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Unituxin (dinutuximab) – Summary of product characteristics - L01XC

Updated on site: 10-Oct-2017

Medication nameUnituxin
ATC CodeL01XC
Substancedinutuximab
ManufacturerUnited Therapeutics Europe Ltd

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Unituxin 3.5 mg/mL concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 mL of concentrate contains 3.5 mg of dinutuximab.

Each vial contains 17.5 mg of dinutuximab in 5 mL.

Dinutuximab is a chimeric human/mouse monoclonal antibody produced in a murine myeloma cell line (Sp2/0) by recombinant DNA technology.

Excipient with known effect:

authorised

 

Each 5 mL vial contains 17.2 mg sodium. For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

 

 

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless liquid.

 

longer

4.

CLINICAL PARTICULARS

no

 

 

 

 

4.1 Therapeutic indications

4.2 Posology and method of administration

Unituxin is indicated for the treatment ofproducthigh-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapyMedicinaland autologous stem cell transplantation (ASCT). It is administered in combination with granulocyte-macrophage colo y-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

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.

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).
Table 2: Courses 2 and 4 dosing schedule for Unituxin and IL-2; Courses 2, 4, and 6 dosing schedule for isotretinoin

Table 1: Courses 1, 3, and 5 dosing schedule for Unituxin, GM-CSF and isotretinoin

Day

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

1.Granulocyte macrophage colony-stimulating factor (GM-CSF): 250 μg/m2/day, administered by either subcutaneous injection (strongly recommended) or intravenous infusion over 2 hours.

2.Dinutuximab: 17.5 mg/m2/day, administered by intravenous infusion over 10–20 hours.

3.Isotretinoin: for body weight greater than 12 kg: 80 mg/m2 administered orally twice daily for a total dose of

Day

12-14

15-28

 

IL-21

X

X

X

X

 

 

 

X

X

X

X

 

 

 

Dinutuximab2

 

 

 

 

 

 

 

X

X

X

X

 

 

 

Isotretinoin3

 

 

 

 

 

 

 

 

 

 

 

 

X

 

1.

and4.5 MIU/m2/day on Days 8-11.

 

 

 

 

 

 

 

 

 

 

 

2.

Dinutuximab: 17.5 mg/m2/day, administered by intravenous infusion over 10-20

ours.

3.

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 or llyauthorisedtwice daily for 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.

 

longer

Table 3: Clinical criteria that must be evaluated prior to the start of each treatment course of Unituxin

no

 

Central nervous system (CNS) toxicityproduct

Delay course initiation until CNS toxicity is Grade 1 or resolved and/or seizure disorder is well controlled

Hepatic dysfunction

Thrombocytopenia

Delay initiation ofMedicinalfirst course until alanine aminotransferase (ALT) is less than 5 times upper limit of normal (ULN). Delay initiation of courses 2-6 until ALT is less than 10 times ULN.

Delay course initiation until platelet count is at least 20,000/μL.

If patient has CNS m tastases, delay course initiation and give platelet transfusion to maintain platelet count at least 50,000/μL.

Respiratory dysfunction

Delay course initiation until dyspnoea at rest has been resolved and/or peripheral oxygen saturation is at least 94 % on room air.

Renal dysfunction

Delay course initiation until creatinine clearance or glomerular filtration rate (GFR) is at least

70 mL/min/1.73 m2

Systemic infection or sepsis

Delay course initiation until systemic infection or sepsis has resolved.

Leukopaenia

Delay initiation of first course until absolute phagocyte count (APC) is at least 1,000/μL.

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.

Table 4: Dose modification guidance for the management of treatment-emergent adverse reactions during administration of dinutuximab in combination with GM-CSF, IL-2 and isotretinoin.

Allergic reactions

Grade 1 or 2

Onset of symptoms

 

Reduce rate of infusion to 0.875 mg/m2/h.

 

 

• Administer supportive measures (see section 4.4).

