Blincyto 38.5 mcg powder for concentrate for solution for infusion

Patient Information Leaflet

Introduction

Package Leaflet: Information for the patient

BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion

blinatumomab

This medicinal product is subject to additional monitoring, which will allow quicker detection of new safety information. You can help by reporting any side effects you may experience. Information on how to report side effects is included at the end of section 4.

Read this entire leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to refer to it again.
• Your doctor will also provide you with the following informational materials:
• Patient and caregiver information leaflet, which contains important safety information you should know before receiving BLINCYTO and during treatment with BLINCYTO.
• Patient information card containing contact details of your medical team and information on when to call your doctor or nurse. Always carry your patient information card with you.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any side effects, consult your doctor, pharmacist, or nurse, even if they are side effects not listed in this leaflet. See section 4.

Leaflet Contents

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

1. What BLINCYTO is and what it is used for

The active substance in BLINCYTO is blinatumomab. It belongs to a group of medicines called antineoplastic agents that target cancer cells.

BLINCYTO is used to treat adults, children, and young adults with acute lymphoblastic leukemia. Acute lymphoblastic leukemia is a blood cancer in which a particular type of white blood cells called "B cells" grows uncontrollably. This medicine works by enabling your immune system to attack and destroy these abnormal cancerous white blood cells. BLINCYTO is used when acute lymphoblastic leukemia has relapsed or has not responded to previous treatment (known as relapsed or refractory acute lymphoblastic leukemia).

It is also used in adult patients with acute lymphoblastic leukemia who still have a small number of cancer cells remaining after prior treatment (known as minimal residual disease).

BLINCYTO is also used during consolidation therapy. Consolidation therapy for acute lymphoblastic leukemia is a treatment phase that occurs after the initial phase, with the goal of further eliminating any remaining leukemia cells that may persist after the first phase of treatment.

2. What you need to know before starting BLINCYTO

Do not use BLINCYTO

• if you are allergic to blinatumomab or to any of the other ingredients of this medicine (listed in section 6).
• if you are breastfeeding.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting BLINCYTO if any of the following apply to you. BLINCYTO may not be suitable for you:

• if you have ever had neurological problems, for example, tremor (or shaking), abnormal sensations, seizures, memory loss, confusion, disorientation, loss of balance, or difficulty speaking. Inform your doctor if you still have neurological diseases or problems. If your leukemia has spread to the brain and/or spinal cord, your doctor may need to treat this condition before you can start treatment with BLINCYTO. Your doctor will evaluate your nervous system and perform tests before deciding whether you should receive BLINCYTO. Your doctor may need to provide you with special care during treatment with BLINCYTO.
• if you have an active infection.
• if you have ever experienced an infusion reaction after previously using BLINCYTO. Symptoms may include wheezing (a whistling sound when breathing), flushing, facial swelling, difficulty breathing, or low or high blood pressure.
• if you think you may need any vaccinations in the near future, including those required for travel to other countries. Some vaccines should not be administered within two weeks before, during, or for several months after receiving BLINCYTO treatment. Your doctor will determine whether you should receive the vaccine.

Immediately inform your doctor, pharmacist, or nurse if you experience new symptoms, including the following (among others), while receiving BLINCYTO, as they may require treatment and adjustment of your dose:

• effects on the nervous system. Symptoms include feeling confused, difficulty concentrating, and difficulty speaking or writing. Some of these symptoms may be signs of a serious immune reaction called "immune effector cell-associated neurotoxicity syndrome" (ICANS).
• if you have chills or tremors, or feel hot; your temperature should be taken, as you may have a fever; these may be signs of infection.
• if you develop a reaction at any time during the infusion, which may include dizziness, feeling faint, nausea, facial swelling, difficulty breathing, wheezing (a whistling sound when breathing), or skin rash.
• if you develop persistent and severe stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially life-threatening condition known as pancreatitis (inflammation of the pancreas).

Your doctor or nurse will monitor you for signs and symptoms of these reactions.

Patients with Down syndrome may have an increased risk of seizures during treatment with BLINCYTO, and may therefore be given an anti-seizure medication before starting BLINCYTO.

Consult your doctor, pharmacist, or nurse immediately if you become pregnant during treatment with BLINCYTO. Your doctor will advise you on precautions regarding vaccinations for your baby.

Before each infusion cycle of BLINCYTO, you will be given medications to help reduce a potentially life-threatening complication known as tumor lysis syndrome, which is caused by chemical imbalances in the blood due to the breakdown of dying cancer cells. You may also be given medications to reduce fever.

