Consumer medicine information

Qarziba

Dinutuximab beta

BRAND INFORMATION

Brand name

Qarziba

Active ingredient

Dinutuximab beta

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Qarziba.

What is in this leaflet

This leaflet answers some common questions about QARZIBA. It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking QARZIBA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor.

Keep this leaflet with the medicine. You may need to read it again.

What QARZIBA is used for

QARZIBA contains dinutuximab beta, which belongs to a group of medicines called ‘monoclonal antibodies’. These are proteins, which specifically recognise and bind to other unique proteins in the body. Dinutuximab beta binds to the molecule known as disialoganglioside 2 (GD2), which is present on cancer cells, and this activates the body’s immune system, causing it to attack the cancer cells.

QARZIBA is used to treat neuroblastoma that has a high risk of coming back after a series of treatments and who have achieved at least a partial response.

Neuroblastoma is a type of cancer that grows from abnormal nerve cells in the body, in particular in the glands above the kidneys. It is one of the most common cancers in infancy.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you start QARZIBA

When you must not have it

Do not take QARZIBA:

  • If you are allergic to dinutuximab beta or any of the other ingredients of this medicine (listed at the end of this leaflet)
  • If you have acute grade 3 or 4, or extensive long-lasting graft-versus-host disease

This disease is a reaction in which cells of transplanted tissue attack cells of the recipient).

Do not have this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If the medicine has expired or is damaged, your doctor will return it to the hospital pharmacist for disposal.

Before you start treatment

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Warnings and precautions

Before receiving QARZIBA, you will have blood tests to check your liver, lung, renal and bone marrow functions.

You might notice the following 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 infusion. Therefore, your doctor will give you an appropriate pain treatment starting 3 days before and continuing during use of QARZIBA.
  • Allergic reactions or other infusion-related reactions:
    Tell your doctor or nurse if you have any kind of reaction during or after the infusion, such as:
    - fever, shivering and/or low blood pressure
    - difficulties in breathing
    - skin rash, hives
    You will receive appropriate treatment to prevent these reactions and be closely monitored for these symptoms during infusion of QARZIBA.
  • Leakage from small blood vessels (capillary leak syndrome):
    Leakage of blood components from small blood vessels may cause rapid swelling in arms, legs and other parts of the body. Rapid drop in blood pressure, light-headedness and breathing difficulties are further signs.
  • Eye problems:
    You may notice changes to your vision.
  • Problems with your nerves:
    You may notice numbness, tingling or burning in your hands, feet, legs or arms, reduced sensation or weakness with movement.
  • Spinal cord and brain problems (central nervous system, CNS)
    Tell your doctor or nurse if you have any kind of CNS symptoms, such as: substantial prolonged neurological deficit without apparent reason such as muscle weakness or loss of muscle strength in the legs (or arms), or mobility problems or unusual sensations and numbness. Persistent or sudden onset of a headache, or progressive loss of memory and cognitive ability, subtle personality changes, inability to concentrate, lethargy, and progressive loss of consciousness

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

Your doctor may decide to stop your treatment if you have any of the problems mentioned here. In some cases your treatment may be able to start again after a break or at a slower rate, but sometimes it may need to be stopped completely.

Your doctor will do blood tests and may do eye tests while you are taking this medicine.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Talk to your doctor before you receive QARZIBA if you are of childbearing age. It is recommended to use contraception for 6 months after discontinuation of treatment with QARZIBA. You may only use QARZIBA if your doctor assesses that benefits outweigh risks for a foetus.

Tell your doctor if you are breast-feeding. Do not breast-feed during treatment with QARZIBA and for 6 months after the last dose. It is not known if the medicine can pass into breast-milk.

Taking other medicines

Tell your doctor if you are using, have recently used or might use 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 course, unless prescribed by your doctor. 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 afterwards.

How to take QARZIBA

A doctor experienced in the use of medicines to treat cancer will direct your treatment. The administration of the medicine will be started by a doctor or nurse while you are in hospital. It is given into one of your veins (intravenous infusion) usually by using special tubes (catheters) and a pump. During and after the infusion, you will be checked regularly for infusion-related side effects.

QARZIBA will be given to you in five treatment courses of 35 days and the infusion will last 5 or 10 days in the beginning of each course. The recommended dose for patients weighing over 12 kg is 100 mg dinutuximab beta per square metre of body surface per treatment course. The recommended dose for patients weighing over 5 kg but below 12 kg is 3.3 mg/kg per course. The doctor will calculate your body surface area from your height and weight.