After resolution

 

Resume infusion at the original rate. If not tolerated, reduce rate to

 

 

 

0.875 mg/m2/h.

 

 

Grade 3 or 4

 

 

 

 

 

Onset of symptoms

 

Immediately discontinue dinutuximab and intravenous GM-CSF or IL-2.

 

 

• Administer supportive measures (see section 4.4).

After resolution

 

If signs and symptoms resolve rapidly with the above measures,

 

 

 

dinutuximab infusion may be resumed at a rate of 0.875 mg/m2/h.

 

 

• Do not resume GM-CSF or IL-2 until the following day.

 

 

• For GM-CSF courses, administer GM-CSF at 50 % of the dose starting

 

 

 

the next day, and if tolerated, GM-CSF may be given at full dose after

 

 

 

completing dinutuximab dosing for that course.

 

 

For IL-2 courses, administer IL-2 50 % of the dose starting the next day

 

 

 

 

 

authorised

 

 

 

and continue for the remaind of the course.

 

 

• If symptoms recur with the addition of GM-CSF or IL-2 discontinue GM-

 

 

 

CSF or IL-2 and dinutuximab.

 

 

 

• If symptoms resolve the following day, resume dinutuximab at tolerated

 

 

 

 

longer

 

 

 

 

rate without GM-CSF or IL-2.

 

 

 

 

no

 

 

Recurrence

 

Discontinue dinu uximab and GM-CSF or IL-2 for that day.

 

 

• If symptoms resolve that day, resume the next day with premedication in

 

 

 

the intensive care setting (see section 4.4).

Subsequent courses

 

Maintain tolerated dinutuximab infusion rate for all subsequent courses

 

 

 

withproductGM-CSF or IL-2.

 

Anaphylaxis

 

 

 

 

 

Grade 3 or 4

 

 

 

 

 

 

 

• Permanently discontinue dinutuximab and GM-CSF or IL-2.

Capillary leak syndrome

 

 

 

 

Grade 3 (severe)

Medicinal

 

 

Onset of symptoms

 

Discontinue dinutuximab and intravenous GM-CSF or IL-2.

 

 

• Administer supportive measures (see section 4.4).

After resolution

 

Resume dinutuximab infusion at 0.875 mg/m2/h.

 

 

• Resume GM-CSF or IL-2 the following day at 50 % of the dose until the

 

 

 

last dose of dinutuximab for that course.

Subsequent courses

 

If patient tolerated 50 % dose of GM-CSF or IL-2, start at this dose and

 

 

 

dinutuximab rate of 0.875 mg/m2/h. If tolerated, increase GM-CSF or

 

 

 

IL-2 to full dose the next day.

 

 

 

• If GM-CSF is not tolerated at 50 % of the dose, administer dinutuximab

 

 

 

alone for the remainder of the GM-CSF courses.

 

 

• If IL-2 is not tolerated at 50 % of the dose, substitute with GM-CSF for

 

 

 

the remainder of the IL-2 courses.

Grade 4(life-threatening)

 

 

 

 

Onset of symptoms

 

Discontinue dinutuximab and GM-CSF or IL-2 for that course.

 

 

• Administer supportive measures (see section 4.4).

Subsequent courses

 

If capillary leak syndrome occurred during IL-2 course, substitute

GM-CSF for remainder of IL-2 courses.

If capillary leak syndrome occurred during GM-CSF course, administer dinutuximab alone for subsequent GM-CSF courses.

Hyponatraemia

Grade 4(life-threatening) - < 120 mmol/L despite appropriate fluid management

Permanently discontinue dinutuximab and GM-CSF or IL-2.

Hypotension

Symptomatic and/or systolic BP less than 70 mmHg or a decrease that is more than 15% below baseline

Onset of symptoms

 

• Discontinue dinutuximab and intravenous GM-CSF or IL-2.

 

 

• Administer supportive measures (see section 4.4).

