Unituxin
dinutuximab
dinutuximab
This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.
Occasionally a young person who is taking this medicne may be reading the package leaflet, but usually it will be a parent/carer. Nevertheless the leaflet will refer to ‘you’ throughout.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or nurse.
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What Unituxin is and what it is used for
What you need to know before you are given Unituxin
How Unituxin will be given
Possible side effects
How to store Unituxin
Contents of the pack and other information
Medicinal product no longer authorised
Unituxin is a cancer medicine that contains the active substance dinutuximab. It belongs to a group of medicines called ‘monoclonal antibodies’. These work like the antibodies produced naturally by the body. They help the immune system to target certain cells, such as cancer cells, by ‘sticking’ to them.
Unituxin is used to treat ‘high-risk neuroblastoma’ in babies, children and adolescents aged 12 months to 17 years old.
Neuroblastoma is a type of cancer that grows from abnormal nerve cells in the body. Some neuroblastomas are classed as ‘high risk’ if the cancer has spread to various parts of the body and contains certain types of cells. High-risk neuroblastomas are more likely to come back again after treatment.
To reduce the risk of the cancer coming back, Unituxin is given at the last stage of the treatment to eliminate small amounts of disease which may still be present after the cancer has responded to chemotherapy, surgery, and an autologous (self-donating) blood cell transplant.
Unituxin recognises and attaches to a cell surface target called ‘GD2’. GD2 is found on the surface of neuroblastoma cells. When Unituxin attaches to the GD2 on the cancer cells, the patient’s immune system starts to attack these cells and kill them.
Unituxin has been shown to delay the progression or relapse of the disease and to increase survival.
you are allergic to dinutuximab or any of the other ingredients of this medicine (listed in section 6).
If you are not sure, talk to your doctor or nurse before you are given dinutuximab.
Talk to your doctor or nurse before you are given Unituxin if:
you have ever had fits (convulsions)
you have liver problems
you have a low number of white blood cells or platelets in your blood – shown in tests
you have breathing problems such as shortness of breath when resting
you have kidney problems
you have any infections.
If any of the above apply to you (or you are not sure), talk to your doctor or nurse before being given Unituxin.
You might notice the following when you first receive Unituxin and during the course of treatment:
Medicinal product no longer authorised
See section 4 for a full list of known side effects.
Your doctor will do blood tests and may do eye tests while you are taking this medicine.
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines.
In particular, tell your doctor or nurse if you have recently received:
medicines called ‘corticosteroids’ – these can affect the activity of your immune system which is important for Unituxin to work.
‘intravenous immunoglobulin’ – you should not have this type of medicine in the two weeks before
Unituxin treatment and for at least one week after treatment has finished.
If any of the above apply to you (or you are not sure), tell your doctor or nurse before you are given Unituxin.
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or nurse for advice before being given this medicine.
If it is possible for you to become pregnant and you are not using contraception, talk to your doctor before being given this medicine.
It is recommended to use contraception for 6 months after discontinuation of this medicine.
If you are breastfeeding, talk to your doctor or nurse before being given this medicine.
You should not breastfeed during treatment with this medicine. This is because it is not known if the medicine can pass into breast-milk. The recommended interval time between treatment discontinuation and breastfeeding is 6 months.
Medicinal product no longer authorised
Unituxin has many side effects, and this will affect your ability to drive and use machines
This medicine contains less than 1 mmol sodium (23 mg) per dose. This means it is essentially ‘sodiumfree’.
Unituxin will be given to you by a doctor or nurse while you are in hospital. It is given as a drip into one of your veins (intravenous infusion).
Unituxin is used with three other medicines:
Isotretinoin
GM-CSF
IL-2
These medicines will be given to you over six courses. Each course lasts one month. You will not be given all of the medicines in every course.
Unituxin will be given to you in five of the six courses. The recommended dose is 17.5 mg/m2. Your doctor will work out your dose based on your body surface area.
Unituxin is given as a drip into one of your veins – for about 10 hours each day for four days.
GM-CSF is given as either an injection under the skin or as a drip into one of your veins each day for 14 days.
You will be given isotretinoin to take by mouth for the last 14 days of each course.
Unituxin is given as a drip into one of your veins – for about 10 hours each day for four days.
IL-2 is given as a drip into one of your veins for four days in a row (continuous infustion) – for the first four days of the first week and the first four days of the second week of each course.
You will be given isotretinoin to take by mouth for the last 14 days of each course.
You will only be given isotretinoin to take by mouth.
