BESPONSA 1 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

BESPONSA 1mg powder for concentrate for solution for infusion

inotuzumab ozogamicin

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

Contents of the pack

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

1. What is BESPONSA and what is it used for

The active substance of BESPONSA is inotuzumab ozogamicin. It belongs to a group of medicines whose target is cancer cells. These medicines are called antineoplastic agents.

BESPONSA is used for the treatment of adults with acute lymphoblastic leukemia. Acute lymphoblastic leukemia is a blood cancer in which there are too many white blood cells. BESPONSA is designed for the treatment of acute lymphoblastic leukemia in adult patients who have previously used other treatments that have failed.

BESPONSA works by binding to cells with a protein called CD22. Leukemia cells have this protein. Once bound to the leukemia cells, the medicine releases a substance inside the cells, which interferes with the DNA of the cells and destroys them.

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

Do not use BESPONSA

• if you are allergic to inotuzumab ozogamicin or any of the other ingredients of this medicine (listed in section 6).
• if you have previously had severe veno-occlusive disease (a condition in which the blood vessels of the liver are damaged and blocked by blood clots) or currently have veno-occlusive disease.
• if you have severe liver disease, such as cirrhosis (a condition in which the liver does not function properly due to prolonged damage), nodular regenerative hyperplasia (a condition with signs and symptoms of portal hypertension that may be caused by chronic use of medications) or active hepatitis (a disease characterized by liver inflammation).

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with BESPONSA if:

• you have a history of liver problems or diseases, or if you have signs and symptoms of a severe disease called hepatic veno-occlusive disease, a condition in which the blood vessels of the liver are damaged and blocked by blood clots. Hepatic veno-occlusive disease can be fatal and is associated with rapid weight gain, pain in the upper right side of the abdomen, enlargement of the liver, accumulation of fluid that causes swelling in the abdomen, and blood tests with elevated bilirubin and/or liver enzymes (which can lead to a yellowish color of the skin and eyes). This condition can occur during treatment with BESPONSA or after subsequent stem cell transplant treatment. Stem cell transplantation is an operation to transplant stem cells (cells that become new blood cells) from another person into your bloodstream. This operation may be performed if your disease responds completely to treatment
• you have signs or symptoms of a low number of blood cells known as neutrophils (sometimes accompanied by fever), red blood cells, white blood cells, lymphocytes, or a low number of blood components known as platelets; these signs and symptoms include the development of an infection or fever, easy bruising or frequent nosebleeds
• you experience signs and symptoms of a infusion-related reaction, such as fever and chills or breathing problems during or shortly after the infusion of BESPONSA
• you experience signs and symptoms of tumor lysis syndrome, which may be related to symptoms in the stomach and intestine (such as nausea, vomiting, diarrhea), heart (such as changes in heart rate), kidneys (such as decreased urine output, blood in the urine), and nerves and muscles (such as muscle spasms, weakness, cramps) during or shortly after the infusion of BESPONSA
• you have a history of or tendency to prolongation of the QT interval (a change in the electrical activity of the heart that can produce serious irregular heart rhythms), are taking medications that are known to prolong the QT interval, and/or have abnormal levels of electrolytes (such as calcium, magnesium, potassium)
• you have elevated levels of amylase or lipase enzymes that may be a sign of problems with your pancreas or liver, and the gallbladder or bile ducts.

Tell your doctor, pharmacist, or nurse immediatelyif you become pregnant during the treatment period with BESPONSA and up to 8 months after the end of treatment.

Your doctor will perform regular blood tests to monitor your blood count during treatment with BESPONSA. See also section 4.

During treatment, especially in the first few days after starting treatment, your white blood cell count may decrease severely (neutropenia) and may be accompanied by fever (febrile neutropenia).

During treatment, especially in the first few days after starting treatment, you may have elevated liver enzymes. Your doctor will perform regular blood tests to monitor your liver enzymes during treatment with BESPONSA.

Treatment with BESPONSA may prolong the QT interval (a change in the electrical activity of the heart that can produce serious irregular heart rhythms). Your doctor will perform an electrocardiogram (ECG) and blood tests to measure electrolytes (such as calcium, magnesium, potassium) before the first dose of BESPONSA, and will repeat them during treatment. See also section 4.