After resolution

 

• Resume dinutuximab infusion at 0.875 mg/m2/h.

 

 

• If blood pressure (BP) remains stable for at least 2 hours, resume GM-

 

 

CSF or IL-2.

 

 

 

• If BP remains stable for at least 2 hours after resuming GM-CSF or IL-2,

 

 

increase the dinutuximab infusion to 1.75 mg/m2/h.

Recurrence

 

• Discontinue dinutuximab and GM-CSF or IL-2.

 

 

• Resume dinutuximab at 0.875 mg/m2/h once BP is stable.

After resolution

 

• Resume GM-CSF or IL-2 the following day at 50 % of the dose if BP

 

 

remains stable.

 

 

 

• Start GM-CSF or IL-2 at 50 % of the dose when administered with

 

 

dinutuximab. Then increase to full dose if t lerated for the remainder of

 

 

the course.

 

 

 

• If GM-CSF is not tolerated at 50 % of the dose, administer dinutuximab

 

 

 

 

longer

 

 

alone for the remainder of the couauthorised.

 

 

• If IL-2 is not tolerated at 50 % of the dose, administer dinutuximab alone

 

 

for the remainder of the course.

Subsequent courses

 

• Start GM-CSF or IL-2 at 50 % of the dose, increase to full dose if

 

 

 

no

 

 

 

tolerated the next day.

 

 

 

product

 

 

 

• If GM-CSF is not tolerated at 50 % of the dose, administer dinutuximab

 

 

alone for the remainder of the GM-CSF courses.

 

 

• If IL-2 is not tolerated at 50 % of the dose, substitute with GM-CSF for

 

 

remainder of the IL-2 courses.

Neurological disorders of the eye

 

 

 

Medicinaladminister dinutuximab at 0.875 mg/m2/h and full dose GM-CSF or IL-2.

Dilated pupil with sluggish light ref ex

 

Onset of symptoms

 

• Discontinue dinutuximab and GM-CSF or IL-2.

After resolution

 

• Administer dinutuximab at 0.875 mg/m2/h and resume GM-CSF or IL-2.

Recurrence

 

• Discontinue dinutuximab, GM-CSF, and IL-2 for remaining courses.

Subsequent courses

 

• If abnormalities remain stable or improve before the next course

 

 

• If tolerated without worsening symptoms, administer dinutuximab at

1.75 mg/m2/h for subsequent courses.

If symptoms recur, discontinue dinutuximab, GM-CSF, and IL-2 for remaining courses.

Serum sickness

Grade 4 (life-threatening)

Permanently discontinue dinutuximab and GM-CSF or IL-2.

Systemic infection or sepsis

Grade 3 or 4

Onset of symptoms

Discontinue dinutuximab and GM-CSF or IL-2 for remainder of course.

After resolution

Proceed with subsequent planned dinutuximab and GM-CSF or IL-2

 

 

courses.

Pain

Grade 4

Discontinue dinutuximab and GM-CSF or IL-2.

Peripheral neuropathy

Grade 2 peripheral motor neuropathy

Permanently discontinue dinutuximab and GM-CSF or IL-2.

Grade 3 (sensory changes for more than 2 weeks, objective motor weakness) or Grade 4

Discontinue dinutuximab and GM-CSF or IL-2.

Atypical Haemolytic Uraemic Syndrome

Permanently discontinue dinutuximab and GM-CSF or IL-2.

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 beauthorisedextended up to 20 hours to help

minimise reactions during infusion (see sections 4.4 and 4.8) that do not respond ad quately 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 (see section 4.4). For instructions on dilution of the medicinal product beforelongeradministration, see section 6.6.

4.3 Contraindications

Hypersensitivity (Grade 4) to the active substance ornoto any of the excipients listed in section 6.1.

4.4 Special warnings and precautionsproductfor se

Allergic reactions

Patients should be monitored for signs and symptoms of infusion reactions for 4 hours after the completion of the Unituxin infusion.

