glucose solution for injection), using the single-use syringe supplied in the pack (required to avoid aggregate 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 seal tab from the vial and clean the surface with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper. Direct the flow of liquid against the glass wall of the vial, not directly onto the powder. Remove the syringe and needle after adding 10.5 ml of diluent to the vial.
To minimize foam formation, gently swirl and rotate the vial for at least 30 seconds or until the powder is completely dissolved. Do not shake. Although some foam may remain on the surface of the reconstituted solution, a sufficient excess of belatacept is included in each vial to account for potential losses during withdrawal. Therefore, 10 ml of a 25 mg/ml belatacept solution can be withdrawn from each vial.
The reconstituted solution should be clear to slightly opalescent and colourless to pale yellow. Do not use if opaque particles, colour changes, or foreign matter are present. 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 a final volume of 100 ml with either 9 mg/ml (0.9%) sodium chloride solution for injection or 5% glucose solution for injection. From a 100 ml infusion bag or bottle (generally, a 100 ml infusion volume will be appropriate for most patients and doses, although total infusion volumes ranging from 50 ml to 250 ml may be used), withdraw and discard a volume of 9 mg/ml (0.9%) sodium chloride or 5% glucose solution equal to the volume (ml = total dose in mg divided by 25) of reconstituted NULOJIX solution required to achieve the dose. Slowly add the required amount of reconstituted NULOJIX solution from each vial to the infusion bag or bottle using the same single-use syringe used for reconstitution. Gently mix the infusion container. The final concentration of belatacept in the infusion solution must be between 2 mg and 10 mg of belatacept per ml of solution.
Any unused portion remaining in the vial must be discarded according to local regulations.

Administration
When reconstitution and dilution are performed under aseptic conditions, NULOJIX infusion should be started immediately or completed within 24 hours of reconstitution. If not used immediately, the infusion solution may be stored refrigerated (2°C–8°C) for up to 24 hours. Do not freeze. The infusion solution may be kept for a maximum of 4 hours of the total 24 hours at temperatures below 25°C. The infusion must be completed within 24 hours of reconstitution of the powder. Prior to administration, visually inspect the infusion solution for particulate matter or colour changes. Do not use the solution if particulate matter or colour changes are observed.
The entire diluted solution must be administered over 30 minutes using an infusion set with a sterile, non-pyrogenic filter with low protein binding (pore size from 0.2 μm to 1.2 μm). After administration, it is recommended to flush the intravenous line with the infusion fluid to ensure complete delivery of the dose.
NULOJIX must not be infused concomitantly with other agents through the same intravenous line. No physical or biochemical compatibility studies have been conducted to evaluate co-administration of NULOJIX with other agents.
Do not store unused infusion solution for later use.

Disposal
Any unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.

Nulojix