Your doctor or nurse will check you during and after the infusion. To reduce the risk of side effects, your doctor may increase the time allowed for the Unituxin infusion up to 20 hours. If you have any further questions on the use of this medicine, ask your doctor or nurse.
Like all medicines, this medicine, which is given with GM-CSF, IL-2 and isotretinoin can cause side effects, although not everybody gets them.
Any kind of allergic reaction or other reaction at the injection site – symptoms may include a skin rash, hives, swelling in the face or throat, dizziness, a rapid heart beat or palpitations, being short of breath and difficulty breathing, fever, feeling sick, aches and pains in your joints .
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Rapid swelling of the arms, legs and other parts of your body, rapid drop in blood pressure, lightheadedness and breathing difficulties (Capillary Leak Syndrome).
Any kind of pain: in the stomach, throat, chest, face, hands, feet, legs or arms (such as numbness, tingling or burning) back, neck, joint, bone, muscle, mouth, eye, genitals.
These are very common (may affect more than 1 in 10 people).
If you notice any of these effects, tell your doctor or nurse straight away.
cough
itching
loss of appetite
diarrhoea, being sick
low blood pressure that may make you feel dizzy or faint or high blood pressure
abnormal blood tests such as low platelets, low red or white blood cells, low level of albumin (this can cause swelling and make you feel weak and tired), abnormal liver function, low level of potassium,
sodium, calcium, phosphates, or high level of glucose.
weight loss, weight gain
chills
headache
feeling tired, irritable
constipation, blood in stools
damage to the nerves around the body which may affect movement
blurred vision, being sensitive to light, the pupils of your eyes staying large (‘dilated’)
not being able to urinate, blood or protein in your urine
higher risk of getting infections especially from the devices used to give you the medicine, blood or gut infections
skin problems where the injection was given, a red rash with small bumps
abnormal blood tests such as low levels of magnesium, glucose, high level of acids or creatinine.
unequal pupils
fluid in or around the lungs
kidney failure
over-active thyroid
serum sickness – an illness similar to an allergy
abnormal heart rhythm
swelling in the back part of the brain (Posterior Reversible Encephalopathy Syndrome) – symptoms may include high blood pressure, headache, fits, change in vision or behaviour, feeling drowsy or tired.
atypical haemolytic uraemic syndrome (aHUS) – an illness that affects the blood system and kidney –
symptoms may include flu-like symptoms that do not go away, confusion, lethargy, loss of appetite, or dark coloured urine.
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Keep this medicine out of the sight and reach of children.
Medicinal product no longer authorised
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C). Do not freeze. Keep the vial in the outer carton in order to protect from light.
Chemical and physical in-use stability has been demonstrated at ambient conditions (less than 25 °C). From a microbiological point of view, the diluted solution should be used immediately.
Do not use this medicine if you notice any particulate matter or discolouration prior to administration.
Do not throw away any medicines via wastewater or household waste. The doctor or nurse will throw away medicines you no longer use. These measures will help protect the environment.
The active substance is dinutuximab. Each vial contains 17.5 mg of dinutuximab in 5 mL. Each mL of
concentrate contains 3.5 mg of dinutuximab.
The other ingredients are histidine, polysorbate 20 (E 432), sodium chloride and water for injection. See section 2 for further information about sodium.
Unituxin is a clear, colourless solution for infusion, provided in a clear glass vial. One carton contains one vial.
United Therapeutics Europe, Ltd. Unither House
Curfew Bell Road
Chertsey Surrey KT16 9FG
United Kingdom
Tel: +44 (0)1932 664884
Fax: +44 (0)1932 573800
. There are also links to other websites about rare diseases and treatments.
This leaflet is available in all EU/EEA languages on the European Medicines Agency website.
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Medicinal product no longer authorised
Unituxin 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 a healthcare professional prepared to manage severe allergic reactions including anaphylaxis in an environment where full resuscitation services are immediately available.
Posology
Unituxin is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on Days 4–7 during Courses 1, 3, and 5 (each course lasting approximately 24 days) and on Days 8–11 during Courses 2 and 4 (each course lasting approximately 28 days).
The treatment regimen consists of dinutuximab, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses. The complete dosing regimen is outlined in Table 1 and Table 2.
Day | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15-24 |
GM-CSF1 | X | X | X | X | X | X | X | X | X | X | X | X | X | X | |
Dinutuximab2 | X | X | X | X | |||||||||||
Isotretinoin3 | X | X | X | X | X |
Granulocyte macrophage colony-stimulating factor (GM-CSF): 250 μg/m2/day, administered by either subcutaneous injection (strongly recommended) or intravenous infusion over 2 hours.