While you are using QARZIBA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking QARZIBA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things to be careful of

QARZIBA has several side effects that may affect your ability to drive and use machines. Do not perform these activities if your ability to concentrate and react is affected.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking QARZIBA.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately if you have any of the following:

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

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

Other side effects and their frequencies include:

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

  • fever, chills
  • vomiting, diarrhoea, constipation
  • inflammation of the mouth and lips (stomatitis)
  • cough
  • itching, rash
  • low blood pressure, increased heartbeat
  • oxygen deficiency
  • tissue swelling (in the face, lip, around the eye, in the lower limbs)
  • increased weight
  • infection, in particular infection associated with the catheter that delivers the medicine
  • headache
  • dilated pupils or abnormal pupil reactions
  • abnormal blood or urine tests (blood cells and other components, liver function, renal function)

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

  • life-threatening infection (sepsis)
  • fits
  • agitation, anxiety
  • nerve disorder in the arms and/or legs (with abnormal sensations or weakness), light-headedness, trembling, muscle spasms
  • paralysis of eye muscles, blurred vision, light sensitivity, swelling in the retina
  • high blood pressure
  • cardiac failure, fluid around the heart
  • respiratory failure, fluid in the lungs
  • sudden constriction of the airways (bronchospasm, laryngospasm), rapid breathing
  • decreased appetite, nausea, abdominal distension, accumulation of fluid in the abdominal cavity
  • injection-site reactions, skin problems such as reddening, dry skin, eczema, excessive sweating, reaction to light
  • unable to pass urine or passing reduced urine volume
  • decreased weight, loss of fluids (dehydration)

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

  • shock due to decreased body fluid volume
  • formation of blood clots in the small blood vessels
  • a type of allergy (serum sickness) with fever, rash, joint inflammation
  • a brain disorder characterised by headache, confusion, seizures and loss of vision
  • inflammation of the intestine, injury to the liver
  • kidney failure
  • a condition in which some of the small veins in the liver are obstructed

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using QARZIBA

Storage

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. 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 carton in order to protect from light.

Once opened, QARZIBA is intended for immediate use. Opened vials not immediately used are to be discarded.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Product description

What it looks like

QARZIBA is a colourless to slightly yellow liquid provided in a clear glass vial with a rubber stopper and aluminium seal.

Each carton contains 1 single use vial.

Ingredients

The active substance is dinutuximab beta. 1 mL concentrate contains 4.5 mg dinutuximab beta. Each vial contains 20 mg dinutuximab beta in 4.5 mL.

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

Distributor/Supplier

QARZIBA is distributed/supplied in Australia by:

Recordati Rare Diseases Australia Pty Ltd
Suite 1802, Level 18, 233
Castlereagh Street,
Sydney, NSW, 2000
Australia
Phone: +61 (0) 408 061 403
[email protected]

Under licence from EUSA Pharma (UK) Limited.

This leaflet was prepared in April 2023.

AUST R 321016

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Qarziba

Active ingredient

Dinutuximab beta

Schedule

S4

 

1 Name of Medicine

Qarziba (dinutuximab beta).

2 Qualitative and Quantitative Composition

1 mL of concentrate contains 4.5 mg dinutuximab beta.
Each vial contains 20 mg dinutuximab beta in 4.5 mL.
Dinutuximab beta is a mouse-human chimeric monoclonal IgG1 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for solution for infusion. Colourless to slightly yellow liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Qarziba is indicated for the treatment of high-risk neuroblastoma in patients who have previously received induction chemotherapy and achieved at least a partial response.

4.2 Dose and Method of Administration

Qarziba must be administered under the direction of a physician experienced in the use of oncological therapies. The infusion must be initiated by a healthcare professional prepared to manage severe allergic reactions including anaphylaxis in an environment where full resuscitation services are immediately available.

Dosage.