Antihistamine premedication (e.g. hydroxyzine or diphenhydramine) should be administered by intravenous injection approximatelyMedicinal20 minutes before starting each dinutuximab infusion. It is recommended that antihistamine medicinal produ t be repeated every 4–6 hours as required during infusion of Unituxin.

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 (see sections 4.2 and 4.8).

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 (see sections 4.2 and 4.8).

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.

completion of the treatment. It is recommended that additional intravenous bolus doses of an opioid are

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 authorisedduring and until 2 hours after

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 infusionlongerand 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.

Hypotension

Gabapentin may be administered at the time of startinog morphine premedication, at an oral dose of 10 mg/kg/day. The dose may be subsequentlyproductin reased (up to a maximum of 60 mg/kg/day or 3600 mg/day) as needed for pain management.

vasopressor therapy is also ministered if necessary to restore an adequate perfusion pressure.

Intravenous sodium chloride 9 mg/mL (0.9%) solution for injection (10 mL/kg) should be administered over one hour just prior to theMedicinaldinutuxim b 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

Neurological disorders of the eye

Eye disorders may occur, especially with repeated courses (see section 4.8). These changes usually resolve over time. Patients should have an ophthalmic examination before initiating therapy and be monitored for visual changes.

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 (see section 4.8). Electrolytes should be monitored daily during therapy with Unituxin.

Pharmacokinetic interactions
No interaction studies have been performed.

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’.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. A risk for interactions with concomitantly used medicinal products cannot be excluded.

Corticosteroids

It is not recommended to use systemic corticosteroid medicinal products due to possible interference with immune activation which is necessary for the therapeutic action of dinutuximab.

Intravenous immunoglobulin

authorised

 

It is not recommended to use intravenous immunoglobulin after ASCT. If nece ary, its use must be limited to the first 100 days after ASCT, as immunoglobulin may interfere with dinutuximab-dependent cellular cytotoxicity. Immunoglobulin must not be given within two weeks before and one week after completing each course of Unituxin.

Pharmacodynamic interactions

 

no

longer

Severe allergic reactions are more likely when dinutuximab is co-administered with IL-2. Therefore caution

Pregnancy

products

 

 

should be taken when both medicinal

are ombined (see section 4.4).

4.6 Fertility, pregnancy and lactation

There are no data fromMedicinalthe use of dinutuximab in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Hence, this medicinal product is not recommend during pregnancy and 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 Unituxin.

Breast-feeding

Human IgG is known to be secreted in human milk. There is insufficient information on the excretion of dinutuximab in human milk. Breast-feeding should be discontinued during treatment with Unituxin. The recommended interval time between treatment discontinuation and breastfeeding is 6 months.

Fertility

The effects of dinutuximab on fertility in humans are unknown. In animals, fertility studies have not been conducted; however in male and female rats, no adverse effects on reproductive organs were observed (see section 5.3).

4.7Effects on ability to drive and use machines

Unituxin has major influence on the ability to drive and use machines.

4.8Undesirable effects

Eye disorders
Vision blurred,
Posterior reversible encephalopathy syndrome
Unequal pupils
Neuralgia, peripheral neuropathy, headache
Nervous system disorders
Hypomagnesaemia, acidosis, hypoglycaemia,
Endocrine disorders
Metabolism and nutrition disorders
Hyperthyroidism
Immune system disorders
Cytokine release syndrome
Serum sickness
Febrile neutropenia
Atypical haemolytic uraemic syndrome
Infections and infestations
Blood and lymphatic system disorders
Device-related infection, infection susceptibility increased, bacteraemia, enterocolitis
System Organ Class
Common
Uncommon
Tabulated list of adverse reactions

Summary of the safety profile

Adverse reactions reported in four clinical studies (ANBL0032, ANBL0931, CCG-0935A, and DIV-NB- 201) of dinutuximab in patients (N=984) with high-risk neuroblastoma are summarized in Table 5. Adverse reactions are defined as those adverse events that occurred at a higher frequency in the dinutuximab, GM- CSF, IL-2 and isotretinoin-treated group compared with the isotretinoin-treated control group during the ANBL0032 randomised, controlled, pivotal study, and that have a plausible mechanistic relationship to treatment with dinutuximab. Originally reported terms have been coded to preferred terms (using the Medical Dictionary for Regulatory Activities [MedDRA]).

