Elzonris

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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 
 
ELZONRIS 1 mg/mL concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 mL of concentrate for solution for infusion contains 1 mg tagraxofusp. Each vial contains 1 mg of 
tagraxofusp. 
 
Tagraxofusp is a diphtheria toxin-interleukin-3 (IL-3) fusion protein produced by recombinant DNA 
technology in Escherichia coli.  
 
Excipient with known effect 
 
Each vial contains 50 mg of sorbitol (E420). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear, colourless liquid. A few white to translucent particles may be present. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
ELZONRIS is indicated as monotherapy for the first-line treatment of adult patients with blastic 
plasmacytoid dendritic cell neoplasm (BPDCN) (see section 5.1). 
 
4.2 Posologyand method of administration 
 
ELZONRIS should be administered under the supervision of a physician experienced in the use of 
anti-cancer agents. Appropriate resuscitation equipment should be available. 
 
Posology 
 
The recommended dose is 12 mcg/kg tagraxofusp administered as an intravenous infusion over 
15 minutes, once daily, on days 1-5 of a 21-day cycle. The dosing period may be extended for dose 
delays up to day 10 of the cycle. Treatment should be continued until disease progression or 
unacceptable toxicity (see section 4.4). 
 
First treatment cycle 
The first cycle of ELZONRIS should be administered in the in-patient setting. Patients should be 
monitored for signs and symptoms of hypersensitivity or capillary leak syndrome (see section 4.4) 
until at least 24 hours after the last infusion. 
 
Subsequent treatment cycles 



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ELZONRIS can be administered in the in-patient setting or in a suitable out-patient ambulatory care 
setting that is equipped for intensive monitoring of patients with haematopoietic malignancies 
undergoing treatment. 
 
Pre-medication 
Patients should be pre-medicated with a H1-histamine antagonist (e.g. diphenhydramine 
hydrochloride), a H2-histamine antagonist (e.g. ranitidine), a corticosteroid (e.g. 50 mg intravenous 
methylprednisolone or equivalent) and paracetamol approximately 60 minutes prior to the start of 
infusion (see section 4.4). 
 
Dose adjustments 
 
Vital signs should be monitored and albumin, transaminases, and creatinine checked prior to preparing 
each dose of ELZONRIS. See Table 1 for recommended dose modifications and Table 2 for capillary 
leak syndrome (CLS) management guidelines. 
 
Vital signs should be monitored frequently during dosing. 
 
Table 1: Recommended ELZONRIS dosing regimen modifications 
 

Parameter Severity criteria Dose modification 

Serum albumin  
Serum albumin < 3.5 g/dL or reduced 
≥ 0.5 g/dL from value measured prior to 
initiation of the current cycle 

See CLS Management Guidelines (Table 2) 

Body weight  Body weight increase ≥ 1.5 kg over pre-
treatment weight on prior treatment day See CLS Management Guidelines (Table 2) 

Aspartate 
aminotransferase 
(AST) or alanine 
aminotransferase 
(ALT)  

ALT or AST increase > 5 times the 
upper limit of normal  

Withhold treatment until transaminase 
elevations are ≤ 2.5 times the upper limit of 
normal. 

Serum creatinine  
Serum creatinine > 1.8 mg/dL 
(159 micromol/L) or creatinine 
clearance < 60 mL/minute 

Withhold treatment until serum creatinine 
resolves to ≤ 1.8 mg/dL (159 micromol/L) or 
creatinine clearance ≥ 60 mL/minute. 

Systolic blood 
pressure 

Systolic blood pressure ≥ 160 mmHg or 
≤ 80 mmHg 

Withhold treatment until systolic blood 
pressure is < 160 mmHg or > 80 mmHg. 

Heart rate  Heart rate ≥ 130 bpm or ≤ 40 bpm Withhold treatment until heart rate is 
< 130 bpm or > 40 bpm. 

Body temperature  Body temperature ≥ 38 °C Withhold treatment until body temperature is 
< 38 °C. 

Hypersensitivity 
reactions Mild or moderate 

Withhold treatment until resolution of any 
mild or moderate hypersensitivity reaction. 
Resume ELZONRIS at the same infusion 
rate. 

 
Table 2: CLS management guidelines 

Time of 
Presentation 

CLS 
Sign/Symptom 

Recommended 
Action 

ELZONRIS 
Dosing 

Management 
Prior to first dose of 
ELZONRIS 
in cycle 1  

Serum albumin < 3.2 g/dL  Administer ELZONRIS when serum albumin ≥ 3.2 g/dL 

During ELZONRIS 
dosing Serum albumin < 3.5 g/dL  

Administer 25 g intravenous albumin 
every 12 hours (or more frequently as 
practical) until serum albumin is 
≥ 3.5 g/dL AND not reduced by 

Hold dosing 
until the 
relevant CLS 
sign/symptom 



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1 If ELZONRIS dose is held: 
- ELZONRIS administration may resume in the same cycle if all CLS signs/symptoms have resolved and 

the patient did not require measures to treat haemodynamic instability.  
- Administration should be held for the remainder of the cycle if CLS signs/symptoms have not resolved 

or the patient required measures to treat haemodynamic instability (e.g., required administration of 
intravenous fluids and/or vasopressors to treat hypotension) (even if resolved). 

- Administration may only resume in the next cycle if all CLS signs/symptoms have resolved, and the 
patient is haemodynamically stable.  

 
Special populations 
 
Renal impairment 
No data are available for patients with renal impairment (see section 5.2).  
 
Hepatic impairment 
No data are available for patients with hepatic impairment (see section 5.2). 

  
Elderly 
No dose adjustment is required for patients over 65 years of age (see section 5.2).  Generally, safety 
was similar between elderly patients (≥ 65 years of age) and patients less than 65 years of age treated 
with ELZONRIS. 
 
Paediatric population 
The safety and efficacy of ELZONRIS in children and adolescents below 18 years have not been 
established (see section 5.1).  
No data are available. 

Serum albumin reduced by 
≥ 0.5 g/dL from the 
albumin value measured 
prior to ELZONRIS dosing 
initiation of the current 
cycle 

≥ 0.5 g/dL from the value measured 
prior to dosing initiation of the current 
cycle 

has resolved 1 
 

A pre-dose body weight 
that is increased by ≥ 1.5 kg 
over the previous day’s 
pre-dose weight 

Administer 25 g intravenous albumin 
(every 12 hours or more frequently as 
practical), and manage fluid status as 
indicated clinically (e.g., generally 
with intravenous fluids and 
vasopressors if hypotensive and with 
diuretics if normotensive or 
hypertensive), until body weight 
increase has resolved (i.e. the increase 
is no longer ≥ 1.5 kg greater than the 
previous day’s pre-dose weight). 

Oedema, fluid overload 
and/or hypotension 

Administer 25 g intravenous albumin 
(every 12 hours, or more frequently as 
practical) until serum albumin is 
≥ 3.5 g/dL. 
 
Administer 1 mg/kg of 
methylprednisolone (or an equivalent) 
per day, until resolution of CLS 
sign/symptom or as indicated 
clinically. 
 
Aggressive management of fluid status 
and hypotension if present, which 
could include intravenous fluids and/or 
diuretics or other blood pressure 
management, until resolution of CLS 
sign/symptom or as clinically 
indicated.  



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Method of administration 
 
ELZONRIS is for intravenous use. 
 
The prepared dose of diluted ELZONRIS should be administered via an infusion syringe pump over 
15 minutes. The total infusion time should be controlled using an infusion syringe pump to deliver the 
entire dose and the sodium chloride 9 mg/mL (0.9%) solution for injection within 15 minutes. 
 