Treatment with Qarziba consists of 5 consecutive courses, each course comprising 35 days.
For patients weighing > 12 kg, the individual dose is determined based on the body surface area and should be a total of 100 mg/m2 per course.
For patients weighing > 5 kg and ≤ 12 kg, the individual dose is determined based on body weight and should be a total of 3.3 mg/kg per course.
Two modes of administration are possible:
a continuous infusion over the first 10 days of each course (a total of 240 hours) at the daily dose of 10 mg/m2 (for patients weighing > 12 kg) or 0.33 mg/kg (for patients weighing > 5 kg and ≤ 12 kg);
or five daily infusions of 20 mg/m2 (for patients weighing > 12 kg) or 0.66 mg/kg (for patients weighing > 5 kg and ≤ 12 kg) administered over 8 hours, on the first 5 days of each course.
Prior to starting each treatment course, the following clinical parameters should be evaluated and treatment should be delayed until these values are reached:
pulse oximetry > 94% on room air;
adequate bone marrow function: absolute neutrophil count ≥ 500/microL, platelet count ≥ 20,000/microL, haemoglobin > 8.0 g/dL;
adequate liver function: alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) < 5 times upper limit of normal (ULN);
adequate renal function: creatinine clearance or glomerular filtration rate (GRF) > 60 mL/min/1.73 m2.

Method of administration.

Qarziba is for intravenous infusion. The solution should be administered via a peripheral or central intravenous line. Other intravenously co-administered agents should be delivered via a separate infusion line (see Section 6.6 Special Precautions for Disposal).
For continuous infusions, the solution is administered at a rate of 2 mL per hour (48 mL per day) using an infusion pump.
For 8 hour daily infusions, the solution is administered at a rate of approximately 13 mL per hour.
Pre-medication should always be considered before starting each infusion (see Section 4.4 Special Warnings and Precautions for Use).
For instructions on dilution of the medicinal product before administration, see Section 6.4 Special Precautions for Storage.
Product is for single use in one patient only. Discard any residue.

Dosage adjustment.

Based on the physician's evaluation of the severity of adverse drug reactions to dinutuximab beta, patients may undergo a dose reduction of 50% or a temporary interruption of the infusion. As a consequence, either the infusion period is prolonged or, if tolerated by the patient, the infusion rate may be increased up to 3 mL/h (continuous infusion), in order to administer the total dose. See Table 1.
Treatment with dinutuximab beta should be permanently discontinued if the following toxicities occur:
grade 3 or 4 anaphylaxis;
prolonged grade 2 peripheral motor neuropathy;
grade 3 peripheral neuropathy;
grade 3 vision eye toxicity;
grade 4 hyponatremia (< 120 mEq/L) despite appropriate fluid management, recurrent or grade 4 capillary leak syndrome (requires ventilator support);
severe central neurotoxicity that includes grade 3 or 4 with substantial prolonged neurological deficit without any detectable reason, recurrent grade 1-3 neurotoxicity, and permanent neurological deficit;
all grades of posterior reversible encephalopathy syndrome and transverse myelitis.

Renal and hepatic impairment.

There are no data in patients with renal and hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.
Acute grade 3 or 4, or extensive chronic graft-versus-host disease (GvHD).

4.4 Special Warnings and Precautions for Use

Identified precautions.

Pain.

Neuropathic pain usually occurs at the beginning of the treatment and premedication with analgesics, including intravenous opioids, prior to each infusion of dinutuximab beta is required. A triple therapy, including nonopioid analgesics (according to WHO guidelines), gabapentin and opioids, is recommended for pain treatment. The individual dose may vary widely.

Nonopioid analgesics.

Nonopioid analgesics should be used permanently during the treatment, e.g. paracetamol or ibuprofen.

Gabapentin.

The patient should be primed with 10 mg/kg/day, starting 3 days prior to dinutuximab beta infusion. The daily dose of gabapentin is increased to 2 x 10 mg/kg/day orally, the next day and to 3 x 10 mg/kg/day orally, the day before the onset of dinutuximab beta infusion and thereafter. The maximum single dose of gabapentin is 300 mg. This dosing schedule should be maintained for as long as required by the patient.
Oral gabapentin should be tapered off after weaning off intravenous morphine infusion, at the latest after dinutuximab beta infusion therapy has stopped.

Opioids.