Dinutuximab: 17.5 mg/m2/day, administered by intravenous infusion over 10–20 hours.
Isotretinoin: for body weight greater than 12 kg: 80 mg/m2 administered orally twice daily for a total dose of 160 mg/m2/day; for body weight up to 12 kg: 2.67 mg/kg administered orally twice daily for a total daily dose of
5.33 mg/kg/day (round dose up to nearest 10 mg).
Day | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12-14 | 15-28 |
IL-21 | X | X | X | X | X | X | X | X | |||||
Dinutuximab2 | X | X | X | X | |||||||||
Isotretinoin3 | X |
Interleukin-2 (IL-2): 3 MIU/m2/day administered by continuous intravenous infusion over 96 hours on Days 1-4 and4.5 MIU/m2/day on Days 8-11.
Dinutuximab: 17.5 mg/m2/day, administered by intravenous infusion over 10-20 hours.
Isotretinoin: for body weight greater than 12 kg: 80 mg/m2 administered orally twice daily for a total dose of 160 mg/m2/day; for body weight up to 12 kg: 2.67 mg/kg administered orally twice daily for a total daily dose of
5.33 mg/kg/day (round dose up to nearest 10 mg).
Prior to starting each treatment course, refer to Table 3 for a list of criteria that must be evaluated.
Central nervous system (CNS) toxicity |
|
Hepatic dysfunction |
|
Thrombocytopenia |
|
Respiratory dysfunction |
|
Renal dysfunction |
|
Systemic infection or sepsis |
|
Leukopaenia |
|
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In addition to the above criteria, clinician judgement must be exercised in the evaluation of the patient’s cardiovascular functions.
Dose modification
Table 4 provides dose modification guidance for dinutuximab, GM-CSF and IL-2. If patients meet criteria for discontinuation of these medications, treatment may continue with isotretinoin as clinically indicated.
Allergic reactions | |
Grade 1 or 2 | |
Onset of symptoms |
|
After resolution |
|
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Grade 3 or 4 | |
Onset of symptoms |
|
After resolution |
and continue for the remainder of the course. rate without GM-CSF or IL-2. |
Recurrence |
|
Subsequent courses |
|
Anaphylaxis | |
Grade 3 or 4 | |
| |
Capillary leak syndrome | |
Grade 3 (severe) | |
Onset of symptoms |
|
After resolution |
|
Subsequent courses |
the remainder of the IL-2 courses. |
Grade 4(life-threatening) | |
Onset of symptoms |
|
Subsequent courses |
dinutuximab alone for subsequent GM-CSF courses. |
Hyponatraemia | |
Grade 4(life-threatening) - < 120 mmol/L despite appropriate fluid management | |
| |
Hypotension | |
Symptomatic and/or systolic BP less than 70 mmHg or a decrease that is more than 15% below baseline | |
Onset of symptoms |
|
After resolution |
|
increase the dinutuximab infusion to 1.75 mg/m2/h. | |
Recurrence |
|
After resolution |
for the remainder of the course. |
Subsequent courses |
remainder of the IL-2 courses. |
Neurological disorders of the eye | |
Dilated pupil with sluggish light reflex | |
Onset of symptoms |
|
After resolution |
|
Recurrence |
|
Subsequent courses |
1.75 mg/m2/h for subsequent courses.
|
Serum sickness | |
Grade 4 (life-threatening) | |
| |
Systemic infection or sepsis | |
Grade 3 or 4 | |
Onset of symptoms |
|
After resolution |
|
Pain | |
Grade 4 | |
| |
Peripheral neuropathy | |
Grade 2 peripheral motor neuropathy | |
| |
Grade 3 (sensory changes for more than 2 weeks, objective motor weakness) or Grade 4 | |
| |
Atypical Haemolytic Uraemic Syndrome | |
| |
Medicinal product no longer authorised
Paediatric population
The safety and efficacy of Unituxin in children aged less than 12 months have not yet been established. Method of administration
Unituxin should not be administered as an intravenous push or bolus. It should be administered by intravenous infusion over 10 hours. The infusion is started at a dose rate of 0.875 mg/m2/h and continued at this rate for 30 minutes; the rate is then increased to 1.75 mg/m2/h and continued at this rate for the remainder of the infusion, if tolerated. The infusion duration may be extended up to 20 hours to help minimise reactions during infusion that do not respond adequately to other supportive measures. The infusion must be terminated after 20 hours, even if the full dose cannot be delivered within this timeframe.
Pre-medication should always be considered before starting each infusion.
For instructions on dilution of the medicinal product before administration see section 6.6 of the SmPC.