ELZONRIS must not be administered as an intravenous push or bolus. It should be administered 
through a dedicated intravenous line and it must not be mixed with other medicinal products (see 
section 6.2). 
 
Prior to infusion, venous access should be established and maintained with sodium chloride 
9 mg/mL (0.9%) solution for injection. 
 
For instructions on preparation and administration of the medicinal product, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
Capillary leak syndrome 
Capillary leak syndrome (CLS), including life-threatening and fatal cases have been reported with 
most events occuring during the first five days of the first cycle of treatment. The most frequent signs 
and symptoms of CLS included weight increased, hypoalbuminemia and hypotension. The incidence 
of weight increased, hypoalbuminemia, hypotension, and blood alkaline phosphatase increased are all 
higher among patients who experienced CLS compared to patients that did not experience CLS. Renal 
failure and acute kidney injury have been reported in two patients with BPDCN and in one patient 
with AML secondary to CLS (see section 4.8). 
 
Before initiating therapy, ensure that the patient has adequate cardiac function and serum albumin 
≥ 3.2 g/dL. During treatment, regularly monitor serum albumin levels prior to the initiation of each 
dose, or more often as clinically indicated. Additionally, assess patients for other signs/symptoms of 
CLS including weight gain, new onset or worsening oedema, including pulmonary oedema, and 
hypotension including haemodynamic instability (see Table 2).  
 
Patients should be made aware of identifying CLS symptoms and when to seek immediate medical 
attention. Intravenous albumin supplementation and dosing interruptions may be required (see 
section 4.2).  
 
Hypersensitivity reactions  
Severe hypersensitivity reactions have been reported with ELZONRIS. Commonly reported reactions 
include rash (generalised / maculo-papular); wheezing; pruritus; angioedema; swelling face; and 
flushing (see section 4.8). Monitor patients for hypersensitivity reactions during treatment. Depending 
on the severity and the required interventions, temporarily withhold treatment and resume after 
symptoms have resolved (see section 4.2). 
 
Haematological abnormalities  
Thrombocytopenia and neutropenia have been reported in patients treated with ELZONRIS 
monotherapy (see section 4.8). The majority of events were reported in cycle 1 and cycle 2 of 



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treatment, were not dose-limiting and did not recur in subsequent cycles. Patients should be routinely 
monitored and treated as clinically indicated. 
 
Tumour lysis syndrome 
ELZONRIS can cause tumour lysis syndrome (TLS), which may be fatal as a result of its rapid 
anti-tumour activity (see section 4.8).   
 
Identify TLS based on clinical presentation and symptoms, including acute renal failure, 
hyperkalaemia, hypocalcaemia, hyperuricaemia, or hyperphosphataemia from tumour lysis.  Patients 
considered at high risk for TLS due to high tumour burden should be managed as clinically indicated, 
including correction of electrolyte abnormalities, monitoring of renal function and fluid balance, and 
administration of supportive care.   
 
Hepatotoxicity 
Treatment with ELZONRIS has been associated with elevations in liver enzymes (see section 4.8). 
Acute hepatic failure and liver encephalopathy has been reported in a patient treated with ELZONRIS 
at a higher dose (16 mcg/kg). During treatment, regularly monitor ALT and AST levels prior to the 
initiation of each dose. Temporarily withhold treatment if transaminases rise to greater than 5 times 
the upper limit of normal and resume treatment when transaminase elevations are ≤ 2.5 times the 
upper limit of normal (see section 4.2).  
 
Choroid plexus lesions  
Choroid plexitis was identified during non-clinical studies (see section 5.3). While not observed in 
clinical studies, if clinical symptoms or signs suggestive of central nervous system (CNS) damage 
occur, full neurological examination is advised. 
 
CNS-involved BPDCN 
The passage of tagraxofusp through the blood brain barrier is unknown. Other treatment alternatives 
should be considered if CNS disease is present. 
 
Women of childbearing potential/contraception 
In women of childbearing potential, a negative pregnancy test should be obtained within 7 days prior 
to initiation of therapy. Effective contraception should be used before the first dose is administered 
and for at least one week after the last dose. 
 
Hereditary fructose intolerence 
Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unless 
strictly necessary.  
 
A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given 
this medicinal product. 
 
Sodium sensitivity 
This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception 
In women of childbearing potential, a negative pregnancy test should be obtained within 7 days prior 
to initiation of therapy. Effective contraception should be used before the first dose is administered 
and for at least one week after the last dose. 
 



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Pregnancy  
There are no data from the use of ELZONRIS in pregnant women.  
Animal reproduction studies have not been conducted with tagraxofusp (see section 5.3).  
 
ELZONRIS should not be used during pregnancy unless the clinical condition of the woman requires 
treatment with tagraxofusp. 
 
Breast-feeding 
It is unknown whether tagraxofusp/metabolites are excreted in human milk. 
A risk to breast-feeding newborns/infants cannot be excluded.  
 
Breast-feeding should be discontinued during treatment with ELZONRIS and for at least one week 
after the last dose. 
 
Fertility 
No fertility studies have been conducted with tagraxofusp (see section 5.3). There are no data on the 
effect of tagraxofusp on human fertility. 
 
4.7 Effects on ability to drive and use machines 
 
ELZONRIS has no or negligible influence on the ability to drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most serious adverse reaction that may occur during ELZONRIS treatment is CLS (see sections 
4.2 and 4.4) which was reported in 18% of patients with a median time to onset of CLS of 6 days. 
 
Adverse reactions occurring in ≥ 20% of patients treated with ELZONRIS were hypoalbuminemia, 
increased transaminases, thrombocytopenia, nausea, fatigue and pyrexia.  
 
Adverse reactions grade 3 and above according to the Common Terminology Criteria for Adverse 
events (CTCAE) and occurring in > 5% of patients were increased transaminases, thrombocytopenia 
and anaemia. 
 
Tabulated list of adverse reactions  
 
The adverse reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term 
level. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10), common 
(≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100).  
 
The adverse reactions described in this section were identified in clinical studies of patients with 
haematologic malignancies (N=176), including 89 patients with BPDCN. In these studies, ELZONRIS 
was administered as monotherapy at doses of 7 mcg/kg (12/176, 7%), 9 mcg/kg (9/176, 5%) and 
12 mcg/kg (155/176, 88%). Incidence and severity of adverse reaction in patients with BPDCN were 
similar to those of the entire studied population. 
 
Table 3:  Tabulated list of adverse reactions by MedDRA System Organ Class 

MedDRA System 
Organ Class Frequency of all CTCAE grades  Frequency of CTCAE grade 3 and 

above  
Infections and 
infestations 

Common 
Cellulitis 
Uncommon 
Pneumonia 
Urinary tract infection  
Gingivitis 

None 



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MedDRA System 
Organ Class Frequency of all CTCAE grades  Frequency of CTCAE grade 3 and 

above  
Blood and lymphatic 
system disorders 

Very Common 
Thrombocytopenia 
Anaemia 
Common 
Febrile neutropenia 
Neutropenia 
Leukopenia 
Leukocytosis 
Lymphopenia 
 

Very Common 
Thrombocytopenia 
Common 
Febrile neutropenia 
Anaemia 
Neutropenia 
Leukopenia 
Lymphopenia 
Uncommon 
Leukocytosis 

Immune system 
disorders 

Common 
Cytokine release syndrome 

Uncommon 
Cytokine release syndrome 

Metabolism and 
nutrition disorders 

Very Common 
Hypoalbuminemia 
Common 
Decreased appetite 
Tumour lysis syndrome 
Hyperglycaemia 
Hyperuricaemia 
Hypocalcaemia 
Hypomagnesaemia 
Hyponatraemia 
Hypokalaemia 
Hyperkalaemia 
Hyperphosphataemia 
Uncommon 
Hypophosphataemia 
Lactic acidosis 
Acidosis 