Treatment with opioids is standard with dinutuximab beta. The first infusion day and course usually requires a higher dose than subsequent days and courses.
Before initiation of a continuous intravenous morphine infusion, a bolus infusion of 0.02 to 0.05 mg/kg/hour morphine should be started 2 hours before dinutuximab beta infusion.
Subsequently, a dosing rate of 0.03 mg/kg/hour is recommended concomitantly with dinutuximab beta infusion.
With daily infusions of dinutuximab beta, morphine infusion should be continued at a decreased rate (e.g. 0.01 mg/kg/h) for 4 hours after the end of dinutuximab beta infusion.
With continuous infusion, in response to the patient's pain perception, it may be possible to wean off morphine over 5 days by progressively decreasing its dosing rate (e.g. to 0.02 mg/kg/hour, 0.01 mg/kg/hour, 0.005 mg/kg/hour).
If continous morphine infusion is required for more than 5 days, treatment should be gradually reduced by 20% per day after the last day of dinutuximab beta infusion.
After weaning off intravenous morphine, in case of severe neuropathic pain, oral morphine sulphate (0.2 to 0.4 mg/kg every 4 to 6 hours) can be administered on demand. For moderate neuropathic pain, oral tramadol may be administered.

Hypersensitivity reactions.

Severe infusion-related reactions, including cytokine release syndrome (CRS), anaphylactic and hypersensitivity reactions, may occur despite the use of premedication. Occurrence of a severe infusion related reaction (including CRS) requires immediate discontinuation of dinutuximab beta therapy and may necessitate emergency treatment.
Cytokine release syndrome frequently manifests itself within minutes to hours of initiating the first infusion and is characterised by systemic symptoms such as fever, hypotension and urticaria.
Anaphylactic reactions may occur as early as within a few minutes of the first infusion with dinutuximab beta and are commonly associated with bronchospasm and urticaria.

Premedication.

Antihistamine premedication (e.g. diphenhydramine) should be administered by intravenous injection approximately 20 minutes before starting each dinutuximab beta infusion. It is recommended that antihistamine administration be repeated every 4 to 6 hours as required during dinutuximab infusion.
Patients should be closely monitored for anaphylaxis and allergic reactions, particularly during the first and second treatment course.

Treatment of hypersensitivity reactions.

Intravenous antihistamine, epinephrine (adrenaline) and prednisolone for intravenous administration should be immediately available at the bedside during administration of dinutuximab beta to manage life-threatening allergic reactions. It is recommended that treatment for such reactions include prednisolone administered by intravenous bolus, and epinephrine administered by intravenous bolus every 3 to 5 minutes as necessary, according to clinical response. In case of bronchial and/or pulmonary hypersensitivity reaction, inhalation with epinephrine (adrenaline) is recommended and should be repeated every 2 hours, according to clinical response.

Capillary leak syndrome (CLS).

CLS is characterised by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS usually develops within hours after initiation of treatment, while clinical symptoms (i.e. hypotension, tachycardia) are reported to occur after 2 to 12 hours. Careful monitoring of circulatory and respiratory function is required.

Neurological disorders of the eye.

Eye disorders may occur as dinutuximab beta binds to optic nerve cells. No dose modification is necessary in the case of an impaired visual accommodation that is correctable with eye glasses, as long as this is judged to be tolerable.
Treatment must be interrupted in patients who experience Grade 3 vision toxicity (i.e. subtotal vision loss per toxicity scale). In case of any eye problems, patients should be referred promptly to an ophthalmology specialist.

Peripheral neuropathy.

Occasional occurrences of peripheral neuropathy have been reported with Qarziba. Cases of motor or sensory neuropathy lasting more than 4 days must be evaluated and noninflammatory causes, such as disease progression, infections, metabolic syndromes and concomitant medication, should be excluded.
Treatment should be permanently discontinued in patients experiencing any objective prolonged weakness attributable to dinutuximab beta administration. For patients with moderate (Grade 2) neuropathy (motor with or without sensory), treatment should be interrupted and may be resumed after neurologic symptoms resolve.

Central neurotoxicity.

Central neurotoxicity has been reported following treatment with Qarziba. If central neurotoxicity occurs the infusion should be interrupted immediately and the patient treated symptomatically, other influencing factors such as active infection, metastatic spread of neuroblastoma to CNS, neurotoxic concomitant medications should be ruled out.
Treatment with dinutuximab beta should be permanently discontinued following the occurrence of severe neurotoxicity that includes grade 3 or 4 central neurotoxicity with substantial prolonged neurological deficit without any detectable reason, recurrent grade 1-3 neurotoxicity and/or permanent neurological deficit and all grades of posterior reversible encephalopathy syndrome and transverse myelitis.

Systemic infections.