Hypersensitivity (Grade 4) to the active substance or to any of the excipients listed in section 6.1 of the SmPC.
Allergic reactions
Antihistamine premedication (e.g. hydroxyzine or diphenhydramine) should be administered by intravenous injection approximately 20 minutes before starting each dinutuximab infusion. It is recommended that antihistamine medicinal product be repeated every 4–6 hours as required during infusion of Unituxin. Patients should be monitored for signs and symptoms of infusion reactions for 4 hours after the completion of the Unituxin infusion.
Medicinal product no longer authorised
Epinephrine (adrenaline) and hydrocortisone for intravenous administration should be immediately available at the bedside during administration of dinutuximab to manage life-threatening allergic reactions. It is recommended that treatment for such reactions include hydrocortisone administered by intravenous bolus, and epinephrine administered by intravenous bolus once every 3–5 minutes as necessary according to clinical response.
Depending on the severity of the allergic reaction, the rate of infusion should be reduced or treatment discontinued.
Capillary leak syndrome
Capillary leak syndrome is more likely when dinutuximab is co-administered with IL-2. It is recommended to administer oral metolazone or intravenous furosemide every 6–12 hours as required. Supplemental oxygen, respiratory support, and albumin replacement therapy should be used as necessary according to clinical response.
Characteristic symptoms and signs include hypotension, generalized oedema, ascites, dyspnoea, pulmonary oedema and acute renal failure associated with hypoalbuminaemia and haemoconcentration.
Pain
Severe pain (Grade 3 or 4) occurs most frequently during the first 4-day course of dinutuximab, often subsiding over time with subsequent courses.
For severe pain, the Unituxin infusion rate should be decreased to 0.875 mg/m2/hour. Unituxin should be discontinued if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures.
Paracetamol should be administered orally 20 minutes prior to starting each dinutuximab infusion, and repeated every 4-6 hours as needed. Regular dosing every 4–6 hours is recommended when IL-2 is coadministered. If required for persistent pain, ibuprofen should be administered orally every 6 hours between doses of paracetamol. Ibuprofen should not be administered if there is evidence of thrombocytopenia, bleeding, or renal dysfunction.
An opioid, such as morphine sulphate, is recommended to be administered by intravenous infusion prior to each dinutuximab infusion and continued as an intravenous infusion during and until 2 hours after completion of the treatment. It is recommended that additional intravenous bolus doses of an opioid are administered as needed for treatment of pain up to once every 2 hours during the dinutuximab infusion. If morphine is not tolerated, then fentanyl or hydromorphone may be utilised.
Lidocaine may be administered as an intravenous infusion (2 mg/kg in 50 mL of 0.9 % sodium chloride) over 30 minutes prior to the start of each dinutuximab infusion and continued via intravenous infusion at
1 mg/kg/h up to 2 hours after completion of the treatment. Lidocaine infusion should be discontinued if the patient develops dizziness, perioral numbness, or tinnitus.
Gabapentin may be administered at the time of starting morphine premedication, at an oral dose of 10 mg/kg/day. The dose may be subsequently increased (up to a maximum of 60 mg/kg/day or 3600 mg/day) as needed for pain management.
Hypotension
Intravenous sodium chloride 9 mg/mL (0.9%) solution for injection (10 mL/kg) should be administered over one hour just prior to the dinutuximab infusion. If hypotension occurs, this can be repeated, or intravenous albumin or packed red blood cells can be administered as clinically indicated. It is recommended that vasopressor therapy is also administered if necessary to restore an adequate perfusion pressure.
Neurological disorders of the eye
Eye disorders may occur, especially with repeated courses. These changes usually resolve over time. Patients should have an ophthalmic examination before initiating therapy and be monitored for visual changes.
Medicinal product no longer authorised
Hepatic dysfunction
Regular monitoring of liver function is recommended during dinutuximab immunotherapy.
Systemic infections
Patients typically have a central venous catheter in situ and as a consequence of prior ASCT are likely to be immunocompromised during therapy, and therefore, at risk of developing systemic infection. Patients should have no evidence of systemic infection and any identified infection should be under control before beginning therapy.
Laboratory test abnormalities
Electrolyte abnormalities have been reported in patients who received Unituxin. Electrolytes should be monitored daily during therapy with Unituxin.
Atypical Haemolytic Uraemic Syndrome
Haemolytic uraemic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anaemia, and hypertension has been reported. Supportive measures should be instituted including control of hydration status, electrolyte abnormalities, hypertension, and anaemia.
Sodium intake
This medicine contains less than 1 mmol sodium (23 mg) per dose. This means it is essentially ‘sodium free’.