Common 
Tumour lysis syndrome 
Hyperglycaemia 
Hypoalbuminemia 
Hyponatraemia 
Uncommon 
Hyperuricaemia 
Hypocalcaemia 
Hypokalaemia 
Lactic acidosis 
Acidosis 

Psychiatric disorders Common 
Confusional state 
Uncommon 
Anxiety 
Depression 
Insomnia 
Mental status changes 

None 

Nervous system 
disorders 

Common 
Syncope 
Headache 
Dizziness 
Uncommon 
Encephalopathy 
Metabolic encephalopathy 
Cerebrovascular accident 
Facial paralysis 
Dysgeusia  
Multiple sclerosis relapse 
Somnolence 
Paraesthesia 
Parosmia 
Peripheral motor neuropathy 
Peripheral sensory neuropathy 

Common 
Syncope 
Uncommon 
Cerebrovascular accident 
Metabolic encephalopathy 

Eye Disorders Common 
Vision blurred  
Uncommon 
Conjunctival haemorrhage 
Ocular hyperaemia 
Vitreous floaters 

None 

Cardiac Disorders Common 
Pericardial effusion 

Uncommon 
Ventricular fibrillation  



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MedDRA System 
Organ Class Frequency of all CTCAE grades  Frequency of CTCAE grade 3 and 

above  
Tachycardia 
Sinus tachycardia 
Uncommon 
Ventricular fibrillation  
Supraventricular extrasystoles 
Atrial fibrillation 
Bradycardia 
Myocardial infarction 

Pericardial effusion 
Sinus tachycardia 
Myocardial infarction 

Vascular disorders Very Common 
Capillary leak syndrome 
Hypotensiona 
Common 
Flushing 
Uncommon 
Hypertension  
Haematoma 

Common 
Capillary leak syndrome 
Hypotension 

Respiratory, thoracic 
and mediastinal 
disorders 

Common 
Hypoxia 
Pulmonary oedema 
Dyspnoea 
Epistaxis 
Pleural effusion 
Cough 
Uncommon 
Respiratory failure 
Wheezing  
Oropharyngeal pain 
Tachypnoea 

Common 
Hypoxia 
Pulmonary oedema 
Uncommon 
Respiratory failure 
Dyspnoea 

Gastrointestinal 
Disorders 

Very Common 
Nausea 
Vomiting 
Common 
Dysphagia 
Diarrhoea 
Stomatitis 
Dyspepsia 
Dry mouth 
Constipation 
Uncommon 
Abdominal distension 
Abdominal pain 
Gingival bleeding 
Tongue blistering 
Tongue haematoma 

Uncommon 
Nausea 

Hepatobiliary 
disorders 

Common 
Hyperbilirubinemia 

None 

Skin and 
subcutaneous tissue 
disorders 

Common 
Pruritus 
Rashb 
Hyperhidrosis 
Petechiae 
Uncommon 
Angioedema 
Swelling face 
Palmar-plantar erythrodysesthesia 
syndrome 
Urticaria 
Alopecia 
Pain of skin 
Stasis dermatitis 
Cold sweat 

Uncommon 
Angioedema  
Rash 



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MedDRA System 
Organ Class Frequency of all CTCAE grades  Frequency of CTCAE grade 3 and 

above  
Dry skin 

Musculoskeletal and 
connective tissue 
disorders 

Common 
Back pain 
Bone pain 
Myalgia 
Arthralgia 
Pain in extremity 
Muscular weakness 
Uncommon 
Musculoskeletal pain 
Coccydynia 
Muscle spasms 
Rhabdomyolysis 

Uncommon 
Back pain 
Arthralgia 
Rhabdomyolysis 

Renal and urinary 
disorders 

Common 
Acute kidney injury 
Uncommon 
Renal failure 
Urinary retention 
Urinary tract pain  
Pollakiuria 
Proteinuria 

Uncommon 
Acute kidney injury 

General disorders 
and administration 
site conditions 

Very Common 
Pyrexia 
Chills 
Fatiguec 
Oedema peripherald 
Common 
Influenza-like illness 
Chest pain 
Pain 
Malaise  
Uncommon 
Drug intolerance 
Hypothermia 
Systemic inflammatory response 
syndrome 

Common 
Fatigue 
Uncommon 
Pyrexia 
Chills 
Oedema peripheral 
Drug intolerance 

Investigations Very Common 
Transaminases increasede 
Weight increased 
Common 
Electrocardiogram QT prolonged 
Blood alkaline phosphatase increased 
Blood creatinine increased 
Blood lactate dehydrogenase increased 
Blood creatine phosphokinase increased 
Activated partial thromboplastin time 
prolonged 
International normalised ratio increased 
Uncommon 
Blood fibrinogen decreased 
Bacterial test positive 
Weight decreased 

Very Common 
Transaminases increased 
Uncommon 
Electrocardiogram QT prolonged 
Blood lactate dehydrogenase increased 
Bacterial test positive 

Injury, poisoning and 
procedural 
complications 

Common 
Infusion related reaction  
Contusion 

Uncommon 
Infusion related reaction 

a Includes procedural hypotension, orthostatic hypotension 
b Includes rash pustular, rash maculo-papular, rash erythematous, rash generalised, rash macular 
c Includes asthenia, lethargy 
d Includes generalised oedema, oedema, peripheral swelling, fluid retention, fluid overload, periorbital oedema, 
hypervolaemia 



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e Includes ALT/AST increased, liver function test increased, hepatic enzyme increased 
 
Description of selected adverse reactions 
 
Capillary leak syndrome 
Capillary leak syndrome was reported in 18% (32/176), with 12% (21/176) Grade 2, 3% (6/176) 
Grade 3, 1% (2/176) Grade 4, and fatal in 1.7% (3/176). Of the 25 patients that resumed treatment 
after experiencing an event of CLS, only 1 patient experienced a recurrence of CLS. The median time 
to onset of CLS was short (6 days), with all but 2 patients experiencing the first onset of CLS in 
cycle 1. No patient experienced the first onset of CLS after cycle 2. The overall incidence of CLS was 
similar in patients with BPDCN (20%, 18/89), including 12% (11/89) Grade 2, 2% Grade 3 (2/89), 2% 
Grade 4 (2/89) and 3 fatal cases (3%).  Patients are required to have adequate cardiac function prior to 
administration of ELZONRIS (see sections 4.2 and 4.4).   
 
Hepatotoxicity 
ALT and AST elevations were reported as adverse reactions in 47% (83/176) and 46% (81/176) of 
patients treated with ELZONRIS monotherapy, respectively. ≥ Grade 3 ALT and AST increased were 
reported in 23% (40/176) and 23% (40/176), respectively. Elevated liver enzymes occurred in the 
majority of patients in cycle 1 and were reversible following dose interruptions (see section 4.4). 
Similar onset time and incidence were observed in patients with BPDCN, with 51% (45/89) of patients 
experiencing adverse events of ALT and AST elevations, with 23% (40/89) being ≥ Grade 3. Two 
patients with BPDCN met the laboratory criteria for Hy’s Law; in both cases the laboratory 
abnormalities were noted during Cycle 1. 
 
Haematological abnormalities 
Thrombocytopenia was reported in 30% (53/176) of patients treated with ELZONRIS monotherapy 
and in 35% (31/89) of patients with BPDCN. Thrombocytopenia Grade ≥ 3 was reported in 23% 
(40/176) of patients treated with ELZONRIS monotherapy and in 26% (23/89) of patients with 
BPDCN. The majority of thrombocytopenia events were reported in cycle 1 and cycle 2 of treatment. 
Neutropenia was reported in 9% (15/176) of patients treated with ELZONRIS monotherapy and in 11% 
(10/89) of patients with BPDCN, with events ≥ Grade 3-reported in 6% (11/176) and 8% (7/89), 
respectively. 
 