Patients are likely to be immunocompromised as a result of prior therapies. As they typically have a central venous catheter in situ, they are at risk of developing systemic infection.
Patients should have no evidence of systemic infection and any identified infection should be under control before starting therapy.

Haematologic toxicities.

Occurrence of haematologic toxicities has been reported with Qarziba, such as erythropenia, thrombocytopenia or neutropenia. Grade 4 haematologic toxicities, improving to at least Grade 2 or baseline values by start of next treatment course, do not require dose modification.

Laboratory abnormalities.

Regulatory monitoring of liver function and electrolytes is recommended.

Use in the elderly.

No data available.

Paediatric use.

Data in children aged less than 12 months are limited.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed. A risk for indirect reduction of CYP activity due to higher TNF-α and IL-6 levels and, therefore, interactions with concomitantly used medicinal products, cannot be excluded.

Corticosteroids.

Due to their immunosuppressive activity, concomitant treatment with corticosteroids is not recommended within 2 weeks prior to the first treatment course until 1 week after the last treatment course with dinutuximab beta, except for life-threatening conditions.

Vaccinations.

Vaccinations should be avoided during administration of dinutuximab beta until 10 weeks after the last treatment course, due to immune stimulation through dinutuximab beta and possible risk for rare neurological toxicities.

Intravenous immunoglobulin.

Concomitant use of intravenous immunoglobulins is not recommended as they may interfere with dinutuximab beta-dependent cellular cytotoxicity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of dinutuximab beta on fertility in humans are unknown. In animals, dedicated fertility studies have not been conducted, but no adverse effects on reproductive organs were observed in toxicity studies performed in Guinea pig and cynomolgus monkey.
Qarziba should not be used in women of childbearing potential not using contraception. It is recommended that women of childbearing potential use contraception for 6 months after discontinuation of treatment with dinutuximab beta.
(Category C)
There are no data on pregnant women. No animal data are available on teratogenicity or embryotoxicity. Dinutuximab beta target (GD2) is expressed on neuronal tissues, especially during embryofetal development, and may cross the placenta; therefore, Qarziba may cause fetal harm when administered to pregnant women.
Qarziba should not be used during pregnancy.
 There are no data on lactating women. It is unknown whether dinutuximab beta is excreted in human milk. Breast-feeding should be discontinued during treatment with Qarziba and for 6 months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Dinutuximab beta has major influence on the ability to drive and use machines. Patients should not use or drive machines during treatment with dinutuximab beta.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety of dinutuximab beta has been evaluated in 628 patients with high-risk and relapsed/refractory neuroblastoma, who received it as a continuous infusion (212) or as repeated daily infusions (416). It was combined with 13-cis retinoic in most patients and with IL-2 in 307 patients.
The most common adverse reactions were pyrexia (88%) and pain (77%) that occurred despite analgesic treatment. Other frequent adverse reactions were hypersensitivity (74.1%), vomiting (57%), diarrhoea (51%), capillary leak syndrome (40%), anaemia (72.3%), neutropenia (52%), thrombocytopenia (49.6%) and hypotension (42.2%).

Tabulated list of adverse reactions.

Adverse reactions reported in clinical trials are listed by system organ class and by frequency and summarised in Table 2. These adverse reactions are presented by MedDRA system organ class and frequency. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The type of adverse reactions seen in the post-marketing setting is consistent with the reactions seen in clinical trials.

Description of selected adverse reactions.

Hypersensitivity.

The most frequent hypersensitivity reactions included hypotension (42.2%), urticaria (18%) and bronchospasm (5.3%). Cytokine release syndrome was also reported in 32% of the patients. Serious anaphylactic reactions occurred in 3.5% of the patients.

Pain.

Pain typically occurs during the first infusion of dinutuximab beta and decreases over the treatment courses. Most commonly, patients reported abdominal pain, pain in the extremities, back pain, chest pain, or arthralgia.

Capillary leak syndrome (CLS).

Overall, 10% of CLS were severe (grade 3-4) and their frequency decreased over the treatment courses.

Eye problems.

These included impaired visual accommodation that is correctable with eyeglasses, as well as mydriasis (13%), periorbital oedema and eyelid oedema (7.1%), blurred vision (3%) or photophobia (3%), which were usually reversible after treatment discontinuation. Severe eye disorders were also reported including ophthalmoplegia (2%) and optic atrophy.

Peripheral neuropathy.