Your doctor will also monitor the signs and symptoms of tumor lysis syndrome after administration of BESPONSA. See also section 4.

Children and adolescents

BESPONSA should not be used in children and adolescents under 18 years of age, as there are no data available in this population.

Other medicines and BESPONSA

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes medicines obtained without a prescription and herbal remedies.

Pregnancy, breastfeeding, and fertility

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

Contraception

Avoid becoming pregnant or conceiving a child. Women should use effective contraceptive methods during treatment and for at least 8 months after the last dose. Men should use effective contraceptive methods during treatment and for at least 5 months after the last dose of treatment.

Pregnancy

The effects of BESPONSA on pregnant women are unknown, but based on its mechanism of action, BESPONSA may harm the fetus. Do not use BESPONSA during pregnancy unless your doctor considers it the best medicine for you.

Contact your doctor immediately if you or your partner become pregnant during the treatment period with this medicine.

Fertility

Men and women should seek information about fertility preservation before treatment.

Breastfeeding

If you need treatment with BESPONSA, you should stop breastfeeding during treatment and for at least 2 months after treatment. Ask your doctor.

Driving and using machines

If you feel abnormally tired (this is a very common side effect of BESPONSA), you should not drive or use machines.

BESPONSA contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per 1 mg of inotuzumab ozogamicin; i.e., it is essentially “sodium-free”.

3. How BESPONSA is given

Follow exactly the instructions for administration of this medicine given by your doctor, pharmacist, or nurse. If you are unsure, ask your doctor, pharmacist, or nurse again.

How BESPONSA is given

• Your doctor will decide the correct dose.
• A doctor or nurse will give you BESPONSA through a drip into a vein (intravenous infusion) that will last for 1 hour.
• Each dose is given weekly and each treatment cycle consists of 3 doses.
• If the medicine works well and you are going to have a stem cell transplant (see section 2), you may receive 2 cycles or a maximum of 3 cycles of treatment.
• If the medicine works well, but you are not going to have a stem cell transplant (see section 2), you may receive up to a maximum of 6 cycles of treatment.
• If you do not respond to the medicine after 3 cycles, treatment will be stopped.

• Your doctor may change the dose, interrupt, or completely stop treatment with BESPONSA if you experience certain side effects.
• Your doctor may reduce the dose according to your response to treatment.
• Your doctor will perform blood tests during treatment to detect side effects and check your response to treatment.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

Medicines given before treatment with BESPONSA

Before treatment with BESPONSA, you will be given other medicines (premedication) to reduce infusion reactions and other possible side effects. These medicines may be corticosteroids (such as dexamethasone), antipyretics (medicines to reduce fever), and antihistamines (medicines to reduce allergic reactions).

Before your treatment with BESPONSA, you may be given medicines and hydration to prevent tumor lysis syndrome. Tumor lysis syndrome is related to a series of symptoms in the stomach and intestine (such as nausea, vomiting, diarrhea), heart (such as changes in heart rate), kidney (such as decreased urine output, blood in the urine), and nerves and muscles (such as muscle spasms, weakness, cramps).

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects can be serious.

Tell your doctor immediatelyif you have signs and symptoms of any of the following serious side effects:

• infusion-related reactions (see section 2); signs and symptoms include fever and chills during or shortly after the infusion with BESPONSA.
• hepatic veno-occlusive disease (see section 2); signs and symptoms include rapid weight gain, pain in the upper right side of the abdomen, enlargement of the liver, accumulation of fluid that causes swelling in the abdomen, and elevated bilirubin and/or liver enzymes (which can lead to a yellowish color of the skin and eyes).
• a low number of blood cells known as neutrophils (sometimes accompanied by fever), red blood cells, white blood cells, lymphocytes, or a low number of blood components known as platelets (see section 2); signs and symptoms include the development of an infection or fever, easy bruising or frequent nosebleeds.

• tumor lysis syndrome (see section 2); which may be related to symptoms in the stomach and intestine (such as nausea, vomiting, diarrhea), heart (such as changes in heart rate), kidneys (such as decreased urine output, blood in the urine), and nerves and muscles (such as muscle spasms, weakness, cramps).