Hypersensitivity  
Reactions representative of hypersensitivity were reported in 19% (33/176) of patients treated with 
ELZONRIS monotherapy and in 17% (15/89) of patients with BPDCN, with events ≥ Grade 3 
reported in 3% (6/176) and 4% (4/89), respectively (see section 4.4).  
 
Immunogenicity 
Immune response was evaluated by assessment of serum binding reactivity against tagraxofusp (anti-
drug antibodies; ADA) and neutralising antibodies by inhibition of functional activity. Immune 
response was assessed using two immunoassays. The first assay detected reactivity directed against 
tagraxofusp (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of 
tagraxofusp. Two cell-based assays were used to investigate the presence of neutralising antibodies by 
inhibition of a cell-based functional activity.  
 
In 190 patients treated with ELZONRIS in four clinical studies:  
 
• 94% (176/187) of patients evaluable for the presence of pre-existing ADA at baseline before 

treatment were confirmed positive with 27% being positive for the presence of neutralising 
antibodies. The high prevalence of ADA at baseline was anticipated due to diphtheria 
immunisation.  
 

• 100% (N=170) of patients evaluable for treatment-emergent ADA tested positive with most 
patients showing an increase in ADA titre by the end of Cycle 2 of ELZONRIS.  
 



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• 92% (155/169) of ADA-positive patients evaluable for the presence of neutralising antibodies 
post-treatment were neutralising antibody-positive.  
 

• 75% (129/171) of patients evaluable for treatment-emergent anti-IL-3 antibodies tested positive 
with most patients testing positive by Cycle 3 of ELZONRIS. 
 

• 74% (93/126) of patients who tested positive for anti-IL-3 antibodies and were evaluable for the 
presence of neutralising antibodies were neutralising antibody-positive 
 

Reporting of suspected adverse reactions 
Reporting suspected adverse reactions 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 
 
There have been no cases of overdose reported with ELZONRIS. In case of overdose, patients should 
be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic 
treatment provided immediately. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
 
Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents,  
ATC code: L01XX67  
 
Mechanism of action 
 
Tagraxofusp is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and 
truncated diphtheria toxin (DT) fusion protein that targets CD123-expressing cells. Tagraxofusp 
irreversibly inhibits protein synthesis of target cells by inactivating elongation factor 2 (EF2), resulting 
in apoptosis (cell death). 
 
Clinical efficacy and safety 
 
Study STML-401-0114 was a multi-stage (stage 1 dose escalation, stage 2 expansion, stage 3 
confirmatory, stage 4 continued access), non-randomised, open-label, multi-centre study of 
ELZONRIS. ELZONRIS was administered to 65 previously-untreated and 19 previously treated adult 
patients with BPDCN according to the WHO classification who received a 12 mcg/kg dose on days 
1-5 of multiple 21-day cycles (Table 4). Patients who had known active or suspected CNS leukaemia 
were not included in the study. The primary endpoint was the rate of complete response (CR; complete 
resolution of the disease)/clinical complete response (CRc; CR with residual skin abnormality not 
indicative of active disease).  Across all 65 previously untreated patients ELZONRIS resulted in a 
CR/CRc rate of 56.9% (95% CI: 44.0, 69.2), this included 13 patients in the confirmatory efficacy 
cohort where the CR/CRc rate was 53.8% (95% CI: 25.1, 80.8).   (Table 5). 
 
Patient baseline characteristics are presented in Table 4 and key efficacy measures  
in Table 5. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Table 4: Baseline demographics of patients with treatment-naïve BPDCN treated with 
12 mcg/kg of ELZONRIS   
 
 

Parameter 
Treatment-naive 

BPDCN 
N=65 

  
Gender, N (%) 

Male 
Female 

 
52 (80) 
13 (20) 

Race, N (%) 
     White 
      Other                                                                                                      

 
57 (88) 
8 (12) 

Age (years) 
Median 
Minimum, Maximum 

 

68 
22, 84 

ECOG, N (%) 
0 
1 
2 

31 (48) 
31 (48) 

2 (3) 

BPDCN at Baseline, N (%) 
Skin 
Bone Marrow 
Peripheral Blood 
Lymph Nodes 
Visceral 

 
60 (92) 
32 (49) 
17 (26) 
33 (51) 
10 (15) 

 
Table 5: Efficacy measures in patients with treatment-naïve BPDCN treated with 12 mcg/kg of 
ELZONRIS   
 
 

Parameter Confirmatory cohort 
N=13 

Treatment-naive BPDCN 
N=65 

Response rate   

CR/CRc* Rate, N (%) 
(95% CI) 
Duration of CR/CRc (months)** 

Median 
Minimum, Maximum 

7 (54) 
(25.1, 80.8) 

 
NE 

4.7, 28.5 

37 (57) 
(44.0, 62.9) 

 
7.3 

0.7, 49.1  
Overall response rate, N (%) 
(95% CI) 

10 (77) 
(46.2, 95.0) 

49 (75) 
(63.1, 85.2) 

Bridge to stem cell transplant 
Rate, N (%) 
(95% CI) 

 
6 (46) 

(19.2, 74.9) 

 
21 (32) 

(21.2, 45.1) 
Overall survival 

Median 
Minimum, Maximum 

12-month survival, % (95% CI) 
18-month survival, % (95% CI) 
24-month survival, % (95% CI) 

 
18.9 (5.2, NE) 

0.2, 28.9 
53.8 (24.8, 76.0) 
53.8 (24.8, 76.0) 
46.2 (19.2, 69.6) 

 
12.3 (9.3, 35.9) 

0.2, 49.7 
52.2 (38.5, 64.2) 
48.2 (34.6, 60.5) 
40.9 (27.5, 53.9) 

* CRc is defined as complete response with residual skin abnormality not indicative of active disease. 
** Duration of CR/CRc includes patients bridged to stem cell transplantation. 
 



14 

Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ELZONRIS in all subsets of the paediatric population in BPDCN (see section 4.2 for information on 
paediatric use). 
 
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to 
the rarity of the disease it has not been possible to obtain complete information on this medicinal 
product. The European Medicines Agency will review any new information which may become 
available every year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of tagraxofusp has been evaluated in 43 patients with BPDCN. Most patients 
(n=38) had pre-existing anti-drug antibodies (ADA) against the diphtheria toxin (DT) component, due 
to previous vaccination. Pre-existing ADAs resulted in higher clearance and lower tagraxofusp 
concentrations. During treatment, all patients developed high ADA titres, and substantially reduced 
free tagraxofusp levels (see below).  All data referred to below are based on free tagraxofusp 
concentrations in BPDCN patients without pre-existing anti-drug antibodies (ADA, n=5) in the first 
treatment cycle. Descriptive information is included for BPDCN patients with pre-existing ADAs 
(n=38). 
 
Distribution 
Following administration of ELZONRIS 12 mcg/kg via 15-minute infusion in patients with BPDCN 
without pre-existing anti-drug antibodies (ADA, N=5), the mean (SD) unbound area under the plasma 
drug concentration over time curve (AUCunbound) of free tagraxofusp on Day 1 of the first cycle of 
treatment (C1D1) was 230 (123) hr*mcg/L and maximum unbound plasma concentration (Cmax) was 
162 (58.1) mcg/L. 
 
The mean (SD) volume of distribution of free tagraxofusp on C1D1 was 5.1 (1.9) L in 4 patients with 
BPDCN without pre-existing ADA. 
 