Both motor and sensory peripheral neuropathies have been reported, overall in 9% of the patients. Most events were of grade 1-2 and resolved.

Central neurotoxicity.

Reports of central neurotoxicity and severe neurotoxicity have been received including posterior reversible encephalopathy syndrome (0.7%) and seizures (1.7%).

Safety profile with and without IL-2.

The combination of Qarziba with IL-2 increases the risk of adverse drug reactions compared to Qarziba without IL-2, especially for pyrexia (92% vs. 79%), CLS (50% vs. 25%), pain related to dinutuximab beta (75% vs. 63%), hypotension (43% vs. 26%), and peripheral neuropathy (14% vs. 7%), respectively.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) or 0800 764 766 (New Zealand).
No cases of dinutuximab beta overdose have been reported.
In the case of overdose, patients should be carefully observed for signs or symptoms of adverse reactions and supportive care administered, as appropriate.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC16.

Mechanism of action.

Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells.
Dinutuximab beta has been shown in vitro to bind to neuroblastoma cell lines known to express GD2 and to induce both complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC). In the presence of human effector cells, including peripheral blood mononuclear cells from normal human donors, dinutuximab beta was found to mediate the lysis of human neuroblastoma and melanoma cell lines expressing GD2 in a dosedependent manner. Additionally, in vivo studies demonstrated that dinutuximab beta could suppress liver metastasis in a syngeneic liver metastasis mouse model.
Neurotoxicity associated to dinutuximab beta is likely due to the induction of mechanical allodynia that may be mediated by the reactivity of dinutuximab beta with the GD2 antigen located on the surface of peripheral nerve fibres and myelin.

Clinical trials.

The efficacy of dinutuximab beta has been evaluated in a randomised controlled trial comparing the administration of dinutuximab beta with or without IL-2 in the first-line treatment of patients with high-risk neuroblastoma and in two single-arm studies in the relapsed/refractory setting.

First-line patients who received autologous stem cell transplantation.

In study 3, patients with high-risk neuroblastoma were enrolled after they had received induction chemotherapy and achieved at least a partial response, then myeloablative therapy and stem cell transplantation. Patients with progressive disease were excluded. Dinutuximab beta was administered at a dose of 20 mg/m2/day on 5 consecutive days, given by 8-hour intravenous infusion in a 5-week treatment course, and was combined with 13-cis-RA and with or without additional subcutaneous IL-2 at the same posologies as in the previous studies.
A total of 370 patients were randomised and received treatment. These included 64% male and 36% female patients with a median age of 3 years (0.6 to 20); 89% had a tumour INSS stage 4 and MYCN amplification was reported in 44% of the cases. The primary efficacy endpoint was 3-year EFS and secondary endpoint was OS. EFS and OS rates are presented in Tables 3 and 4 according to the evidence of disease at baseline.
For patients without evidence of disease at baseline, addition of IL-2 did not improve EFS and OS.

Immunogenicity.

The development of anti-drug antibodies is a class effect of monoclonal chimeric antibodies. Overall, measurable ADA titres were detected in 65 (62%) of the 105 patients examined.
Given the limitation of the bioanalytical methods, data are currently insufficient to properly evaluate the impact of the formation of anti-drug antibodies on pharmacokinetic and pharmacodynamic parameters, as well as on the efficacy and safety of dinutuximab beta.

5.2 Pharmacokinetic Properties

Absorption and distribution.

Calculations of pharmacokinetic parameters for dinutuximab beta are based upon measurements using non-validated bioanalytical methods. This has to be taken into consideration when interpreting PK parameters (Cmax, exposure, half-life) listed below.
The pharmacokinetics of dinutuximab beta, based on 10-day continuous intravenous infusion of 10 mg/m2/day (equal to a total dose of 100 mg/m2/course) were evaluated in studies 1 and 2. Mean plasma Cmax levels (around 12 microgram/mL) were reached on the last day of infusion. Mean plasma Cmax levels, observed during 8-hour infusions (20 mg/m2/day on five consecutive days), were determined in another study (n=15). The observed Cmax levels were slightly higher (16.5 microgram/mL) and were reached on the fifth infusion.

Metabolism.

Dinutuximab beta is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed.

Excretion.

The half-life observed in studies 1 and 2 was in the range of 190 hours, i.e. 8 days.

Special population.