During treatment, especially in the first few days after starting treatment, you may experience a significant decrease in white blood cell count (neutropenia), a significant decrease in white blood cell count with fever (febrile neutropenia), elevated liver enzyme levels, or increased uric acid. Your doctor will perform regular blood tests to monitor your blood counts during treatment with BLINCYTO.

Children and adolescents

Experience with the use of BLINCYTO for the treatment of children under 1 year of age is limited.

Other medicines and BLINCYTO

Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might need to take any other medicines.

Pregnancy and breastfeeding

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

Contraception

Women of childbearing potential must use effective contraceptive methods during treatment and for at least 48 hours after the end of treatment. Consult your doctor or nurse about appropriate contraceptive methods.

Pregnancy

The effects of BLINCYTO in pregnant women are unknown, but based on the mechanism of action of BLINCYTO, it could harm the fetus. You should not use BLINCYTO during pregnancy unless your doctor considers it the most appropriate treatment for you.

If you become pregnant during treatment with BLINCYTO, inform your doctor or nurse. Your doctor will advise you on precautions regarding vaccinations for your baby.

Breastfeeding

You must not breastfeed during treatment and for at least 48 hours after your last dose. It is unknown whether BLINCYTO passes into breast milk, but the risk to the breastfed infant cannot be excluded.

Driving and use of machines

Do not drive, operate heavy machinery, or perform hazardous activities while being treated with BLINCYTO. BLINCYTO may cause neurological problems such as dizziness, seizures, confusion, and disturbances in coordination and balance.

BLINCYTO contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per 24 hours of infusion; hence, it is essentially "sodium-free".

3. How BLINCYTO will be administered to you

Follow exactly the administration instructions for this medicine given by your doctor, pharmacist, or nurse. If in doubt, consult your doctor, pharmacist, or nurse again.

BLINCYTO will be administered to you intravenously as a continuous infusion over 4 weeks using an infusion pump (this is 1 treatment cycle). After this, you will have a 2-week rest period during which you will not receive the infusion. You will have the infusion catheter in place at all times during each cycle of your treatment. Your doctor will determine how often the BLINCYTO infusion bag should be changed, which may range from every day to every 4 days. The infusion rate may be faster or slower depending on how frequently the bag is changed.

How long you will receive BLINCYTO treatment

BLINCYTO is normally administered for 2 treatment cycles if you have relapsed or refractory acute lymphoblastic leukemia, or for 1 treatment cycle if you have acute lymphoblastic leukemia with minimal residual disease. If you respond to this treatment, your doctor may decide to administer up to 3 additional treatment cycles.

If you have acute lymphoblastic leukemia and are receiving BLINCYTO as part of consolidation therapy, your doctor will determine the number of BLINCYTO cycles to be administered.

The number of treatment cycles and the dose you will receive depend on how well you tolerate and respond to BLINCYTO. Your doctor will discuss with you how long your treatment will last. Your treatment may also be interrupted depending on how well you tolerate BLINCYTO.

How long you will stay in the hospital

If you have relapsed or refractory acute lymphoblastic leukemia, it is recommended that the first 9 days of treatment and the first 2 days of the second cycle be administered in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anticancer medicines.

If you have acute lymphoblastic leukemia with minimal residual disease, it is recommended that the first 3 days of treatment and the first 2 days of subsequent cycles be administered in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anticancer medicines.

If you have acute lymphoblastic leukemia and are receiving BLINCYTO as part of consolidation therapy, it is recommended that the first 3 days of the first treatment cycle and the first 2 days of the second cycle be administered in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anticancer medicines.

If you have or have had neurological problems, it is recommended that you remain in a hospital or clinic for the first 14 days of treatment. Your doctor will discuss with you whether you can continue treatment at home after your initial hospital stay. Treatment may include a bag change performed by a nurse.

What dose of BLINCYTO you will receive

If you have relapsed or refractory acute lymphoblastic leukemia and your body weight is 45 kilograms or more, the recommended initial dose for your first cycle is 9 micrograms per day for 1 week. After this, your doctor may decide to increase your dose to 28 micrograms per day during weeks 2, 3, and 4 of your treatment. If your doctor determines that you should receive additional cycles of BLINCYTO, your pump will be programmed to infuse a dose of 28 micrograms per day for all subsequent treatment cycles.

If your body weight is less than 45 kilograms, the recommended initial dose for the first cycle will be calculated based on your weight and height. During the first week of BLINCYTO treatment, your pump will be programmed to infuse a dose of 5 micrograms/m²/day. The dose should be increased to 15 micrograms/m²/day during weeks 2, 3, and 4, depending on your response to BLINCYTO treatment. If your doctor determines that you should receive additional cycles of BLINCYTO, your pump will be programmed to infuse a dose of 15 micrograms/m²/day for all subsequent treatment cycles. You may not notice a difference between the dose infused during the first week of the first cycle and the higher dose infused during the remainder of the first cycle and subsequent cycles.