Elimination 
Tagraxofusp is expected to be degraded into peptides and its constituent amino acids through 
proteolysis, with no involvement of CYP or transporters.  
 
The mean (SD) clearance of free tagraxofusp at C1D1 was 7.1 (7.2) L/hr in 4 patients with BPDCN 
without pre-existing ADA, and the mean (SD) terminal half-life of tagraxofusp was 0.7 (0.3) hours.  
 
Anti- drug antibody formation affecting pharmacokinetics  
Patients with pre-existing ADA had lower unbound tagraxofusp plasma concentrations (AUC and 
Cmax) at C1D1 than patients without pre-existing ADA. Due to the limitation of the bioanalytical 
method in the presence of ADA, quantitative pharmacokinetic parameters in these patients cannot be 
given.  
 
Pharmacokinetic/pharmacodynamic relationship 
Data collected during Cycle 3 showed increased titres of ADAs and substantially reduced free 
tagraxofusp concentrations.  However, clinical efficacy has been demonstrated beyond Cycle 1 despite 
the reduced exposure. Due to the limitation of the bioanalytical method, the utility of free tagraxofusp 
concentrations as a predictor of response is limited. 
 
Pharmacokinetics in special populations 
Due to the limitation of the bioanalytical method, the pharmacokinetics of tagraxofusp in patients with 
renal or hepatic impairment and the effect of body weight, age, and gender are considered unknown. 
 
Paediatric population 
The pharmacokinetics of tagraxofusp have not been studied in the paediatric population. 
 



15 

5.3 Preclinical safety data 
 
Carcinogenicity or genotoxicity studies have not been performed with tagraxofusp. Tagraxofusp is a 
recombinant protein and is therefore not expected to interact directly with DNA.  
 
At human equivalent doses greater than or equal to 1.6 times the recommended dose based on body 
surface area, severe kidney tubular degeneration/necrosis was observed in cynomolgus monkeys. At 
human equivalent doses equal to the recommended dose, degeneration/necrosis of the choroid plexus 
in the brain was observed in cynomolgus monkeys. These findings were generally noted after 5 days 
of daily dosing. The reversibility of this finding was not assessed at lower doses, but the finding was 
irreversible and became progressively more severe at a human equivalent dose 1.6 times the 
recommended dose, 3 weeks after dosing stopped.  It is unknown if these findings are CD123 
receptor-mediated or non-receptor mediated effects since binding of tagraxofusp to cynomolgus 
monkey CD123 has not been demonstrated. These findings in kidney and choroid plexus are 
considered likely relevant for the clinical situation. 
 
No fertility studies have been conducted with tagraxofusp. A literature-based risk assessment suggests 
that exposure to exogenous IL-3 or blockade of IL-3 signaling may have embryotoxic effects on foetal 
haematopoiesis and embryo-foetal development. The effects of diphtheria toxin exposure on placental 
and embryo-foetal development are unknown. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Trometamol 
Sodium chloride 
Sorbitol (E420) 
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  
2 years. 
 
After opening 
From a microbiological point of view, once opened, the medicinal product should be diluted and 
infused immediately. 
 
After preparation of solution for infusion 
Chemical and physical in-use stability has been demonstrated for 4 hours at 25 °C.  
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user.  
 
6.4 Special precautions for storage 
 
Store and transport frozen (-20 °C ±5 °C). 
 
Do not refreeze after thawing. 
 



16 

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. 
 
6.5 Nature and contents of container  
 
Type I plus glass vial with a butyl rubber stopper and an aluminium/plastic flip-off seal, containing 
1 mL concentrate. 
 
Pack size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
General precautions 
Procedures for proper handling, including personal protective equipment (e.g. gloves), and disposal of 
anticancer medicines should be followed. 
The solution for infusion should be prepared by a healthcare professional using proper aseptic 
technique throughout the handling of this medicinal product. 
 
Preparation and administration 
 
Preparing the infusion 
Ensure the following components required for dose preparation and administration are available prior 
to thawing ELZONRIS: 
 
• One infusion syringe pump 
• One empty 10 mL sterile vial  
• Sodium chloride 9 mg/mL (0.9%) solution for injection 
• Three 10 mL sterile syringes 
• One 1 mL sterile syringe  
• One mini-bifuse Y-connector  
• Microbore tubing  
• One 0.2 µm low protein binding polyethersulfone in-line filter 
 
Use only if the solution is clear and colourless or with a few white to translucent particles. 
Allow vials to thaw at 25 °C or below for up to 1 hour in the outer carton. Do not refreeze a vial once 
thawed. 
 
Determining dosage amount  
Calculation to determine the total ELZONRIS dose (mL) to be administered (see section 4.2):   
 

ELZONRIS dose (mcg/kg) x  patient's body weight (kg)
Diluted vial concentration (100 mcg/ml)

=  Total dose (mL) to be administered 

 
A 2-step process is required for preparation of the final ELZONRIS dose:  
 
Step 1 -prepare 10 mL of 100 mcg/mL ELZONRIS  

- Using a sterile 10 mL syringe, transfer 9 mL of sodium chloride 9 mg/mL (0.9%) solution for 
injection to an empty sterile 10 mL vial. 

- Gently swirl the ELZONRIS vial to mix the contents, remove the cap, and using a sterile 1 mL 
syringe, withdraw 1 mL of thawed ELZONRIS from the product vial. 

- Transfer the 1 mL of ELZONRIS into the 10 mL vial containing the 9 mL of sodium chloride 
9 mg/mL (0.9%) solution for injection. Gently invert the vial at least 3 times to mix the 
contents. Do not shake vigorously. 

- Following dilution the final concentration of ELZONRIS is 100 mcg/mL. 
 



17 

Step 2 – Prepare the ELZONRIS infusion set. 
- Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patient’s 

weight. 
- Draw up the required volume into a new syringe (if more than 10 mL of diluted ELZONRIS 

(100 mcg/mL) is required for the calculated patient dose, repeat step 1 with a second vial of 
ELZONRIS). Label the ELZONRIS syringe. 

- Prepare a separate syringe with at least 3 mL of sodium chloride 9 mg/mL (0.9%) solution for 
injection to be used to flush the administration set once the ELZONRIS dose is delivered. 

- Label the sodium chloride 9 mg/mL (0.9%) solution for injection flush syringe. 
- Connect the sodium chloride 9 mg/mL (0.9%) solution for injection flush syringe to one arm 

of the Y-connector and ensure the clamp is closed. 
- Connect the product syringe to the other arm of the Y-connector and ensure the clamp is 

closed. 
- Connect the terminal end of the Y-connector to the microbore tubing. 
- Remove the cap from the supply side of the 0.2 µm filter and attach it to the terminal end of 

the microbore tubing. 
- Unclamp the arm of the Y-connector connected to the sodium chloride 9 mg/mL (0.9%) 

solution for injection flush syringe. Prime the Y-connector up to the intersection (do not prime 
the full infusion set with sodium chloride 9 mg/mL (0.9%) solution for injection). Re-clamp 
the Y-connector line on the sodium chloride 9 mg/mL (0.9%) solution for injection flush arm. 

- Remove the cap on the terminal end of the 0.2 µm filter and set it aside. Unclamp the arm of 
the Y-connector connected to the product syringe, and prime the entire infusion set, including 
the filter. Recap the filter, and re-clamp the Y-connector line on the product side. The infusion 
set is now ready for delivery for dose administration. 

 
The diluted solution should be used immediately once prepared. 
 
Administration 
 

1. Establish venous access and maintain with sterile sodium chloride 9 mg/mL (0.9%) solution 
for injection. 

2. Administer the prepared ELZONRIS dose via infusion with an infusion syringe pump over 
15 minutes. The total infusion time will be controlled using an infusion syringe pump to 
deliver the entire dose and the sodium chloride 9 mg/mL (0.9%) solution for injection flush 
over 15 minutes.  