A population pharmacokinetic modelling approach was used to investigate the influence of covariates. The population pharmacokinetic model included allometric scaling (reference weight of 18.1 kg) on clearance and volume of distribution with exponents of 0.75 and 1, respectively.
The exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion) is predicted to be similar in subjects with ages less than or equal to 12 years and decreases slightly for older, heavier subjects. Effects of gender and age were not found to influence the pharmacokinetics of dinutuximab beta but data in children less than 2 years of age are very limited and insufficient to support dosing.
An effect of ADA formation on the volume of distribution was found (increase of 37% in volume). Therefore, ADA formation would be predicted to have a slight impact (less than 10% decrease) on exposure within 24 hours after administration, under non-steady state conditions. After reaching steady state, no difference in exposure is predicted, with and without ADA formation.
Markers for renal (eGFR) and hepatic (bilirubin) function did not show a relationship with exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion).

5.3 Preclinical Safety Data

General toxicology.

Dinutuximab beta has been administered to male and female juvenile Guinea pigs, as well as male and female young cynomolgus monkeys, as repeat-dose regimens that exceeded the recommended clinical dose. Findings of note included changes (decrease) in thymus weight as well as bone marrow changes (atrophy affecting myeloid and erythroid precursor cell lines), reduced activity, food consumption and body weight gain possibly due to pain associated with drug treatment. The bone marrow changes were slight to severe and recovered after cessation of dosing. No effects on cardiovascular functions (ECG, blood pressure) were observed in monkeys.

Genotoxicity.

No mutagenicity studies in animals have been performed with dinutuximab beta.

Carcinogenicity.

No carcinogenicity studies in animals have been performed with dinutuximab beta.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine, sucrose, polysorbate 20, water for injections, hydrochloric acid (for pH adjustment).

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.4 Special Precautions for Storage.

6.3 Shelf Life

Unopened vial.

4 years.

Diluted solution (solution for infusion).

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), after cumulative storage in a refrigerator (2°C to 8°C) for 72 hours (see Section 6.4 Special Precautions for Storage).
To reduce microbiological hazard, use as soon as practicable after preparation. If storage is necessary, hold at 2-8°C for not more than 24 hours.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze).
Keep the vial in the outer carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see Section 6.3 Shelf Life.
Opened vials not immediately used are to be discarded.

Special precautions for handling.

The solution for infusion 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 (see Section 4.2 Dose and Method of Administration).
Qarziba should be diluted aseptically to the patient specific concentration/dose with sodium chloride 9 mg/mL (0.9%) solution for infusion containing 1% human albumin (e.g. 5 mL of human albumin 20% per 100 mL sodium chloride solution).
For continuous infusions, the solution for infusion can be prepared freshly on a daily basis, or sufficient for up to 5 days of continuous infusion. An in-line filter of 0.2 micrometre must be used in combination with infusion bags throughout the duration of the 5 days administration (or shorter, if applicable). The daily dose is 10 mg/m2. The amount of solution to be infused per day (within a treatment course of 10 consecutive days) should be 48 mL; with 240 mL for a 5-day dose. It is recommended to prepare 50 mL solution in a 50 mL syringe, or 250 mL in an infusion bag suitable for the employed infusion pump, i.e. an overfill of 2 mL (syringe) or 10 mL (infusion bag) to allow for dead volumes of the infusion systems.
For repeated daily 8-hour infusions, the daily dose is 20 mg/m2 and the calculated dose should be diluted in 100 mL sodium chloride 9 mg/mL (0.9%) containing 1% human albumin.
The solution for infusion should be administered via a peripheral or central intravenous line.
Other intravenously co-administered agents should be delivered via a separate infusion line. The container should be inspected visually for particulates prior to administration. It is recommended that a 0.22 micrometre in-line filter is used during infusion.
For continuous infusions, any medical device suitable for infusion at a rate of 2 mL per hour can be used, e.g. syringe infusion pumps/infusors, electronic ambulatory infusion pumps. Note that elastomeric pumps are not considered suitable in combination with in-line filters.

6.5 Nature and Contents of Container

Clear Type I glass vial (6 mL) with a halobutyl rubber stopper and aluminium flip-off cap, containing a minimum extractable volume of 4.5 mL concentrate for solution for infusion.
Each carton contains 1 single use vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1363687-32-4.

Molecular formula.

C6422H9978N1722O2006S48 (without glycosylation).
C6546H10182N1730O2094S48 (including glycosylation).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes