Qarziba

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. This will allow for rapid identification of new safety information. You can help by reporting any adverse reactions you experience while taking this medicine. See the end of section 4 for information on how to report adverse reactions.
Please 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 questions, ask your doctor.
• If you get any side effects, including any not listed in this leaflet, talk to your doctor. See section 4.

Contents of this 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 called "monoclonal antibodies". These are proteins that specifically recognise and bind to other specific proteins in the body. Dinutuximab beta binds to the molecule known as disialoganglioside 2 (GD2), present on tumour cells, thereby activating the body's immune system to attack the tumour cells.
Qarziba is used for the treatment of neuroblastoma that carries a high risk of recurrence after a series of treatments, including stem cell transplantation to rebuild the immune system. It is also used for the treatment of neuroblastoma that has recurred (relapsed) or that may not have been completely cured by previous therapies.
Before treating relapsed neuroblastoma, the doctor will first stabilise any actively progressing disease using appropriate additional measures.
The doctor will also decide whether it is necessary to administer a second medicine, interleukin-2, concomitantly for the treatment of the cancer.
Neuroblastoma is a type of cancer arising from abnormal nerve cells in the body, particularly in the glands located above the kidneys. It is one of the most common types of cancer in childhood.
It is used in patients from 12 months of age.

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 had extensive chronic or acute graft-versus-host disease grade 3 or 4. This disease is a reaction in which transplanted tissue cells attack the recipient's cells.

Warnings and precautions
Before taking Qarziba, blood tests are required to check liver, lung, kidney, and bone marrow function.
When receiving your first dose of Qarziba and during the treatment cycle, you may experience the following:

• 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 an appropriate analgesic to be started 3 days before and continued during Qarziba treatment.

• Allergic reactions or other infusion-related reactions
  Contact your doctor or nurse if you experience any type of reaction during or after the infusion, such as:

  • fever, chills and/or low blood pressure
  • difficulty breathing
  • skin rashes, hives
    You will receive appropriate treatment to prevent such reactions and 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 sudden swelling in arms, legs, and other parts of the body. A sudden drop in blood pressure, dizziness, and difficulty breathing are further signs.

• Eye problems
  You may notice changes in vision.

• Nerve-related problems
  You may notice numbness, tingling, or burning sensations in hands, feet, legs, or arms, reduced sensitivity, or motor weakness.

• Problems affecting the spinal cord and brain (central nervous system, CNS)
  Inform your doctor or nurse if you experience any symptoms affecting the CNS, such as: substantial prolonged neurological deficit without apparent cause, including muscle weakness or loss of muscle strength in legs (or arms), mobility problems, unusual sensations, or numbness. Also report sudden or persistent headache, progressive loss of memory and cognitive ability, mild personality changes, inability to concentrate, or progressive loss of consciousness.

Inform your doctor immediately if you notice any of these problems.
Your doctor may decide to stop treatment if any of the above-mentioned problems occur. In some cases, you may resume treatment after a pause or at a reduced rate, but sometimes treatment will need to be permanently discontinued.
Your doctor will prescribe blood tests and likely eye examinations while you are taking this medicine.

Children
This medicine should not be prescribed to children under 12 months of age, as there is insufficient experience in this age group.

Other medicines and Qarziba
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Do not use medicines that suppress the immune system starting 2 weeks before the first dose of Qarziba and until 1 week after the last treatment cycle, unless prescribed by your doctor. Examples of medicines that suppress the immune system include corticosteroids used to reduce inflammation or prevent organ transplant rejection.
Avoid vaccinations during treatment with Qarziba and for 10 weeks following.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor before taking this medicine.
Speak to your doctor before using Qarziba if you are of childbearing age. You are advised to use contraception for 6 months after stopping treatment with Qarziba. You may only use Qarziba if your doctor determines that the benefits outweigh the risks to the fetus.
Inform your doctor if you are breastfeeding. Do not breastfeed during treatment with Qarziba and for 6 months after the last dose. It is not known whether the medicine passes into breast milk.

Driving and using machines
Qarziba has numerous side effects that may affect your ability to drive vehicles or operate machinery. Do not perform these activities if your concentration or reaction ability is impaired.

3. How to use Qarziba

Your treatment will be supervised by a doctor experienced in the use of anticancer medications.
It will be administered to you by a doctor or nurse while you are in hospital. It will be given intravenously (intravenous infusion), usually through special lines (catheters) and a pump. During and after the infusion, you will be monitored regularly for any infusion-related adverse effects.
Qarziba will be administered in five treatment cycles of 35 days each, with the infusion lasting 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 height and weight.
If your doctor decides to administer interleukin-2 concomitantly, it will be given twice, by subcutaneous injection, each time for 5 consecutive days (before and during treatment with Qarziba).

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Contact your doctor or nurse immediately if you notice any of the following:
Very common (may affect more than 1 in 10 people):

• sudden swelling of arms, legs and other parts of the body, sudden drop in blood pressure, dizziness and breathing difficulties (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 and throat, difficulty breathing, dizziness, hives, noticeable or rapid heartbeat, low blood pressure, rash, fever or nausea.

Other side effects and their frequency include:
Very common (may affect more than 1 in 10 people):

• fever, chills
• vomiting, diarrhoea, constipation
• inflammation of the mouth (stomatitis)
• cough
• itching, rash
• low blood pressure, rapid heartbeat
• oxygen deficiency
• tissue swelling (in face, lips, around eyes, lower limbs)
• weight gain
• infection, especially catheter-related infection
• headache
• dilated pupils or abnormal pupil reactions
• abnormal blood and urine tests (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 disorders in arms and/or legs (with abnormal sensations 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 airway obstruction (bronchospasm, laryngospasm), laboured breathing
• decreased appetite, nausea, abdominal bloating, fluid accumulation in the abdominal cavity
• injection site reactions, skin problems such as redness, dry skin, eczema, excessive sweating, light sensitivity
• inability to urinate or reduced urine flow
• weight loss, fluid loss (dehydration)

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

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

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse.
You can also report side effects directly via the national reporting system detailed in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store 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 packaging following "Exp". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C). Keep the vial in the outer packaging to protect the medicine from light.
Once opened, Qarziba must be used immediately.

6. Package contents and other information

What Qarziba contains

• The active substance is dinutuximab beta. 1 mL 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).

Description of the appearance of Qarziba and contents of the pack
Qarziba is a liquid, colourless to slightly yellow, supplied in a clear glass vial with a rubber stopper and aluminium seal.
Each pack contains 1 vial.

• Marketing Authorisation Holder Recordati Netherlands B.V. Beechavenue 54, 1119PW Schiphol-Rijk Netherlands
• Manufacturer Millmount Healthcare Ltd Block 7, City North Business Campus Stamullen, Co. Meath K32 YD60 Ireland

Patheon Italia S.P.A.
Via Morolense,
5 – 03013 Ferentino
Italy

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and their therapeutic treatments are provided.

The following information is intended for healthcare professionals only

Qarziba is restricted to hospital use only and must be administered under the supervision of a physician experienced in the use of oncological therapies. It must be administered by healthcare professionals trained in the management of severe allergic reactions, including anaphylaxis, in a setting where resuscitation facilities are immediately available.

Dosage

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

Two modes of administration are possible:

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

If IL-2 is administered in combination with dinutuximab beta, it should be given subcutaneously for 5 consecutive days, twice per cycle. The first 5-day treatment should start 7 days before the first infusion of dinutuximab beta. The second 5-day treatment with IL-2 should start simultaneously with the dinutuximab beta infusion (days 1 to 5 of each cycle). IL-2 is administered at a dose of 6x10⁶ IU/m²/day, for a total dose of 60x10⁶ IU/m² per cycle.

Preparation of the infusion solution

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

The patient-specific daily dose of Qarziba is calculated based on body surface area. Qarziba must be aseptically diluted according to the patient-specific concentration/dose with sodium chloride 9 mg/mL (0.9%) for infusion 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 prepared daily or in sufficient quantity for up to 5 days of continuous infusion. The daily dose is 10 mg/m². The volume to be administered daily (over a 10-day treatment cycle) must be 48 mL; 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 infusion bag compatible with the infusion pump used, i.e., with an overfill of 0.2 mL (syringe) or 10 mL (infusion bag) to compensate for the "dead volume" of 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%) containing 1% human albumin.

Administration of the infusion

The infusion solution must be administered via a central or peripheral intravenous line. Other intravenous agents administered concomitantly must be delivered using a separate infusion line. The container should be inspected visually for particulate matter prior to administration. Use of a 0.22-micron in-line filter during infusion is recommended.

For continuous infusions, any medical device suitable for infusions at a rate of 2 mL/hour may be used, e.g., syringe infusion pump/infusers, ambulatory electronic infusion pump. Note that elastomeric pumps are not considered suitable when used in conjunction 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 (in a 50 mL syringe) and up to 7 days at 37°C (in a 250 mL infusion bag), provided that cumulative refrigerated storage (2°C–8°C) does not exceed 72 hours.

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

Disposal

Any unused medicine or waste material derived from this medicine must be disposed of in accordance with local regulations.