3. Insert the ELZONRIS syringe into the infusion syringe pump, open the clamp on the 
ELZONRIS side of the Y-connector and deliver the prepared ELZONRIS dose.  

4. Once the ELZONRIS syringe has been emptied, remove it from the pump and place the 
sodium chloride 9 mg/mL (0.9%) solution for injection flush syringe in the infusion syringe 
pump. 

5. Open the clamp on the sodium chloride 9 mg/mL (0.9%) solution for injection flush side of 
the Y-connector and resume infusion via the infusion syringe pump at the pre-specified flow 
to push the remaining ELZONRIS dose out of the infusion line to complete delivery.  

 
Disposal 
 
ELZONRIS is for single use only. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Stemline Therapeutics B.V. 
Prins Bernhardplein 200, 
1097 JB Amsterdam 



18 

Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1504/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
  
   

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


19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE MARKETING 
AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 



20 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
FUJIFILM Diosynth Biotechnologies U.S.A., Inc 
6051 George Watts Hill Drive 
Research Triangle Park  
NC 27709 
USA 
 
Name and address of the manufacturer(s) responsible for batch release 
 
MIAS Pharma Limited 
Suite 2, Stafford House, Strand Road 
Portmarnock 
Dublin 13 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 



21 

Prior to the launch of ELZONRIS in each Member State the Marketing Authorisation Holder (MAH) 
must agree about the content and format of the educational programme, including communication 
media, distribution modalities, and any other aspects of the programme, with the National Competent 
Authority. 
 
The educational programme is aimed at healthcare professionals to enhance their awareness of the 
early signs and symptoms of specific adverse reactions associated with capillary leak syndrome (CLS). 
 
The MAH shall ensure that in each Member State where ELZONRIS is marketed, all healthcare 
professionals who are expected to use ELZONRIS are provided with the following educational 
package: 

• Guide for healthcare professionals 

• Patient alert card 
 

• Guide for healthcare professionals: 

o Description of CLS which can occur with ELZONRIS 

o Before initiating ELZONRIS therapy check cardiac function and serum albumin 

o During treatment monitor serum albumin, weight gain, new onset or worsening oedema, 
including pulmonary oedema and hypotension including haemodynamic instability 

o Inform the patient about the risk of CLS and how to recognise CLS symptoms 

o Provide patients with the patient alert card 
 

• Patient alert card:   

o That ELZONRIS treatment may increase the potential risk of CLS 

o Signs or symptoms of CLS 

o Patients experiencing or suspecting CLS should immediately contact their prescriber 

o Contact details of the ELZONRIS prescriber 
 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 
This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation 
(EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 
 
Description Due date 
In order to collect further safety and efficacy data for ELZONRIS, the MAH should 
submit the results of a study based on a registry in patients with Blastic 
Plasmacytoid Dendritic Cell Neoplasm (BPDCN) according to an agreed protocol. 

Reports to be 
submitted as 
part of the 
annual re-
assessment  

 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ELZONRIS 1 mg/mL concentrate for solution for infusion  
tagraxofusp  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 mg of tagraxofusp in 1 mL of concentrate. 
 
 
3. LIST OF EXCIPIENTS 
 
Trometamol, sodium chloride, sorbitol (E420), water for injections.  See leaflet for further 
information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 mg/mL 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store and transport frozen 
Keep the vial in the outer carton in order to protect from light 
 



25 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Stemline Therapeutics B.V. 
Prins Bernhardplein 200, 
1097 JB Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1504/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
  



26 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ELZONRIS 1 mg/mL sterile concentrate  
tagraxofusp  
IV after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 mg/mL 
 
 
6. OTHER 
 
 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

  
Package leaflet: Information for the user 

 
ELZONRIS 1 mg/mL concentrate for solution for infusion 

tagraxofusp 
 

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. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any 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 is in this leaflet 
 
1. What ELZONRIS is and what it is used for  
2. What you need to know before you are given ELZONRIS 
3. How ELZONRIS is given 
4. Possible side effects  
5. How to store ELZONRIS 
6. Contents of the pack and other information 
 
 
1. What ELZONRIS is and what it is used for 
 
ELZONRIS contains the active substance tagraxofusp. Tagraxofusp, an anti-cancer medicine, is made 
from two proteins from different sources. One of the proteins can kill cancer cells. This protein is 
delivered to the cancer cell by the second protein. 
 
ELZONRIS is used to treat adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).  
 
BPDCN is a cancer of a rare type of immature immune cells called ‘plasmacytoid dendritic cells’.  It 
can affect many organs including the skin, bone marrow, and lymph nodes. 
 
 
2. What you need to know before you are given ELZONRIS  
 
Do not use ELZONRIS 
- if you are allergic to tagraxofusp or any of the other ingredients of this medicine (listed in 

section 6).  
 
Warnings and precautions  
Talk to your doctor before using ELZONRIS and during treatment if you: 
 
- suddenly gain weight after starting treatment, have new or worsening swelling of your face, limbs 

or joints (oedema) or dizziness (a symptom of low blood pressure). These may be signs of a 
potentially life-threatening condition known as capillary leak syndrome. For more information see 
“Capillary Leak Syndrome” in section 4. 

- get a whistling sound during breathing (wheezing) or have difficulty breathing, hives/ rash, 
itching, or swelling (signs of an allergic reaction).  

- have been told you have a low level of platelets in your blood (thrombocytopenia). 
- have been told you have a low level of a type of white blood cell called a neutrophil (neutropenia). 



29 

- have dizziness, decreased urination, confusion, vomiting, nausea, swelling, shortness of breath, or 
changes in heart rhythm (signs of  tumour lysis syndrome). 

- have abnormal liver test results (possible sign of serious liver injury). 
- have hereditary fructose intolerance (HFI), a rare genetic disorder which means you can’t break 

down sugar in foods and drinks.  
- have kidney or liver problems. 
- start getting headaches, or feeling confused or drowsy, or having speech, vision or memory 

problems. 
- have been told you have cancer in your central nervous system (CNS). You may be given a 

different medicine to treat this. 
 

Your doctor will monitor you and perform regular blood tests to make sure that it is safe for you to use 
this medicine. If you have any problems, your treatment may be temporarily stopped and started again 
when you feel better. 
 
Children and adolescents 
ELZONRIS is not recommended for anyone under the age of 18 years. This is because there is limited 
information on how well it works in this age group.  
 
Other medicines and ELZONRIS  
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
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.  
 
You should not use this medicine if you are pregnant unless you and your doctor decide that the 
benefit to you outweighs the potential risk to the unborn baby .  
 
You should not breast-feed during treatment with ELZONRIS and for at least 1 week after your last 
dose. It is not known if ELZONRIS passes into breast-milk. 
 
If you are a woman who can become pregnant, you will have a pregnancy test about a week before 
starting treatment with ELZONRIS.  
 
You should continue to take your contraception for at least 1 week after your last dose of ELZONRIS. 
Talk to your doctor about the best contraception for you and before stopping your contraception.   
 
Driving and using machines 
Tagraxofusp is unlikely to affect your ability to drive or use machines. 
 
ELZONRIS contains sorbitol (E420) and sodium 
Sorbitol is a source of fructose. If you have hereditary fructose intolerance (HFI), a rare genetic 
disorder, you must not receive this medicine. Patients with HFI cannot break down fructose, which 
may cause serious side effects. 
 
You must tell your doctor before receiving this medicine if you have HFI or if you can no longer take 
sweet foods or drinks because you feel sick, vomit or get unpleasant effects such as bloating, stomach 
cramps or diarrhoea. 
 