If you have acute lymphoblastic leukemia with minimal residual disease and your body weight is 45 kilograms or more, your BLINCYTO dose will be 28 micrograms per day for all treatment cycles. If your body weight is less than 45 kilograms, the dose programmed in the pump will be 15 micrograms/m²/day based on your weight and height for all treatment cycles.

If you have acute lymphoblastic leukemia and are receiving BLINCYTO as part of consolidation therapy, and if your body weight is 45 kilograms or more, your BLINCYTO dose will be 28 micrograms per day for all treatment cycles. If your body weight is less than 45 kilograms, the dose programmed in the pump will be 15 micrograms/m²/day based on your weight and height for all treatment cycles.

Medications administered before each BLINCYTO cycle

Before your BLINCYTO treatment, you will be given other medications (premedication) to help reduce infusion reactions and other possible adverse effects. These medications may include corticosteroids (e.g., dexamethasone).

During and before treatment with BLINCYTO, you may also receive chemotherapy via intrathecal injection (injection into the space surrounding the spinal cord and brain) to prevent relapse of acute lymphoblastic leukemia in the central nervous system. If you have any questions about your treatment, consult your doctor.

Infusion catheter

If you have an infusion catheter in place, it is very important to keep the area around the catheter clean; otherwise, you could develop an infection. Your doctor or nurse will show you how to care for the catheter site.

Infusion pump and intravenous tubing

Do not adjust the pump settings, even if there is a problem or the pump alarm sounds. Any change in the pump settings may result in a dose that is too high or too low.

Contact your doctor or nurse immediately if:

• there is a problem with the pump or the pump alarm sounds
• the infusion bag empties before the scheduled bag change date
• the infusion pump stops unexpectedly. Do not attempt to restart your pump.

Your doctor or nurse will advise you on how to carry out your daily activities while connected to the infusion pump. If you have any questions, contact your doctor or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them. Some of these adverse effects may be serious.

Contact your doctor immediately if you experience any of the following adverse effects or a combination of them:

• chills, rigors, fever, rapid heart rate, decreased blood pressure, muscle aches, feeling tired, cough, difficulty breathing, confusion, redness, swelling or discharge from the affected area or from the site where the infusion line is placed. These may be signs of an infection.
• neurological events: rigors (tremors), confusion, disturbances in brain function (encephalopathy), difficulty communicating (aphasia), seizures.
• fever, swelling, chills, increased or decreased blood pressure and fluid in the lungs, which may become severe; these may be signs of a condition called cytokine release syndrome.
• persistent and severe stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially life-threatening condition known as pancreatitis (inflammation of the pancreas).
• Haemophagocytic lymphohistiocytosis (HLH)/HLH-like syndrome associated with immune effector cells (HLH-IC): a rare condition in which the immune system produces an excess of histiocytes and lymphocytes—cells that normally fight infections. This may cause enlargement of the liver or spleen. Symptoms may include fever, swollen lymph nodes, breathing problems, and easy bruising or bleeding.

Treatment with BLINCYTO may cause a decrease in certain white blood cell levels, with or without fever (febrile neutropenia or neutropenia), or may lead to increased blood levels of potassium, uric acid and phosphate, and decreased blood calcium levels (tumour lysis syndrome). Your doctor will perform regular blood tests during your treatment with BLINCYTO.

Other adverse effects include:

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

• blood infection, including bacterial, viral or other types of infection
• decreased levels of certain white blood cells with or without fever (leucopenia, neutropenia [febrile]), decreased red blood cell levels, decreased platelet levels
• fever, swelling, chills, increased or decreased blood pressure and fluid in the lungs, which may become severe (cytokine release syndrome)
• trouble sleeping, headache, rigors (tremors). These may be symptoms of neurological problems related to a condition called immune effector cell-associated neurotoxicity syndrome (ICANS).
• rapid heart rate (tachycardia)
• low blood pressure
• high blood pressure (hypertension)
• cough
• nausea, diarrhoea, vomiting, constipation, abdominal pain
• skin rash
• back pain, limb pain
• fever (pyrexia), swelling of face, lips, mouth, tongue or throat that may cause difficulty swallowing or breathing (oedema), chills
• low levels of antibodies called “immunoglobulins”, which help the immune system fight infections (decreased immunoglobulins)
• elevated liver enzyme levels (ALT, AST, GGT)
• infusion-related reactions may include wheezing (whistling sound when breathing), flushing, facial swelling, difficulty breathing, and low or high blood pressure

