Qarziba 4.5 mg/ml concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Qarziba 4.5 mg/ml concentrate for solution for infusion

dinutuximab beta

This medicinal product is subject to additional monitoring, which will enable rapid identification of new information on its safety. 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 the entire leaflet carefully before starting to use this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor.
• If you experience any side effects, consult your doctor, even if they are side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Qarziba is and what it is used for

Qarziba contains dinutuximab beta, which belongs to a group of medicines known as "monoclonal antibodies". These are proteins that specifically recognize and bind to certain unique proteins in the body. Dinutuximab beta binds to a molecule called disialoganglioside 2 (GD2), present on cancer cells, and activates the body's immune system, causing it to attack the cancer cells.

Qarziba is used to treat neuroblastoma with a high risk of recurrence following a series of treatments, including stem cell transplant to restore the immune system. It is also used to treat neuroblastoma that has recurred (relapsed) or that could not be completely treated with prior therapies.

Before treating relapsed neuroblastoma, your doctor will stabilize the disease, if active, using appropriate additional measures.

Your doctor will also decide whether it is necessary to administer a second medicine, interleukin-2, concomitantly for the treatment of your cancer.

Neuroblastoma is a type of cancer that develops from abnormal nerve cells in the body, particularly in the glands located above the kidneys. It is one of the most common cancers in childhood.

It is used in patients aged 12 months or older.

2. What you need to know before using Qarziba

Do not use Qarziba:

• if you are allergic to dinutuximab beta or to any of the other ingredients of this medicine (listed in section 6)
• if you have acute grade 3 or 4 graft-versus-host disease, or severe chronic graft-versus-host disease. This is a condition in which the transplanted tissue cells attack the recipient's cells.

Warnings and precautions

Before receiving Qarziba, you will have blood tests to check your liver, lung, kidney, and bone marrow function.

You may experience the following effects when you first receive Qarziba and during the course of treatment:

• Pain

Pain is one of the most common side effects of Qarziba. It usually occurs at the beginning of the infusion. Therefore, your doctor will prescribe appropriate pain treatment starting 3 days before and continuing throughout the use of Qarziba.

• Allergic reactions or other infusion-related reactions

Inform your doctor or nurse if you experience any reaction during or after the infusion, such as:

• fever, chills, or low blood pressure
• difficulty breathing
• skin rash, hives.

You will receive appropriate treatment to prevent these reactions, and you will be closely monitored for these symptoms during Qarziba infusion.

• Leakage from small blood vessels (capillary leak syndrome)

Leakage of blood components from small blood vessels may cause rapid swelling of the arms, legs, and other parts of the body. Other signs include a rapid drop in blood pressure, dizziness, and difficulty breathing.

• Eye problems

You may notice changes in vision.

• Nerve problems

You may experience numbness, tingling, or burning sensations in the hands, feet, legs, or arms, reduced sensitivity, or weakness when moving.

• Problems of the spinal cord and brain (central nervous system, CNS)

Inform your doctor or nurse if you experience any CNS symptoms, such as: significant and prolonged neurological deficits without apparent cause, for example, muscle weakness or loss of muscle strength in the legs (or arms), mobility problems, unusual sensations, or numbness. Persistent or sudden headache, progressive memory loss and cognitive decline, subtle personality changes, inability to concentrate, lethargy, and progressive loss of consciousness.

• Symptoms of kidney failure

Inform your doctor or nurse if you do not urinate or if your urination frequency is altered.

Contact your doctor immediately if you notice any of these problems.

If you experience any of the mentioned problems, your doctor may decide to interrupt treatment. In some cases, treatment may be resumed after a break or at a slower rate, but sometimes it may need to be permanently discontinued.

Your doctor will perform blood tests and possibly eye examinations while you are receiving this medicine.

Children

This medicine must not be given to children under 12 months of age due to insufficient experience in this age group.

Other medicines and Qarziba

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

Do not use medicines that suppress the immune system from 2 weeks before the first dose of Qarziba until 1 week after the last treatment cycle, unless prescribed by your doctor. Some examples of medicines that suppress the immune system are corticosteroids used to reduce inflammation or prevent organ transplant rejection.

Avoid vaccinations during treatment with Qarziba and for 10 weeks thereafter.