This medicine contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially 
‘sodium-free’. 
 
 
3. How ELZONRIS is given 
 
ELZONRIS will be given to you in a hospital or clinic under the supervision of a doctor.  



30 

 
About an hour before your treatment begins, you will be given medicines to help prevent an allergic 
reaction, including anti-histamines, a corticosteroid and paracetamol.  
 
The amount of ELZONRIS given to you is based on your body weight and will be calculated by your 
doctor. The daily recommended dose is 12 micrograms per kilogram of your body weight.  It is given 
as a 15-minute drip into a vein (intravenous infusion), once a day, for the first 5 days of a 21-day 
cycle. 
 
The first cycle will be given to you in hospital. You will be monitored for any side effectsduring 
treatment and for at least 24 hours after the last dose. 
 
You will usually have more than one cycle of treatment. Your doctor will decide how many treatments 
you will receive. 
 
If the first cycle does not cause troublesome side effects, your next cycle of treatment may be given in 
a clinic. You will be monitored during treatment. 
 
If you miss a dose of ELZONRIS  
It is very important for you to keep all your appointments to receive ELZONRIS. If you miss an 
appointment, ask your doctor when to schedule your next dose.  
 
If you stop using ELZONRIS  
Do not stop treatment with ELZONRIS without first talking to your doctor. Stopping your treatment 
may make your condition worse. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects: 
Tell your doctor immediately if you experience the following side effects, as you may need urgent 
medical attention: 
 
• any one or combination of: weight gain,  swelling or puffiness, which may be associated with 

passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and 
a general feeling of tiredness. These symptoms generally develop in a rapid fashion. These could 
be symptoms of a condition called “capillary leak syndrome” which causes blood to leak from the 
small blood vessels into your body and needs urgent medical attention. 

 
Other side effects: 
Tell your doctor if you notice any of the following side effects: 
 
Very common (may affect more than 1 in 10 people): 
- Abnormal blood tests (decreased platelets [thrombocytopenia]; red blood cells [anaemia]; 

decreased albumin in the blood [hypoalbuminemia]) 
- Low blood pressure (hypotension) 
- Feeling or being sick (nausea; vomiting) 
- Fever (pyrexia) 
- Chills 
- Tiredness (fatigue) 
- Swelling of limbs and/or joints (peripheral oedema) 
- Abnormal liver function tests (increased aspartate aminotransferase; increased alanine 

aminotransferase) 



31 

- Weight gain  
 
Common (may affect up to 1 in 10 people): 
- Skin infection (cellulitis) 
- Decreased white blood cells with/without a fever (neutropenia, leukopenia, lymphopenia; febrile 

neutropenia) 
- Complications from breakdown of cancer cells (tumour lysis syndrome) 
- Reaction to treatment [including fever, feeling sick, headache, rash, rapid heartbeat] (cytokine 

release syndrome) 
- Abnormal blood tests [Increased white blood cells (leukocytosis), increased uric acid in the blood 

(hyperuricaemia); decreased calcium in the blood (hypocalcaemia); decreased magnesium in the 
blood (hypomagnesaemia); decreased sodium in the blood (hyponatraemia); decreased potassium 
in the blood (hypokalaemia), increased blood potassium (hyperkalaemia), increased blood 
phosphate (hyperphosphataemia), increased bile pigment in the blood (hyperbilirubinemia), 
increased level of blood sugar (hyperglycaemia), incresed time for blood t clot (activated partial 
thromboplastin time prolonged, international normalised ratio increased)] 

- Decreased appetite 
- Feeling confused 
- Fainting (syncope) 
- Headache 
- Dizziness 
- Blurred vision 
- Fluid around the heart (percardial effusion) 
- Abnormal or fast heartbeat (tachycardia, sinus tachycardia) 
- Blushing (flushing) 
- Decreased level of oxygen in the body (hypoxia) 
- Fluid in the lungs (pulmonary oedema) 
- Build-up of fluid around the lungs that may cause breathlessness (pleural effusion) 
- Difficulty breathing (dyspnoea) 
- Nose bleeds (epistaxis) 
- Coughing 
- Difficulty swallowing (dysphagia) 
- Diarrhoea 
- Constipation 
- Dry mouth or a swollen and sore mouth (stomatitis) 
- Indigestion (dyspepsia) 
- Itchy skin (pruritis) 
- Skin rashes 
- Excessive sweating (hyperhydrosis) 
- Very small purple, red, or brown spots on the skin (petechiae) 
- Pain in shoulders, neck, wrists, legs, and/or arms (pain in extremity), chest, back, joints 

(arthralgia), muscles (myalgia) or bones. 
- Muscle weakness 
- Kidneys suddenly stop working (acute kidney injury) and/or abnormal kidney function tests 

(increased blood creatinine) 
- Flu-like symptoms such as aches and pains, fever and shaking  
- Chest pain 
- Generally feeling unwell (malaise) 
- Abnormal heart rhythm (Electrocardiogram QT prolonged) 
- Increased levels of enzymes in the blood seen in blood tests (lactate dehydrogenase, alkaline 

phosphatase and creatine phosphokinase) 
- Flushing, shivering, fits, fever, trouble breathing, low blood pressure, rapid heartbeat, sudden 

swelling of your face, tongue, or trouble swallowing during the infusion or after the infusion on the 
first day of treatment (infusion-related reaction) 

- Bruising (contusions) 
 



32 

Uncommon: may affect up to 1 in 100 people: 
- Lung infection (pneumonia) 
- Urinary tract infection 
- Gum disease (gingivitis) including bleeding gums 
- Blood test abnormalities [, decreased phosphate in the blood (hypophosphataemia), increased 

lactic acid in the bloodstream (lactic acidosis/acidosis), decreased levels of a blood clotting protein 
(blood fibrinogen decreased)] 

- Unusual mood changes including depression and anxiety 
- Trouble sleeping (insomnia) 
- Brain function disturbances (encephalopathy/ metabolic encephalopathy) 
- Stroke 
- Loss of movement in face (facial paralysis) 
- Persistent bad taste in mouth (dysgeusia)  
- Worsening of multiple sclerosis (relapse) 
- Drowsiness (somnolence) 
- Tingling or numbness (paraesthesia, peripheral sensory neuropathy) 
- Weakness in muscles (peripheral motor neuropathy) 
- Bleeding in the white of the eye (conjunctival haemorrhage) 
- Eye redness (ocular hyperaemia) 
- Eye floaters (vitreous floaters) 
- Irregular heartbeat which can lead to the heart stopping (supraventricular extrasystoles, ventricular 

fibrillation, atrial fibrillation) 
- Slow heart rate (bradycardia) 
- Heart attack (myocardial infarction) 
- High blood pressure (hypertension) 
- Lungs do not function as they should, causing breathlessness (respiratory failure)  
- Noisy breathing (wheezing) 
- Mouth and/or throat pain (oropharyngeal pain) 
- Rapid breathing (tachypnoea) 
- Bloated stomach and stomach ache 
- Blisters on the tongue 
- Blood blister on tongue (tongue haematoma) 
- Swelling of the face, tongue, limbs or joints (angioedema) 
- Redness, swelling and pain on the palms of the hands and/or the soles of the feet (palmar-plantar 

erythrodysesthesia syndrome) 
- Hives (urticaria) 
- Hair loss (alopecia) 
- Skin pain 
- Dry, red, itchy skin and/or sores on the lower legs (stasis dermatitis) 
- Cold sweat 
- Dry skin 
- Pain of joints, muscles and/or bones, including tail bone (musculoskeletal pain, coccydynia) 
- Muscle spasm 
- Muscle pain, weakness, dark or brown urine (rhabdomyolysis) 
- Kidney failure 
- Difficulty passing urine 
- Pain in lower back/ abdomen and/or painful urination (urinary tract pain)  
- Frequent daytime urination (pollakiuria) 
- Urine test abnormality [increased protein (proteinuria)] 
- Inability to tolerate side effects of this medicine (drug intolerance) 
- Low body temperature (hypothermia) 
- Fever or low body temperature, increased heart rate, increased breathing (systemic inflammatory 

response syndrome) 
- Increase in time taken for blood to clot (shown in blood tests)  
- Test positive for bacteria 
- Decreased weight 
 



33 

Reporting of side effects 
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. 
 