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

• severe infection that may lead to organ failure or shock, or may be fatal (septicaemia)
• lung infection (pneumonia)
• fungal infection
• increased white blood cell count (leucocytosis), decreased levels of certain white blood cells (lymphopenia)
• allergic reaction
• complications occurring after cancer treatment that cause increased blood levels of potassium, uric acid and phosphorus, and decreased blood calcium levels (tumour lysis syndrome)
• confusion, disorientation, disturbances in brain function (encephalopathy), such as difficulty communicating (aphasia), skin tingling (paraesthesia), seizures, difficulty thinking or processing thoughts, memory problems, difficulty controlling movements (ataxia), drowsiness (somnolence), numbness, dizziness. These may be symptoms of neurological problems related to a condition called immune effector cell-associated neurotoxicity syndrome (ICANS).
• nerve problems affecting the head and neck such as visual disturbances, drooping eyelid and/or facial muscle weakness on one side of the face, hearing problems or difficulty swallowing (cranial nerve disorders)
• wheezing or difficulty breathing (dyspnoea), dyspnoea (respiratory failure)
• redness
• cough with phlegm
• increased bilirubin in the blood
• bone pain
• chest pain or other pain
• elevated blood levels of certain enzymes
• weight gain

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

• fever, enlarged liver or spleen, swollen lymph nodes, breathing problems, and easy bruising. These may be symptoms associated with overactivity of the immune system; a condition called HLH/HLH-IC, which may be potentially life-threatening.
• swollen lymph nodes (lymphadenopathy)
• fever, swelling, chills, low or high blood pressure, and fluid in the lungs, which may be severe and potentially fatal (cytokine storm)
• a disorder causing leakage of fluid from small blood vessels into the body (capillary leak syndrome)
• difficulty speaking and/or writing. This may be a symptom of neurological problems related to a condition called immune effector cell-associated neurotoxicity syndrome (ICANS).

In addition, adverse effects observed more frequently in adolescents and children include:

• decreased red blood cell levels (anaemia), decreased platelet levels (thrombocytopenia), decreased levels of certain white blood cells (leucopenia)
• fever (pyrexia)
• infusion-related reactions such as facial swelling, low blood pressure, high blood pressure (infusion-related reaction)
• weight gain
• high blood pressure (hypertension)

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system detailed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of BLINCYTO

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 and the carton after EXP or CAD. The expiry date refers to the last day of the month indicated.

Unopened vials:

• Store and transport refrigerated (between 2°C and 8°C).
• Do not freeze.
• Keep the product in its original packaging to protect it from light.

Reconstituted solution (BLINCYTO solution):

• When refrigerated, the reconstituted solution must be used within 24 hours. Alternatively, the vials may be stored at room temperature (up to 27°C) for up to 4 hours.

Diluted solution (prepared infusion bag):

If your infusion bag is changed at home:

• The infusion bags containing BLINCYTO infusion solution will arrive in a special packaging containing cooling packs.
  • Do not open the packaging.
  • Store the packaging at room temperature (up to 27°C).
  • Do not refrigerate or freeze the packaging.
• Your nurse will open the packaging, and the infusion bags will be stored in a refrigerator until the time of infusion.
• When refrigerated, prepared infusion bags must be used within 10 days.
• Once at room temperature (up to 27°C), the solution must be infused within 96 hours.

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

6. Contents of the pack and other information

Composition of BLINCYTO

• The active substance is blinatumomab. Each vial of powder contains 38.5 micrograms of blinatumomab. Reconstitution with water for injections results in a final concentration of blinatumomab of 12.5 micrograms/ml.
• The other components of the powder are monohydrate citric acid (E330), trehalose dihydrate, lysine hydrochloride, polysorbate 80 (E433), and sodium hydroxide.
• The (stabilizing) solution contains monohydrate citric acid (E330), lysine hydrochloride, polysorbate 80 (E433), sodium hydroxide, and water for injections.

Appearance of BLINCYTO and contents of the pack

BLINCYTO is a powder for concentrate and solution for solution for infusion.

Each BLINCYTO pack contains:

1 glass vial containing a white to off-white lyophilized powder.

1 glass vial containing a clear, colourless to slightly yellow solution.