Table 5 summarizes adverse drug reactions reported when dinutuximab was administered in combination with GM-CSF, IL-2, and isotretinoin. As this medicinal product is used in combination with GM-CSF, IL-2, and isotretinoin, it is difficult to ascertain the causal relationship of each adverse reaction to a particular medicinal product.

The most frequently occurring (more than 30% of patients) adverse reactions reported during the

neuroblastoma studies were hypotension (67 %), pain (66 %), hypersensitivity (56 %), pyrexia (53 %), urticaria (49 %), capillary leak syndrome (45 %), anaemia (45 %), hypokalaemiaauthorised(41 %), platelet count

decreased (40 %), hyponatraemia (37 %), alanine aminotransferase increased (35 %), decreased lymphocyte

count (34%) and decreased neutrophil count (31%). Additional adverse reacti ns characteristic of an allergic response were also reported – including anaphylactic reaction (18 %) and bronchospasm (4 %).

Adverse reactions reported for subjects receiving dinutuximab in combination with GM-CSF, IL-2, and

isotretinoin are summarised in Table 5. These adverse reacti ns are presented by MedDRA system organ

class and frequency. Frequency categories are defined as:longervery common (≥1/10); common

 

no

(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are

product

 

presented in order of decreasing seriousness.

 

Table 5: Adverse reactions that have occurred uring studies in high risk neuroblastoma patients receiving dinutuximab in combination with GM-CSF, IL-2, and isotretinoin.

MedicinalVery Common

Anaemia

Anaphylactic reaction, hypersensitivity

Hypokalaemia,

hyponatraemia,

hypocalcaemia,

hypophosphataemia,

hypoalbuminaemia,

hyperglycaemia, decreased appetite

System Organ Class

Very Common

 

Common

 

Uncommon

 

 

 

photophobia, mydriasis

 

Cardiac disorders

Tachycardia (sinusal,

 

 

 

 

Atrial fibrillation,

 

atrial, ventricular)

 

 

 

 

ventricular arrhythmia

Vascular disorders

Capillary leak syndrome,

 

 

 

 

 

hypotension,

 

 

 

 

 

 

hypertension

 

 

 

 

 

Respiratory, thoracic and

Hypoxia, cough,

 

Bronchospasm,

Stridor, laryngeal

mediastinal disorders

dyspnoea

 

pulmonary oedema

oedema

Gastrointestinal

Diarrhoea, vomiting,

 

Constipation, lower

 

disorders

nausea

 

gastrointestinal

 

 

 

 

haemorrhage

 

Skin and subcutaneous

Urticaria, pruritus

 

Maculo-papular rash

 

tissue disorders

 

 

 

 

 

 

Renal and urinary

 

 

Urinary retention,

Renal failure

disorders

 

 

proteinuria, haematuria

 

General disorders and

Pyrexia, pain1, face

 

Peripheral oedema,

 

administration site

oedema

 

 

 

authorised

 

chills, fatigue, irritability

 

conditions

 

 

Injection site reaction

 

Investigations

Decreased platelet count,

Increased gamma-

Blood culture positive

 

decreased lymphocyte

 

glutamyltransferase,

 

 

count, decreased white

 

increased blood

 

 

blood cell count,

 

creatinine, increased

 

 

decreased neutrophil

 

 

longer

 

 

 

 

weight

 

 

 

count, increased

 

 

 

 

 

 

aspartate

 

 

 

 

 

 

aminotransferase,

no

 

 

 

 

increased alanine

 

 

 

 

 

 

 

 

 

 

aminotransferase

 

 

 

 

 

 

product

 

 

 

 

 

1 Includes preferred terms abdominal pain, abdominal pain upper, arthralgia, back pain, bladder pain, bone pain, chest

pain, facial pain, gingival pain, musculoskeletal chest pain, myalgia, neck pain, neuralgia, oropharyngeal pain, pain, pain in extremity, and proctalgia.