• prolongation of the QT interval (see section 2); signs and symptoms include a change in the electrical activity of the heart that can produce serious irregular heart rhythms. Tell your doctor if you have symptoms such as dizziness, lightheadedness, or fainting.

Other side effects may include:

Very common: may affect more than 1 in 10 people

• infections
• reduced number of white blood cells that can lead to general weakness and favor the development of infections
• reduced number of lymphocytes (a type of white blood cell) that can favor the development of infections
• reduced number of red blood cells that can lead to fatigue and shortness of breath
• decreased appetite
• headache
• bleeding
• abdominal pain
• vomiting
• diarrhea
• nausea
• mouth inflammation
• constipation
• elevated bilirubin levels that can lead to a yellowish color of the skin, eyes, and other tissues
• fever
• chills
• fatigue
• high levels of liver enzymes in the blood (which can indicate liver damage)

Common: may affect up to 1 in 10 people

• reduction in the number of several types of blood cells
• excess uric acid in the blood
• excessive fluid accumulation in the abdomen
• abdominal inflammation
• changes in heart rate (may appear on the electrocardiogram)
• abnormally high levels of amylase in the blood (an enzyme necessary for digestion and conversion of starch into sugars)
• abnormally high levels of lipase in the blood (an enzyme necessary for processing fat in the diet)
• hypersensitivity

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the Spanish Medicines Monitoring System for Human Use: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of BESPONSA

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 is the last day of the month stated.

Unopened vial

• Store in a refrigerator (between 2°C and 8°C).
• Keep in the original package to protect from light.
• Do not freeze.

Reconstituted solution

• Use immediately or store in a refrigerator (between 2°C and 8°C) for a maximum of 4 hours.
• Protect from light.
• Do not freeze.

Diluted solution

• Use immediately or store at room temperature (between 20°C and 25°C) or in a refrigerator (between 2°C and 8°C). The maximum time elapsed from reconstitution to the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution.
• Protect from light.
• Do not freeze.

Inspect this medicine for particles or discoloration before administration. Do not use this medicine if you notice particles or discoloration.

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

6. Container Contents and Additional Information

BESPONSA Composition

• The active ingredient is inotuzumab ozogamicin. Each vial contains 1 mg of inotuzumab ozogamicin. After reconstitution, 1 ml of solution contains 0.25 mg of inotuzumab ozogamicin.
• The other components are sucrose, polysorbate 80, sodium chloride, and tromethamine (see section 2).

Product Appearance and Container Contents

BESPONSA is a powder for concentrate for solution for infusion (powder for concentrate).

Each BESPONSA container contains:

• A glass vial with a white to off-white lyophilized paste or powder.

Marketing Authorization Holder

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Brussels

Belgium

Manufacturer

Pfizer Service Company BV

Hoge Wei 10

B-1930, Zaventem

Belgium

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Spain

Pfizer, S.L.

Tel: +34 91 490 99 00

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/. There are also links to other websites on rare diseases and orphan medicines.

On the European Medicines Agency website, this leaflet can be found in all languages of the European Union/European Economic Area.

This information is intended only for healthcare professionals. Please consult the full information on dosage and dosage modifications in the Summary of Product Characteristics.

Method of Administration

BESPONSA is administered intravenously. The infusion should be administered over 1 hour.

Do not administer BESPONSA as an intravenous rapid injection or bolus.

BESPONSA must be reconstituted and diluted before administration.

BESPONSA should be administered in cycles of 3 to 4 weeks.

For patients who are going to undergo hematopoietic stem cell transplantation (HSCT), the recommended treatment duration is 2 cycles. A third cycle may be considered for those patients who do not achieve a CR/CRi and negative MRD after 2 cycles. For patients who are not going to undergo HSCT, up to a maximum of 6 cycles may be administered. Patients who do not achieve a CR/CRi after 3 cycles should discontinue treatment (see section 4.2 of the Summary of Product Characteristics).

The table below shows the recommended dosing schedules.