Marketing Authorization Holder and Manufacturer

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

Marketing Authorization Holder

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

Manufacturer

Amgen NV

Telecomlaan 5-7

1831 Diegem

Belgium

For further information regarding this medicinal product, please contact the local representative of the Marketing Authorization Holder:

Belgium/Belgium/Belgium s.a. Amgen n.v. Tel/Tel: +32 (0)2 7752711	Lithuania Amgen Switzerland AG Vilnius Branch Tel: +370 5 219 7474
	Luxembourg/Luxembourg s.a. Amgen Belgium/Belgium Tel/Tel: +32 (0)2 7752711
Czech Republic Amgen s.r.o. Tel: +420 221 773 500	Hungary Amgen Kft. Tel.: +36 1 35 44 700
Denmark Amgen, branch of Amgen AB, Sweden Tlf.: +45 39617500	Malta Amgen S.r.l. Italy Tel: +39 02 6241121
Germany Amgen GmbH Tel.: +49 89 1490960	Netherlands Amgen B.V. Tel: +31 (0)76 5732500
Estonia Amgen Switzerland AG Vilnius Branch Tel: +372 586 09553	Norway Amgen AB Tlf: +47 23308000
Greece Amgen Hellas Pharmaceutical E.P.E. Tel: +30 210 3447000	Austria Amgen GmbH Tel: +43 (0)1 50 217
Spain Amgen S.A. Tel: +34 93 600 18 60	Poland Amgen Biotechnologia Sp. z o.o. Tel.: +48 22 581 3000
France Amgen S.A.S. Tél: +33 (0)9 69 363 363	Portugal Amgen Biofarmaceutica, Lda. Tel: +351 21 422 0606
Croatia Amgen d.o.o. Tel: +385 (0)1 562 57 20	Romania Amgen Romania SRL Tel: +4021 527 3000
Ireland Amgen Ireland Limited Tel: +353 1 8527400	Slovenia AMGEN zdravila d.o.o. Tel: +386 (0)1 585 1767
Iceland Vistor Sími: +354 535 7000	Slovakia Amgen Slovakia s.r.o. Tel: +421 2 321 114 49
Italy Amgen S.r.l. Tel: +39 02 6241121	Finland Amgen AB, branch in Finland/Amgen AB, filial i Finland Puh/Tel: +358 (0)9 54900500
Cyprus C.A. Papaellinas Ltd Tel: +357 22741 741	Sweden Amgen AB Tel: +46 (0)8 6951100
Latvia Amgen Switzerland AG Riga Branch Tel: +371 257 25888

Date of the most recent review of this summary:

Other sources of information

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

This information is intended for healthcare professionals only:

BLINCYTO infusion solution is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump over a period of up to 96 hours.

B-cell precursor ALL in refractory or relapsed disease

The recommended daily dose depends on body weight. Patients with a body weight equal to or greater than 45 kg receive a fixed dose, whereas for patients with a body weight below 45 kg, the dose is calculated based on the patient's body surface area (BSA). See the table below for the recommended daily dose for B-cell precursor ALL in refractory or relapsed disease.

Body weight	Cycle 1	Subsequent cycles
Days 1-7	Days 8-28	Days 29-42	Days 1-28	Days 29-42
Weight equal to or greater than 45 kg (fixed dose)	9 µg/day via continuous infusion	28 µg/day via continuous infusion	14-day treatment-free interval	28 µg/day via continuous infusion	14-day treatment-free interval
Weight less than 45 kg (dose based on BSA)	5 μg/m²/day via continuous infusion (should not exceed 9 μg/day)	15 μg/m²/day via continuous infusion (should not exceed 28 μg/day)	15 μg/m²/day via continuous infusion (should not exceed 28 μg/day)

Pediatric patients with high-risk first relapse of B-cell precursor ALL may receive 1 cycle of treatment with BLINCYTO following induction and 2 cycles of consolidation chemotherapy. See the following table for the recommended daily dose based on body weight for pediatric patients with high-risk first relapse of B-cell precursor ALL after induction chemotherapy.

One consolidation cycle	Body weight greater than or equal to 45 kg (fixed dose)	Body weight less than 45 kg (dose based on BSA)
Days 1–28	28 µg/day	15 µg/m²/day (should not exceed 28 µg/day)

B-cell precursor ALL with MRD positive

The recommended daily dose depends on body weight. The recommended dose of BLINCYTO for patients weighing 45 kg or more during each 4-week treatment cycle is 28 μg/day. For patients weighing less than 45 kg, the dose is calculated based on BSA. The recommended dose of BLINCYTO during each 4-week treatment cycle is 15 μg/m²/day.

Adults with B-cell precursor ALL in the consolidation phase

The recommended daily dose depends on body weight. The recommended dose of BLINCYTO for patients weighing 45 kg or more during each 4-week treatment cycle is 28 μg/day. For patients weighing less than 45 kg, the dose is calculated based on BSA. The recommended dose of BLINCYTO during each 4-week treatment cycle is 15 μg/m²/day.