Description of selected adverse reactions

Allergic reactions

Refer to section 4.2 forMedicinaladvice on tapering off or discontinuation of this medicinal product. Refer to section 4.4 for actions to be taken for specific adverse reactions.

Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin included facial and upper airway oedema, dyspnoea, bronchospasm, stridor, urticaria, and hypotension. Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion. Serious anaphylactic/allergic reactions were reported in 14% of patients. Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity/allergic reactions in some cases.

Capillary leak syndrome

Capillary leak syndrome was a very common adverse reaction (45 % of patients) that occurred more frequently when Unituxin was co-administered with IL-2; it was severe (> Grade 3) in 14% of patients.

Pain

Pain typically occurred during the Unituxin infusion and was most commonly reported as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia; 41% of patients suffered severe pain. Analgesics including intravenous opioids should be administered prior to each dose of Unituxin and continued until two hours following completion of Unituxin infusion.

Pharmacodynamic effects
Mechanism of action

Peripheral sensory neuropathy was reported in 3% of patients and peripheral motor neuropathy in 2% of patients; less than 1% of patients experienced serious peripheral neuropathy.

Laboratory test abnormalities

Electrolyte abnormalities occurring in at least 25 % of patients who received Unituxin included hyponatraemia and hypokalaemia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions that occur after authorisation 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 via the national reporting system listed in Appendix V.

4.9 Overdose

No cases of dinutuximab overdose have been reported. In clinical trials, scheduled dinutuximab doses of up to 120 mg/m2 (60 mg/m2/day) have been administered with an adverse reaction profile similar to that described in section 4.8. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies,authorisedATC code: L01XC16 Dinutuximab is a monoclonal chimeric antibody compnosedlongerof murine variable heavy and light chain regions and the human constant region for the heavy chain IgG1 and light chain kappa. Dinutuximab reacts specifically with the ganglioside GD2, productwhich is highly expressed on the surface of neuroblastoma cells and minimally expressed on the surface of normal h man neurons, peripheral pain fibres, and skin melanocytes.

Dinutuximab has beenMedicinalshown to bind to neuroblastoma cell lines known to express GD2 in vitro. In addition, it has been shown to duce both antibody dependent cell-mediated cytotoxicity (ADCC) and

complement-dependent cytotox city vitro. Specifically, in the presence of human effector cells including peripheral blood mononucl ar cells (PBMC) and granulocytes from normal human donors, dinutuximab was found to mediate the lysis of several neuroblastoma cell lines in a dose-dependent manner. Granulocytes were found to be more effective than PBMCs in mediating dinutuximab dependent cytotoxicity of neuroblastoma cells, with enhanced cell lysis observed with the addition of GM-CSF. Additionally, in vivo studies demonstrate that dinutuximab either alone or in combination with IL-2 can partially inhibit tumour growth in mice. Augmentation of ADCC in the presence of GM-CSF and IL-2 provided the rationale for combining these cytokines with dinutuximab in clinical studies.

Non-clinical studies demonstrate that dinutuximab-induced neurotoxicity is likely due to the induction of mechanical allodynia that may be mediated by reactivity of dinutuximab with GD2 antigen located on the surface of peripheral nerve fibres and/or myelin.

Clinical efficacy and safety

ANBL0032 was a randomised, controlled study that evaluated the effects of dinutuximab administered in combination with GM-CSF, IL-2, and isotretinoin compared with isotretinoin alone in high-risk neuroblastoma subjects. High-risk neuroblastoma was based on the patient age (greater than 12 months) and tumour stage at diagnosis and / or the presence of biological risk factors, such as MYCN amplification.