Pregnancy, breastfeeding, and fertility

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

Inform your doctor before receiving Qarziba if you are of childbearing age. It is recommended to use contraceptive methods for 6 months after stopping treatment with Qarziba. Qarziba may only be used if your doctor considers that the benefits outweigh the risks to the fetus.

Inform your doctor if you are breastfeeding. Breastfeeding must be avoided during treatment with Qarziba and for 6 months after the last dose. It is unknown whether the medicine can pass into breast milk.

Driving and using machines

Qarziba has several adverse effects that may affect your ability to drive and use machines. Do not perform these activities if your ability to concentrate and react is impaired.

3. How to use Qarziba

Your treatment will be supervised by a doctor experienced in the use of cancer medicines. It will be administered by a doctor or nurse in a hospital. It is given into a vein (intravenous infusion), usually using special tubes (catheters) and a pump.

During and after the infusion, you will be monitored periodically for infusion-related adverse reactions.

You will receive Qarziba in 5 treatment cycles of 35 days each, and the infusion will last 5 or 10 days at the beginning of each cycle. The recommended dose is 100 mg of dinutuximab beta per square metre of body surface area per treatment cycle. Your doctor will calculate your body surface area based on your weight and height.

If your doctor considers concomitant administration of interleukin-2 appropriate, it will be given twice, by injection under the skin, for 5 consecutive days each time (before and during treatment with Qarziba).

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Tell your doctor or nurse immediately if you experience any of the following adverse effects:

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

• rapid swelling of the arms, legs, and other body parts, rapid drop in blood pressure, dizziness, and difficulty breathing (capillary leak syndrome)
• stomach, throat, chest, face, hands, feet, legs, arms, back, neck, joint, or muscle pain
• allergic reactions and cytokine release syndrome with symptoms such as swelling of the face or throat, difficulty breathing, dizziness, hives, rapid or noticeable heartbeat, low blood pressure, skin rash, fever, or nausea

Other side effects and their frequencies are:

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

• fever, chills
• vomiting, diarrhea, constipation
• inflammation of the mouth and lips (stomatitis)
• cough
• itching, skin rash
• low blood pressure, increased heart rate
• oxygen deficiency
• tissue swelling (in the face, lips, around the eyes, in the lower limbs)
• weight gain
• infection, particularly catheter-related infection
• headache
• pupil dilation or abnormal pupillary reactions
• abnormal blood or urine test results (blood cells and other components, liver function, kidney function)

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

• potentially life-threatening infection (sepsis)
• seizures
• agitation, anxiety
• nerve disorder in the arms and/or legs (with abnormal sensation or weakness), dizziness, tremor, muscle spasms
• eye muscle paralysis, blurred vision, light sensitivity, retinal swelling
• high blood pressure
• heart failure, fluid around the heart
• respiratory failure, fluid in the lungs
• sudden narrowing of the airways (bronchospasm, laryngospasm), rapid breathing
• loss of appetite, nausea, abdominal distension, fluid accumulation in the abdominal cavity
• injection site reactions, skin problems such as redness, dry skin, eczema, excessive sweating, light reaction
• inability to urinate or reduced urine volume
• weight loss, fluid loss (dehydration)

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

• shock due to reduced body fluid volume
• blood clot formation in small blood vessels (disseminated intravascular coagulation)
• a type of allergy (serum sickness) with fever, skin rash, joint inflammation
• a brain disorder characterized by headache, confusion, seizures, and vision loss (reversible posterior encephalopathy syndrome)
• intestinal inflammation, liver injury
• kidney failure
• a disorder in which some of the small veins in the liver become blocked (veno-occlusive disease)

Frequency not known (cannot be estimated from available data):

• extreme tiredness and difficulty breathing (which may be due to low red blood cell count), bleeding and bruising (which may be due to low platelet count), and kidney disease with little or no urine output (atypical hemolytic uremic syndrome)

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or nurse, even if it is a side effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V.

By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Qarziba

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the label and carton after EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator (between 2 °C and 8 °C). Keep the vial in the outer packaging to protect it from light.

Once opened, Qarziba should be used immediately.

6. Contents of the container and other information

Composition of Qarziba

• The active substance is dinutuximab beta.