The initial volume (270 ml) is greater than the volume administered to the patient (240 ml) to compensate for priming of the intravenous tubing and to ensure that the patient receives the complete dose of BLINCYTO.

The infusion of the final prepared BLINCYTO infusion solution must be administered according to the instructions on the label of the prepared bag at one of the following constant infusion rates:

• Infusion rate of 10 ml/h for 24 hours
• Infusion rate of 5 ml/h for 48 hours
• Infusion rate of 3.3 ml/h for 72 hours
• Infusion rate of 2.5 ml/h for 96 hours

The choice of infusion duration should be made by the specialist physician, taking into account the frequency of bag changes and the patient's weight. The target therapeutic dose of BLINCYTO administered does not vary.

Aseptic preparation

Aseptic handling must be ensured during the preparation of the infusion. Preparation of BLINCYTO must:

• Be carried out under aseptic conditions by trained personnel following good practice guidelines, especially regarding aseptic preparation of parenteral products.

• Be prepared in a laminar flow hood or biological safety cabinet, observing standard precautions for the safe handling of intravenous agents.

It is very important that the preparation and administration instructions provided in this section are strictly followed to minimize medication errors (including administration of an insufficient dose and overdose).

Other instructions

BLINCYTO is compatible with polyolefin infusion bags/pump cassettes, PVC without diethylhexylphthalate (DEHP-free), or ethylene vinyl acetate (EVA).

At the end of the infusion, any unused medicinal product or materials that have come into contact with it must be disposed of in accordance with local regulations.

Preparation of infusion solution

The following supplies are also required, which are not included in the package:

• Sterile, single-use disposable syringes

• 21-23 gauge needle(s) (recommended)

• Water for injections

• Infusion bag containing 250 ml of 9 mg/ml (0.9%) sodium chloride injection solution

• To minimize the number of aseptic transfers, use a pre-filled 250 ml infusion bag. BLINCYTO dose calculations are based on a normal overfill volume of 265 to 275 ml of 9 mg/ml (0.9%) sodium chloride injection solution.

• Only polyolefin, DEHP-free PVC, or EVA infusion bags/pump cassettes should be used.

• Polyolefin, DEHP-free PVC, or EVA intravenous tubing with a low protein-binding, sterile, pyrogen-free in-line filter of 0.2 μm

• Ensure that the tubing is compatible with the infusion pump.

Reconstitute BLINCYTO with water for injections. Do not reconstitute BLINCYTO vials with the (stabilizing) solution.

To prime the intravenous tubing, use only the solution from the bag containing the FINAL prepared BLINCYTO infusion solution. Do not prime with 9 mg/ml (0.9%) sodium chloride injection solution.

Reconstitution of BLINCYTO

1. Determine the number of BLINCYTO vials required for one dose and the duration of infusion.
2. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate with 3 ml of water for injections. Direct the water toward the vial walls and not directly onto the lyophilized powder.

• Do not reconstitute BLINCYTO powder for concentrate with the (stabilizing) solution.
• Adding water for injections to the concentrate powder yields a total volume of 3.08 ml, resulting in a final BLINCYTO concentration of 12.5 µg/ml.

3. Gently rotate the contents to avoid excessive foaming.

• Do not shake.

4. Visually inspect the reconstituted solution for particles and discoloration during reconstitution and before preparing the infusion bag. The resulting solution should be clear to slightly opalescent and colorless to slightly yellow.

• Do not use the solution if it is cloudy or contains precipitates.

Preparation of the BLINCYTO infusion bag

Verify the prescribed dose and infusion duration for each BLINCYTO infusion bag. To minimize errors, use the specific volumes described in Tables 1 and 2 to prepare the BLINCYTO infusion bag.

• Table 1 for patients with a weight equal to or greater than 45 kg
• Table 2 for patients with a weight less than 45 kg

1. Use a pre-filled infusion bag containing 250 ml of 9 mg/ml (0.9%) sodium chloride injection solution, which typically contains a total volume of 265 to 275 ml.
2. To coat the infusion bag, use a syringe to aseptically transfer 5.5 ml of the (stabilizing) solution into the infusion bag. Gently mix the bag contents to avoid foaming. Discard the vial with any remaining (stabilizing) solution.
3. Using a syringe, aseptically transfer the required volume of reconstituted BLINCYTO solution into the infusion bag containing 9 mg/ml (0.9%) sodium chloride injection solution and the (stabilizing) solution. Gently mix the bag contents to avoid foaming.