Patients were aged 11 months to 15 years and had previously achieved at least a partial response to induction chemotherapy, followed by ASCT and radiotherapy. Following ASCT, 226 subjects were randomly assigned 1:1 to either a standard therapy arm (six courses of isotretinoin) or a dinutuximab immunotherapy arm (five courses of dinutuximab in combination with alternating GM-CSF and IL-2; combined with isotretinoin concurrently for six courses). Dinutuximab was administered at a dose equivalent to

17.5 mg/m2/day on four consecutive days (Days 4–7) of Courses 1–5. GM-CSF was administered at a dose of 250 μg/m2/day during Courses 1, 3, and 5 and dosed daily for 14 days. IL-2 was administered concurrently with dinutuximab as a continuous intravenous infusion for four days during Week 1 of Courses 2 and 4 at a dose of 3.0 MIU/m2/day, and during Week 2 of Courses 2 and 4 at a dose of 4.5 MIU/m2/day. During the last two weeks in each of the six courses, subjects in both the control and the dinutuximab immunotherapy arms were also given oral isotretinoin at a dose of 160 mg/m2/day (given as 80 mg/m2 twice daily).

The primary efficacy outcome measure was investigator-assessed event-free survival (EFS) defined as time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death. The primary intent-to-treat (ITT) analysis found an improvement in EFS associated with dinutuximab

immunotherapy plus isotretinoin, as compared to isotretinoin alone. The 2-year estimates of EFS were 66 %

isotretinoin as compared with isotretinoin alone. The 3-year estimatesauthorisedof OS were 80 % compared with 67 % among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone,

among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48 % in subjects

receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical

significance according to the pre-specified plan for interim analyses. In addit on, overall survival (OS) was

evaluated with 3 years of follow-up after the EFS analysis as a secondary endp int with a significant

improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus

respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with 5 years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received

dinutuximab immunotherapy compared to those who received isotretinoin alone. The 5 year estimates of OS

were 74 % for dinutuximab immunotherapy compared to longer57 % for isotretinoin alone (log-rank test

p = 0.030).

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Subgroup analyses of EFS and OS response indicated that patients with minimal residual disease, DNA

 

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hyperploidy, and those having received a purged bone marrow may not have benefited from dinutuximab immunotherapy.

Immunogenicity Medicinal

As with all therapeutic proteins, there is potential for immunogenicity. Data from 409 subjects participating in several neuroblastoma stud es and having samples available for the determination of human anti-chimeric antibodies (HACA) demonstrated that 71 (17%) developed binding antibodies and 15 (4%) developed a neutralising antibody response. Plasma concentrations of dinutuximab, especially trough levels, tended to be lower in patients with HACA. There was no apparent correlation between the development of these antibodies and allergic reactions.

The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay and for these reasons, comparison of the incidence of antibodies to dinutuximab with the incidence of antibodies to other products may be misleading.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Unituxin in one or more subsets of the paediatric population in neuroblastoma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Distribution

Safety pharmacology
General toxicology

The pharmacokinetics of dinutuximab were evaluated in a clinical study of Unituxin in combination with GM-CSF, IL-2, and isotretinoin. In this study, 27 children with high-risk neuroblastoma

(age: 3.9 ± 1.9 years) received up to 5 cycles of Unituxin at 17.5 mg/m2/day as an intravenous infusion over 10 to 20 hours for 4 consecutive days every 28 days. The mean (± standard deviation) maximum plasma concentration observed after the 4th infusion was 11.5 (± 2.3) mcg/mL. In a population pharmacokinetic analysis, the geometric mean volume of distribution at steady state was estimated at 5.2 L.

Biotransformation

Dinutuximab 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.