One millilitre of concentrate contains 4.5 mg of dinutuximab beta. Each vial contains 20 mg of dinutuximab beta in 4.5 ml.

• The other components are histidine, sucrose, polysorbate 20, water for injections, hydrochloric acid (for pH adjustment).

Appearance of the product and contents of the container

Qarziba is a colourless to slightly yellow liquid supplied in a clear glass vial with a rubber stopper and an aluminium cap.

Each carton contains 1 vial.

• Marketing Authorisation Holder

Recordati Netherlands B.V.

Beechavenue 54,

1119PW Schiphol-Rijk

The Netherlands

• Manufacturer

Patheon Italia S.P.A.

Via Morolense,

5 – 03013 Ferentino

Italy

Date of the most recent revision of this leaflet: {MM/YYYY}

Other sources of information

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

This information is intended for healthcare professionals only:

Qarziba is restricted exclusively to hospital use and must be administered under the supervision of a physician experienced in the use of oncological treatments. It must be administered by a healthcare professional prepared to manage severe allergic reactions such as anaphylaxis, in a setting where full resuscitation facilities are immediately available.

Posology

Treatment with dinutuximab beta consists of 5 consecutive cycles, each lasting 35 days. The individual dose is determined based on body surface area and should amount to a total of 100 mg/m² per cycle.

There are two possible modes of administration:

• continuous infusion over the first 10 days of each cycle (a total of 240 hours) with a daily dose of 10 mg/m²
• 5 daily infusions of 20 mg/m² administered over 8 hours on the first 5 days of each cycle.

If IL-2 is combined with dinutuximab beta, it should be administered as subcutaneous injections for 5 consecutive days, twice during each cycle. The first 5-day treatment should begin 7 days before the first dinutuximab beta infusion. The second 5-day IL-2 treatment should start concurrently with the dinutuximab beta infusion (days 1 to 5 of each cycle). IL-2 is administered at a dose of 6 × 10⁶ IU/m² per day, for a total dose of 60 × 10⁶ IU/m² per cycle.

Preparation of the infusion

The infusion solution must be prepared under aseptic conditions. The solution must not be exposed to direct sunlight or heat.

The patient-specific daily dose of Qarziba is calculated based on body surface area. Qarziba must be diluted under aseptic conditions to the patient-specific concentration/dose with a sodium chloride 9 mg/ml (0.9%) infusion solution containing 1% human albumin (e.g., 5 ml of 20% human albumin per 100 ml of sodium chloride solution).

• For continuous infusions, the infusion solution may be freshly prepared daily or in sufficient quantity for up to 5 days of continuous infusion. The maximum daily dose is 10 mg/m². The volume to be infused per day (in a 10-day treatment cycle) should be 48 ml, for a total of 240 ml for a 5-day dose. It is recommended to prepare 50 ml of solution in a 50 ml syringe, or 250 ml in an appropriate infusion bag compatible with the infusion pump used, i.e., with an overfill of 2 ml (syringe) or 10 ml (infusion bag) to account for residual volumes in the infusion systems.

• For repeated daily infusions, the daily dose is 20 mg/m², and the calculated dose must be diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solution containing 1% human albumin.

Administration of the infusion

The infusion solution must be administered via a peripheral or central intravenous route. If other medicinal products are administered concomitantly intravenously, they must be given through a separate infusion line. The container should be inspected visually for the presence of solid particles before administration. Use of an in-line filter of 0.22 µm during infusion is recommended.

For continuous infusions, any suitable infusion medical device delivering at a rate of 2 ml/h may be used, such as syringe drivers/infusion pumps or ambulatory electronic infusion pumps. It should be noted that elastomeric pumps are not considered suitable when used in combination with in-line filters.

Storage of the diluted solution

Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 °C (50 ml syringe) and for up to 7 days at 37 °C (250 ml infusion bag), following cumulative refrigerated storage (between 2 °C and 8 °C) for 72 hours.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the user is responsible for the storage periods and conditions during use, which should normally not exceed 24 hours at 2 °C to 8 °C, unless the dilution was performed under controlled and validated aseptic conditions.

Disposal

The disposal of unused medicine and all materials that have come into contact with it must be carried out in accordance with local regulations.