• Refer to Table 1 for the specific volume of reconstituted BLINCYTO for patients weighing 45 kg or more.
• Refer to Table 2 for the specific volume of reconstituted BLINCYTO for patients weighing less than 45 kg (dose based on BSA).
• Discard any unused reconstituted BLINCYTO solution remaining in the vial.

4. Remove air from the infusion bag. This is particularly important when using an ambulatory infusion pump.
5. Under aseptic conditions, connect the intravenous tubing to the infusion bag with a sterile 0.2-micron in-line filter. Ensure that the tubing is compatible with the infusion pump.
6. Prime the intravenous infusion line only with the infusion solution in the bag containing the FINAL prepared BLINCYTO infusion solution.
7. If not used immediately, store refrigerated between 2°C and 8°C.

Table 1. For patients with body weight equal to or greater than 45 kg: volumes of 9 mg/ml (0.9%) sodium chloride injection solution, (stabilizing) solution, and reconstituted BLINCYTO to be added to the infusion bag

Sodium chloride 9 mg/ml (0.9%) injection solution (initial volume)	250 ml (normal overfill volume of 265 to 275 ml)
Stabilizing solution (fixed volume for infusion durations of 24, 48, 72, and 96 hours)	5.5 ml
Infusion duration	Dose	Infusion rate	Reconstituted BLINCYTO
Volume	Vials
24 hours	9 µg/day	10 ml/hour	0.83 ml	1
28 µg/day	10 ml/hour	2.6 ml	1
48 hours	9 µg/day	5 ml/hour	1.7 ml	1
28 µg/day	5 ml/hour	5.2 ml	2
72 hours	9 µg/day	3.3 ml/hour	2.5 ml	1
28 µg/day	3.3 ml/hour	8 ml	3
96 hours	9 µg/day	2.5 ml/hour	3.3 ml	2
28 µg/day	2.5 ml/hour	10.7 ml	4

Table 2. For patients weighing less than 45 kg: volumes of injectable sodium chloride 9 mg/mL (0.9%) solution, (stabilizing) solution, and reconstituted BLINCYTO to add to the infusion bag