Elimination

The geometric mean clearance was estimated at 0.025 L/hr and increased with body size. The terminal half- life was estimated at 10 (+ 6) days.

A population pharmacokinetic analysis conducted on all clinical dataauthorisedavailable sugg sts that the disposition of dinutuximab is not altered by age, race, gender, concomitant medications (IL-2, GM-CSF) and the

presence of capillary leak syndrome, renal or hepatic impairment. However, the presence of HACA appears to increase the clearance of dinutuximab by approximately 60%.

5.3 Preclinical safety data

Dinutuximab (or the murine monoclonal antibody 14.18) longerhas been administered to mice, rabbits, rats, and dogs in single- or repeat-dose regimens that exceed thenodose that is used clinically. Findings of note included treatment related adverse reactions of theproductliver in ra s (characterized by centrilobular congestion, abnormal cell division, hepatocellular necrosis and pericentral vein/interlobular fibrosis) which may be related to circulatory disturbances and changes indicative of increased haematopoiesis (high reticulocyte ratio and/or platelet count, increased cellularity of the haematopoietic cells in the femoral and sternal bone marrow,

and/or extramedullary haematopoiesis in the liver and spleen). These changes were noted to be very slight to slight in severity and recoveredMedicinalor tended to recover following the cessation of dosing. No clinical signs of CNS toxicity were observed.

Dinutuximab was administered to cynomolgous monkeys resulting in effects on the cardiovascular system, which consisted of moderate increases in blood pressure (one of three animals) and heart rate (two of three animals). No direct effects on electrocardiogram parameters or on the respiratory system were observed.

Other

No non-clinical studies to evaluate the potential of dinutuximab to cause carcinogenicity, genotoxicity, or developmental and reproductive toxicity have been conducted. In male and female rats, administration of dinutuximab resulted in no adverse effects on reproductive organs at exposures that were at least 60-fold higher than those observed clinically.

Non-clinical data reveal no special hazard for humans based on conventional studies conducted to date. These studies support the current dinutuximab dosing regimen of 17.5 mg/m2/day administered for four consecutive days during five monthly courses.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Histidine
Polysorbate 20 (E 432) Sodium chloride Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial 18 months

Diluted solution

Chemical and physical in-use stability has been demonstrated for 24 hours at ambient conditions (less than 25°C).

From a microbiological point of view, unless the method of opening/reconstituting/dilution precludes the

 

 

 

authorised

risks of microbial contamination, the product should be used imm diately. If not used immediately, in-use

storage times and conditions are the responsibility of the user.

 

6.4 Special precautions for storage

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Store and transport refrigerated (2°C – 8°C).

 

Do not freeze.

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Keep the vial in the outer carton in order to protect from light.

6.5 Nature and cont nts of container

For storage conditionsMedicinalafter dilut on of the medicinal product, see section 6.3.

Clear Type I glass vial with bromobutyl rubber stopper and aluminium flip-off seal containing 5 mL of concentrate for solution for infusion.

Each carton contains one vial.

6.6Special precautions for disposal and other handling

The exact volume of Unituxin concentrate for solution for infusion required for the patient dose (see section 4.2) must be injected into a 100 mL bag of sodium chloride 9 mg/mL (0.9 %) solution for injection.

The required volume of dinutuximab should be withdrawn and injected into a 100 mL bag of sodium chloride 9 mg/mL (0.9 %) solution for injection. The solution should be mixed by gentle inversion.

Dilution must be carried out under aseptic conditions. From a microbiological point of view, the product should be used immediately. For shelf life after dilution, see section 6.3. The diluted solution for infusion must be used within 24 hours of preparation.

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

7. MARKETING AUTHORISATION HOLDER

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

E-mail: druginfo@unither.com

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THEauthorisedAUTHORISATION8. MARKETING AUTHORISATION NUMBER(S)

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is avai ab n the website of the European Medicines

Agency http://www.ema.europa.eu.

 

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