For the first cycle, the recommended total dose for all patients is 1.8 mg/m2 per cycle, administered in 3 divided doses on days 1 (0.8 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2). Cycle 1 has a duration of 3 weeks, but may be extended to 4 weeks if the patient achieves a CR or CRi, and/or to allow for recovery from toxicity.

For subsequent cycles, the recommended total dose is 1.5 mg/m2 per cycle administered in 3 divided doses on days 1 (0.5 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2) for patients who achieve a CR/CRi or 1.8 mg/m2 per cycle administered in 3 divided doses on days 1 (0.8 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2) for patients who do not achieve a CR/CRi. Subsequent cycles have a duration of 4 weeks.

Instructions for Reconstitution, Dilution, and Administration

Use adequate aseptic technique for reconstitution and dilution procedures. Inotuzumab ozogamicin (which has a density of 1.02 g/ml at 20 °C) is sensitive to light and should be protected from ultraviolet light during reconstitution, dilution, and administration.

The maximum time from reconstitution to the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution.

Reconstitution:

• Calculate the dose (mg) and the number of BESPONSA vials required.
• Reconstitute each 1 mg vial with 4 ml of water for injections, to obtain a single-use solution of 0.25 mg/ml of BESPONSA.
• Gently swirl the vial in circles to help dissolve. Do not shake.
• Inspect the reconstituted solution for particles or discoloration. The reconstituted solution should be clear or slightly turbid, colorless, and practically free from visible foreign particles. Do not use if particles or discoloration are observed.
• BESPONSA does not contain bacteriostatic preservatives. The reconstituted solution should be used immediately. If the reconstituted solution cannot be used immediately, it can be stored in a refrigerator (between 2 °C and 8 °C) for up to 4 hours. Protect from light and do not freeze.

Dilution:

• Calculate the required volume of the reconstituted solution needed to achieve the desired dose based on the patient's body surface area. Withdraw this volume from the vial(s) with a syringe. Protect from light. Discard any unused reconstituted solution remaining in the vial.
• Add the reconstituted solution to an infusion container with sodium chloride 9 mg/ml (0.9%) injection solution, to a total nominal volume of 50 ml. The final concentration should be between 0.01 and 0.1 mg/ml. Protect from light. A polyvinyl chloride (PVC) infusion container (with or without di(2-ethylhexyl)phthalate [DEHP]), polyolefin (polypropylene and/or polyethylene), or ethylene-vinyl acetate (EVA) is recommended.
• Gently invert the infusion container to mix the diluted solution. Do not shake.
• The diluted solution should be used immediately or stored at room temperature (between 20 °C and 25 °C) or in a refrigerator (between 2 °C and 8 °C). The maximum time from reconstitution to the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do not freeze.

Administration:

• If the diluted solution is stored in a refrigerator (between 2 °C and 8 °C), allow it to reach room temperature (between 20 °C and 25 °C) for approximately 1 hour before administration.
• Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES), polyvinylidene fluoride (PVDF), or hydrophilic polysulfone (HPS) filters are recommended. Do not use filters made of nylon or cellulose acetate.
• Protect the intravenous bag from light with a cover that blocks ultraviolet light (e.g., amber, dark brown, or green bags, or aluminum foil) during infusion. The infusion line does not need to be protected from light.
• Infuse the diluted solution over 1 hour at a rate of 50 ml/h at room temperature (between 20 °C and 25 °C). Protect from light. Infusion lines made of PVC (with or without DEHP), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.

Do not mix BESPONSA with other medicinal products or administer in the same infusion line.

The following shows the storage times and conditions for the reconstituted and diluted BESPONSA solution.

Storage Conditions and Shelf-Life

Unopened Vials

5 years.

Reconstituted Solution

BESPONSA does not contain bacteriostatic preservatives. The reconstituted solution should be used immediately. If the reconstituted solution cannot be used immediately, it can be stored in a refrigerator (between 2 °C and 8 °C) for up to 4 hours. Protect from light and do not freeze.

Diluted Solution

The diluted solution should be used immediately or stored at room temperature (between 20 °C and 25 °C) or in a refrigerator (between 2 °C and 8 °C). The maximum time from reconstitution to the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do not freeze.