Sodium chloride 9 mg/ml (0.9%) injection solution (initial volume)	250 ml (normal overfill volume of 265 to 275 ml)
Stabilizing solution (fixed volume for infusion durations of 24, 48, 72 and 96 hours)	5.5 ml
Infusion duration	Dose	Infusion rate	BSA (m²)*	Reconstituted BLINCYTO
Volume	Vials
24 hours	5 µg/m²/day	10 ml/hour	1.5 – 1.59	0.7 ml	1
1.4 – 1.49	0.66 ml	1
1.3 – 1.39	0.61 ml	1
1.2 – 1.29	0.56 ml	1
1.1 – 1.19	0.52 ml	1
1.0 – 1.09	0.47 ml	1
0.9 – 0.99	0.43 ml	1
0.8 – 0.89	0.38 ml	1
0.7 – 0.79	0.33 ml	1
0.6 – 0.69	0.29 ml	1
0.5 – 0.59	0.24 ml	1
0.4 – 0.49	0.2 ml	1
24 hours	15 µg/m²/day	10 ml/hour	1.5 – 1.59	2.1 ml	1
1.4 – 1.49	2 ml	1
1.3 – 1.39	1.8 ml	1
1.2 – 1.29	1.7 ml	1
1.1 – 1.19	1.6 ml	1
1.0 – 1.09	1.4 ml	1
0.9 – 0.99	1.3 ml	1
0.8 – 0.89	1.1 ml	1
0.7 – 0.79	1 ml	1
0.6 – 0.69	0.86 ml	1
0.5 – 0.59	0.72 ml	1
0.4 – 0.49	0.59 ml	1
48 hours	5 µg/m²/day	5 ml/hour	1.5 – 1.59	1.4 ml	1
1.4 – 1.49	1.3 ml	1
1.3 – 1.39	1.2 ml	1
1.2 – 1.29	1.1 ml	1
1.1 – 1.19	1 ml	1
1.0 – 1.09	0.94 ml	1
0.9 – 0.99	0.85 ml	1
0.8 – 0.89	0.76 ml	1
0.7 – 0.79	0.67 ml	1
0.6 – 0.69	0.57 ml	1
0.5 – 0.59	0.48 ml	1
0.4 – 0.49	0.39 ml	1
48 hours	15 µg/m²/day	5 ml/hour	1.5 – 1.59	4.2 ml	2
1.4 – 1.49	3.9 ml	2
1.3 – 1.39	3.7 ml	2
1.2 – 1.29	3.4 ml	2
1.1 – 1.19	3.1 ml	2
1.0 – 1.09	2.8 ml	1
0.9 – 0.99	2.6 ml	1
0.8 – 0.89	2.3 ml	1
0.7 – 0.79	2 ml	1
0.6 – 0.69	1.7 ml	1
0.5 – 0.59	1.4 ml	1
0.4 – 0.49	1.2 ml	1
72 hours	5 µg/m²/day	3.3 ml/hour	1.5 – 1.59	2.1 ml	1
1.4 – 1.49	2 ml	1
1.3 – 1.39	1.8 ml	1
1.2 – 1.29	1.7 ml	1
1.1 – 1.19	1.6 ml	1
1.0 – 1.09	1.4 ml	1
0.9 – 0.99	1.3 ml	1
0.8 – 0.89	1.1 ml	1
0.7 – 0.79	1 ml	1
0.6 – 0.69	0.86 ml	1
0.5 – 0.59	0.72 ml	1
0.4 – 0.49	0.59 ml	1
72 hours	15 µg/m²/day	3.3 ml/hour	1.5 – 1.59	6.3 ml	3
1.4 – 1.49	5.9 ml	3
1.3 – 1.39	5.5 ml	2
1.2 – 1.29	5.1 ml	2
1.1 – 1.19	4.7 ml	2
1.0 – 1.09	4.2 ml	2
0.9 – 0.99	3.8 ml	2
0.8 – 0.89	3.4 ml	2
0.7 – 0.79	3 ml	2
0.6 – 0.69	2.6 ml	1
0.5 – 0.59	2.2 ml	1
0.4 – 0.49	1.8 ml	1
96 hours	5 µg/m²/day	2.5 ml/hour	1.5 – 1.59	2.8 ml	1
1.4 – 1.49	2.6 ml	1
1.3 – 1.39	2.4 ml	1
1.2 – 1.29	2.3 ml	1
1.1 – 1.19	2.1 ml	1
1.0 – 1.09	1.9 ml	1
0.9 – 0.99	1.7 ml	1
0.8 – 0.89	1.5 ml	1
0.7 – 0.79	1.3 ml	1
0.6 – 0.69	1.2 ml	1
0.5 – 0.59	0.97 ml	1
0.4 – 0.49	0.78 ml	1
96 hours	15 µg/m²/day	2.5 ml/hour	1.5 – 1.59	8.4 ml	3
1.4 – 1.49	7.9 ml	3
1.3 – 1.39	7.3 ml	3
1.2 – 1.29	6.8 ml	3
1.1 – 1.19	6.2 ml	3
1.0 – 1.09	5.7 ml	3
0.9 – 0.99	5.1 ml	2
0.8 – 0.89	4.6 ml	2
0.7 – 0.79	4 ml	2
0.6 – 0.69	3.4 ml	2
0.5 – 0.59	2.9 ml	2
0.4 – 0.49	2.3 ml	1

ASC = Body surface area

• The safety of BLINCYTO administration has not been established for an ASC less than 0.4 m².

For administration instructions, refer to section 4.2 of the Summary of Product Characteristics.

Method of administration

Important note: Do not flush the BLINCYTO infusion line, especially when changing infusion bags. Flushing when changing bags or at the end of infusion may result in overdose, with consequent complications. When administration is performed via a multi-lumen venous catheter, BLINCYTO must be administered through a dedicated lumen.

BLINCYTO infusion solution is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump over a period of up to 96 hours.

BLINCYTO infusion solution must be administered using an intravenous set containing a low-protein-binding, apyrogenic, sterile in-line filter with a pore size of 0.2 micrometers.

The infusion bag must be changed by a healthcare professional at least every 96 hours for sterility reasons.

Storage conditions and shelf life

Unopened vials:

5 years (at 2 °C to 8 °C)

Reconstituted solution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C or for 4 hours at a temperature of 27 °C or below.

From a microbiological standpoint, unless the reconstitution method excludes the risk of microbial contamination, the reconstituted solution should be diluted immediately. If not diluted immediately, the in-use storage times and conditions prior to dilution are the responsibility of the user.

Diluted solution (prepared infusion bag):

Chemical and physical in-use stability has been demonstrated for 10 days at 2 °C to 8 °C or for 96 hours at a temperature of 27 °C or below.

From a microbiological standpoint, prepared infusion bags should be used immediately. If not used immediately, the in-use storage times and conditions prior to use are the responsibility of the user and normally will not exceed 24 hours at 2 °C to 8 °C, unless dilution has taken place under controlled and validated aseptic conditions.