 
5. How to store ELZONRIS  
 
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 vial and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Unopened vial: Store and transport frozen (-20 °C±5 °C) 
  
Keep the vial in the outer carton in order to protect from light. 
 
Diluted solution: use immediately or store below 25 °C and use within 4 hours.  Do not re-freeze, once 
thawed. 
 
Do not throw away any medicines via wastewater or household waste. Your healthcare professional 
will throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ELZONRIS contains  
- The active substance is tagraxofusp. Each vial contains 1 mg of tagraxofusp in 1mL of concetrate.  
- The other ingredients are trometamol, sodium chloride, sorbitol (E420) and water for injections 

(see section 2 ‘ELZONRIS contains sorbitol (E420) and sodium’).  
 
What ELZONRIS looks like and contents of the pack 
ELZONRIS concentrate for solution for infusion (sterile concentrate) is a clear, colourless liquid. A 
few white to translucent particles may be present. 
 
The pack size is 1 glass vial per carton. 
 
Marketing Authorisation Holder  
Stemline Therapeutics B.V. 
Prins Bernhardplein 200, 
1097 JB Amsterdam 
Netherlands 
 
Manufacturer 
MIAS Pharma Ltd 
Suite 2, Stafford House, Strand Road, 
Portmarnock 
Dublin 13 
Ireland 
 
 
This leaflet was last revised in  
 
 
Other sources of information 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


34 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website.  
 
--------------------------------------------------------------------------------------------------------------------------- 
  
The following information is intended for healthcare professionals only: 
 
General precautions 
Procedures for proper handling, including personal protective equipment (e.g. gloves), and disposal of 
anticancer medicines should be followed. 
The solution for infusion should be prepared by a healthcare professional using proper aseptic 
technique throughout the handling of this medicinal product. 
 
Preparation and administration 
 
Preparing the infusion 
Ensure the following components required for dose preparation and administration are available prior 
to thawing ELZONRIS: 
 
• One infusion syringe pump 
• One empty 10 mL sterile vial  
• Sodium chloride 9 mg/mL (0.9%) solution for injection 
• Three 10 mL sterile syringes 
• One 1 mL sterile syringe  
• One mini-bifuse Y-connector  
• Microbore tubing  
• One 0.2 µm polyethersulfone in-line low protein-binding filter 
 
Use only if the solution is clear and colourless or with a few white to translucent particles. 
Allow vials to thaw at 25 °C or below for up to 1 hour in the outer carton. Do not refreeze a vial once 
thawed. 
 
Determining dosage amount   
Calculation to determine the total ELZONRIS dose (mL) to be administered (see section 4.2):   
 

ELZONRIS dose (mcg/kg) x  patient's body weight (kg)
Diluted vial concentration (100 mcg/ml)

=  Total dose (mL) to be administered 

 
 
A 2-step process is required for preparation of the final ELZONRIS dose:  
 
Step 1 -prepare 10 mL of 100 mcg/mL ELZONRIS  

- Using a sterile 10 mL syringe, transfer 9 mL of sodium chloride 9 mg/mL (0.9%) solution for 
injection to an empty sterile 10 mL vial. 

- Gently swirl the ELZONRIS vial to mix the contents, remove the cap, and using a sterile 1 mL 
syringe, withdraw 1 mL of thawed ELZONRIS from the product vial. 

- Transfer the 1 mL of ELZONRIS into the 10 mL vial containing the 9 mL of sodium chloride 
9 mg/mL (0.9%) solution for injection. Gently invert the vial at least 3 times to mix the 
contents. Do not shake vigorously. 

- Following dilution the final concentration of ELZONRIS is 100 mcg/mL. 
 

Step 2 – Prepare the ELZONRIS infusion set. 
- Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patient’s 

weight. 



35 

- Draw up the required volume into a new syringe (if more than 10 mL of diluted ELZONRIS 
(100 mcg/mL) is required for the calculated patient dose, repeat step 1 with a second vial of 
ELZONRIS). Label the ELZONRIS syringe. 

- Prepare a separate syringe with at least 3 mL of sodium chloride 9 mg/mL (0.9%) solution for 
injection to be used to flush the administration set once the ELZONRIS dose is delivered. 

- Label the sodium chloride 9 mg/mL (0.9%) solution for injection flush syringe. 
- Connect the sodium chloride 9 mg/mL (0.9%) solution for injection flush syringe to one arm 

of the Y-connector and ensure the clamp is closed. 
- Connect the product syringe to the other arm of the Y-connector and ensure the clamp is 

closed. 
- Connect the terminal end of the Y-connector to the microbore tubing. 
- Remove the cap from the supply side of the 0.2 µm filter and attach it to the terminal end of 

the microbore tubing. 
- Unclamp the arm of the Y-connector connected to the sodium chloride 9 mg/mL (0.9%) 

solution for injection flush syringe. Prime the Y-connector up to the intersection (do not prime 
the full infusion set with sodium chloride 9 mg/mL (0.9%) solution for injection). Re-clamp 
the Y-connector line on the sodium chloride 9 mg/mL (0.9%) solution for injection flush arm. 

- Remove the cap on the terminal end of the 0.2 µm filter and set it aside. Unclamp the arm of 
the Y-connector connected to the product syringe, and prime the entire infusion set, including 
the filter. Recap the filter, and re-clamp the Y-connector line on the product side. The infusion 
set is now ready for delivery for dose administration. 

 
The diluted solution should be used immediately once prepared. 
 
Administration 
 

1. Establish venous access and maintain with sterile sodium chloride 9 mg/mL (0.9%) solution 
for injection. 

2. Administer the prepared ELZONRIS dose via infusion with an infusion syringe pump over 
15 minutes. The total infusion time will be controlled using an infusion syringe pump to 
deliver the entire dose and the sodium chloride 9 mg/mL (0.9%) solution for injection flush 
over 15 minutes.  

3. Insert the ELZONRIS syringe into the infusion syringe pump, open the clamp on the 
ELZONRIS side of the Y-connector and deliver the prepared ELZONRIS dose.  

4. Once the ELZONRIS syringe has been emptied, remove it from the pump and place the 
sodium chloride 9 mg/mL (0.9%) solution for injection flush syringe in the infusion syringe 
pump. 

5. Open the clamp on the sodium chloride 9 mg/mL (0.9%) solution for injection flush side of 
the Y-connector and resume infusion via the infusion syringe pump at the pre-specified flow 
to push the remaining ELZONRIS dose out of the infusion line to complete delivery.  

 
  



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

CONCLUSIONS ON THE GRANTING OF THE MARKETING AUTHORISATION UNDER 
EXCEPTIONAL CIRCUMSTANCES  

 

 



37 

Conclusions presented by the European Medicines Agency on: 

• Marketing authorisation under exceptional circumstances 

The CHMP having considered the application is of the opinion that the risk-benefit balance is 
favourable to recommend the granting of the marketing authorisation under exceptional circumstances 
as further explained in the European Public Assessment Report. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET
	CONCLUSIONS ON THE GRANTING OF THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES