Spectrila

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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 
 
Spectrila 10,000 U powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 10,000 units of asparaginase*. 
One unit (U) is defined as the quantity of enzyme required to liberate one µmol ammonia per minute at 
pH 7.3 and 37°C. 
 
After reconstitution each ml contains 2,500 units of asparaginase. 
 
*Produced in Escherichia coli cells by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Spectrila is indicated as a component of antineoplastic combination therapy for the treatment of acute 
lymphoblastic leukaemia (ALL) in paediatric patients from birth to 18 years and adults. 
 
4.2 Posology and method of administration 
 
Spectrila should be prescribed and administered by physicians and health care personnel experienced 
in the use of antineoplastic products. It should only be given in a hospital setting where appropriate 
resuscitation equipment is available. 
 
Posology 
Spectrila is usually employed as part of combination chemotherapy protocols with other antineoplastic 
agents (see also section 4.5). 
 
Adults and children older than 1 year  
The recommended intravenous dose of asparaginase is 5,000 units per square metre (U/m²) body 
surface area (BSA) given every third day.  
 
Treatment may be monitored based on the trough serum asparaginase activity measured three days 
after administration of Spectrila.  If asparaginase activity values fail to reach target levels, a switch to 
a different asparaginase preparation could be considered (see section 4.4). 
 
Data on efficacy and safety of Spectrila in adults are limited. 
 
Data on efficacy and safety of Spectrila in the post-induction treatment phases are very limited. 



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Special populations 
 
Renal impairment 
No dose adjustment is necessary in patients with renal impairment. 
 
Hepatic impairment 
No dose adjustment is necessary in patients with mild to moderate hepatic impairment. However, 
Spectrila should not be used in patients with severe hepatic impairment (see section 4.3).  
 
Elderly 
Limited data are available for the treatment of patients older than 65 years of age. 
 
Children 0 – 12 months old 
Based on limited data, the recommended dose in infants is as follows: 
- age less than 6 months:  6,700 U/m² BSA,  
- age 6 – 12 months:    7,500 U/m² BSA.  
 
Method of administration 
 
Spectrila is for administration by intravenous infusion only. 
 
The daily amount of Spectrila needed per patient can be diluted in a final volume of 50 - 250 ml 
sodium chloride 9 mg/ml (0.9 %) solution for infusion. The diluted solution of asparaginase may be 
infused over 0.5 to 2 hours. 
 
Asparaginase must not be administered as a bolus dose. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance, any native (non-pegylated) E. coli-asparaginase  

preparation or to any of the excipients listed in section 6.1. 
• Pancreatitis. 
• Severe hepatic impairment (bilirubin > 3 times upper limit of normal [ULN]; transaminases 

> 10 times ULN). 
• Pre-existing known coagulopathy (e.g. haemophilia). 
• History of pancreatitis, serious haemorrhage or serious thrombosis with prior asparaginase 

therapy. 
 



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4.4 Special warnings and precautions for use 
 
Traceability 
It is strongly recommended that every time Spectrila is administered to a patient, the tradename and 
batch number of the product should clearly be recorded in order to link the patient and the batch of the 
product. 
 
The following life-threatening situations may arise during asparaginase treatment in patients of all age 
groups: 
• acute pancreatitis, 
• hepatotoxicity, 
• anaphylaxis, 
• coagulation disorders including symptomatic thrombosis related to the use of central venous 

catheters,  
• hyperglycaemic conditions. 
 
Before initiating therapy bilirubin, hepatic transaminases and coagulation parameters (e.g. partial 
thromboplastin time [PTT], prothrombin time [PT], antithrombin III and fibrinogen) should be 
determined. 
After administration of any asparaginase preparation, close monitoring of bilirubin, hepatic 
transaminases, blood/urinary glucose, coagulation parameters (e.g. PTT, PT, antithrombin III, 
fibrinogen and D-dimer), amylase, lipase, triglycerides and cholesterol is recommended. 
 
Acute pancreatitis 
Treatment with asparaginase should be discontinued in patients developing acute pancreatitis. Acute 
pancreatitis has developed in less than 10 % of patients. In rare cases, haemorrhagic or necrotising 
pancreatitis occurs. There have been isolated reports of fatal outcomes. Clinical symptoms include 
abdominal pain, nausea, vomiting and anorexia. Serum amylase and lipase are usually elevated, 
although in some patients they can be normal due to impaired protein synthesis. Patients with severe 
hypertriglyceridaemia are at increased risk of developing acute pancreatitis. 
These patients should no longer be treated with any asparaginase preparation (see also sections 4.3 
and 4.8). 
 
Hepatotoxicity 
In rare cases severe liver impairment has been described, including cholestasis, icterus, hepatic 
necrosis and hepatic failure with fatal outcome (see sections 4.8 and 4.5). Liver parameters should be 
monitored closely before and during treatment with asparaginase. 
Treatment with asparaginase should be interrupted if patients develop severe hepatic impairment 
(bilirubin > 3 times the upper limit of normal [ULN]; transaminases > 10 times ULN), severe 
hypertriglyceridaemia, hyperglycaemia or coagulation disorder (e.g. sinus vein thrombosis, severe 
bleeding). 
 
Allergy and anaphylaxis 
Because of the risk of severe anaphylactic reactions asparaginase should not be administered as a 
bolus intravenous injection.  
A previous intracutaneous test or a small intravenous test dose can be used. Both procedures, however, 
do not allow for predicting accurately which patients will experience an allergic reaction. 
If allergic symptoms occur, administration of asparaginase must be discontinued immediately and 
appropriate treatment given, which may include antihistamines and corticosteroids. 
 
Coagulation disorders 
Due to the inhibition of protein synthesis (decreased synthesis of factors II, V, VII, VIII, and IX, 
proteins C and S, antithrombin III [AT III]) caused by asparaginase, coagulation disorders can occur 
which can manifest either as thrombosis, disseminated intravascular coagulation (DIC), or bleeding. 
The risk of thrombosis seems to be higher than the risk of bleeding. Symptomatic thromboses related 
to the use of central venous catheters have been described, too.  



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Approximately half of the thrombotic events is localised in cerebral vessels. Sinus vein thrombosis can 
occur. Ischaemic strokes are rare. 
Acquired or genetically decreased physiologic coagulation inhibitors (protein C, protein S, 
antithrombin) are also described in relation to vascular complications. 
Frequent evaluation of coagulation parameters is important before and during asparaginase treatment. 
Expert advice should be sought in cases where AT III is decreased. 
 
Hyperglycaemic conditions 
Asparaginase may induce hyperglycaemia as a consequence of decreased insulin production. 
Additionally it may decrease insulin secretion from pancreatic β-cells and impair insulin receptor 
function. The syndrome is generally self-limiting. However, in rare cases it can result in diabetic 
ketoacidosis. Concomitant treatment with corticosteroids contributes to this effect. Serum and urine 
glucose levels should be regularly monitored and managed as clinically indicated.  
 
Antineoplastic agents 
Asparaginase-induced tumour cell destruction may release large amounts of uric acid, resulting in 
hyperuricaemia. Co-administration of other antineoplastic medicinal products contributes to this 
effect. Aggressive alkalinisation of the urine and use of allopurinol can prevent urate nephropathy. 
 
Glucocorticoids 
A higher risk of thrombosis during induction therapy with asparaginase and prednisone was seen in 
children with a genetic prothrombotic risk factor (factor V G1691A-mutations, prothrombin 
G20210A-variation, methylenetetrahydrofolate reductase [MTHFR] T677T-genotype, increased 
lipoprotein A, hyperhomocysteinaemia). 
 
Contraceptives 
Effective contraception must be used during treatment and for at least 3 months after asparaginase 
discontinuation. Since an indirect interaction between components of the oral contraception and 
asparaginase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such 
clinical situation (see section 4.6). 
 
Philadelphia chromosome-positive patients 
Efficacy and safety of Spectrila have not been established in Philadelphia chromosome-positive 
patients. 
 
Recommended control examinations for patients of all age groups  
 
Asparaginase activity 
Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to rule 
out accelerated reduction of asparaginase activity.  Preferably, levels should be measured three days 
after the last asparaginase administration, i.e. usually directly before the next dose of asparaginase is 
given. Low asparaginase activity levels are often accompanied by the appearance of anti-asparaginase 
antibodies. In such cases, a switch to a different asparaginase preparation should be considered. Expert 
advice should first be sought.  
 
Hypoalbuminaemia 
As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases very 
commonly in patients treated with asparaginase. Since serum protein is important for the binding and 
transport function of some active substances, the serum protein level should be monitored regularly.  
 
Hyperammonaemia 
Plasma ammonia levels should be determined in all patients with unexplained neurologic symptoms or 
severe and prolonged vomiting. In case of hyperammonaemia with severe clinical symptoms, 
therapeutic and pharmacological measures that rapidly reduce plasma ammonia levels (e.g. protein 
restriction and haemodialysis), reverse catabolic states and increase removal of nitrogen wastes should 
be initiated and expert advice sought. 
 



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Reversible posterior leukoencephalopathy syndrome 
Reversible posterior leukoencephalopathy syndrome (RPLS) may occur rarely during treatment with 
any asparaginase (see section 4.8). This syndrome is characterised in magnetic resonance imaging 
(MRI) by reversible (from a few days to months) lesions/oedema, primarily in the posterior region of 
the brain. Symptoms of RPLS essentially include elevated blood pressure, seizures, headaches, 
changes in mental state and acute visual impairment (primarily cortical blindness or homonymous 
hemianopsia). It is unclear whether the RPLS is caused by asparaginase, concomitant treatment or the 
underlying diseases.  
RPLS is treated symptomatically, including measures to treat any seizures. Discontinuation or dose 
reduction of concomitantly administered immunosuppressive medicinal products may be necessary. 
Expert advice should be sought. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
General 
Asparaginase may increase the toxicity of other medicinal products through its effect on liver function, 
e.g. increased hepatotoxicity with potentially hepatotoxic medicines, increased toxicity of medicinal 
products metabolised by the liver or bound to plasma proteins and altered pharmacokinetics and 
pharmacodynamics of medicines bound to plasma proteins. Therefore, caution should be exercised in 
patients receiving other medicines metabolised by the liver.  
Hepatic parameters should be monitored when potentially hepatotoxic medicinal products are given 
concomitantly with asparaginase (see sections 4.4 and 4.8).  
 
Myelosuppressive agents 
During treatment with asparaginase-containing regimens, myelosuppression, potentially affecting all 
three cell lines, and infections can occur. Concomitant treatment with myelosuppressive medicinal 
products and those known to cause infections are major contributing factors and patients should be 
carefully monitored for signs and symptoms of myelosuppression and infection (see section 4.8). 
 
Vincristine 
The toxicity of vincristine may be additive with that of asparaginase if both agents are administered 
concomitantly. Therefore, vincristine should be given 3 to 24 hours before administration of 
asparaginase in order to minimise toxicity. 
 
Glucocorticoids and/ or anticoagulants 
Concomitant use of glucocorticoids and/ or anticoagulants with asparaginase may increase the risk of a 
change in coagulation parameters (see section 4.4).  
This can promote tendency to bleeding (anticoagulants) or thrombosis (glucocorticoids). Caution is 
therefore needed when anticoagulants (e.g. coumarin, heparin, dipyridamole, acetylsalicylic acid or 
nonsteroidal anti-inflammatory medicinal products) or glucocorticoids are given at the same time.  
 
Methotrexate (MTX) 
Inhibition of protein synthesis secondary to the asparaginase-induced depletion of asparagine has been 
shown to attenuate the cytotoxic effect of MTX which requires cell replication for its antineoplastic 
activity. This antagonism is observed if asparaginase is administered prior to or concurrently with 
methotrexate. Conversely, the antitumour effects of methotrexate are enhanced when asparaginase is 
administered 24 hours following methotrexate treatment. This regimen has been shown to reduce the 
gastrointestinal and haematological effects of methotrexate.  
 
Cytarabine 
Laboratory in vitro and in vivo data indicate that the efficacy of high-dose cytarabine is reduced by 
prior administration of asparaginase. However, when asparaginase was given after cytarabine a 
synergistic effect was observed. This effect was most prominent with a treatment interval of about 
120 hours.  



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Vaccination 
Concomitant vaccination with live vaccines increases the risk of serious infection. Immunisation with 
live vaccines should therefore take place at the earliest 3 months after completion of the course of 
antileukaemic treatment. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
Women of childbearing potential have to use effective contraception and avoid becoming pregnant 
while being treated with asparaginase-containing chemotherapy. Since an indirect interaction between 
components of the oral contraception and asparaginase cannot be ruled out, oral contraceptives are not 
considered sufficiently safe in such clinical situation. A method other than oral contraceptives should 
be used in women of childbearing potential (see section 4.4).Men should use effective contraceptive 
measures and be advised to not father a child while receiving asparaginase. The time period following 
treatment with asparaginase when it is safe to become pregnant or father a child is unknown. As a 
precautionary measure it is recommended to wait for three months after completion of treatment. 
However, treatment with other chemotherapeutic agents should also be taken into consideration.  
 
Pregnancy 
There are no data on the use of asparaginase in pregnant women. No reproduction studies in animals 
with asparaginase were performed but studies with asparaginase preparations in mice, rats, chicken 
and rabbits have shown embryotoxic and teratogenic effects (see section 5.3). Based on results from 
animal studies and its mechanism of action, Spectrila should not be used during pregnancy unless the 
clinical condition of the woman requires treatment with asparaginase. 
 
Breast-feeding 
It is unknown whether asparaginase is excreted into human breast milk. Because potential serious 
adverse reactions may occur in nursing infants, Spectrila should be discontinued during breast-feeding. 
 
Fertility 
No human data on the effect of asparaginase on fertility are available.  
 
 
4.7 Effects on ability to drive and use machines 
 
Spectrila has moderate influence on the ability to drive and use machines, especially through its 
potential effects on the nervous and gastrointestinal systems (see section 4.8).  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The primary toxicity of asparaginase results from immunologic reactions caused by exposure to the 
bacterial protein. Hypersensitivity reactions range from transient flushing or rash and urticaria to 
bronchospasm, angioedema and anaphylaxis. 
 
In addition, treatment with asparaginase can result in disturbances in organ systems which exhibit a 
high level of protein synthesis. Decreased protein synthesis can predominantly lead to liver 
impairment, acute pancreatitis, decreased insulin production with hyperglycaemia, decreased 
production of clotting factors (especially fibrinogen and antithrombin III) leading to coagulation 
disorders (thrombosis, bleeding), and decreased production of lipoproteins resulting in 
hypertriglyceridaemia. 
 
Most serious side effects of Spectrila include severe hypersensitivity reactions such as anaphylactic 
shock (rare), thromboembolic events (common), acute pancreatitis (common), and severe 
hepatotoxicity, e.g. jaundice, hepatic necrosis, hepatic failure (rare). 



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Most frequently (very common) observed side effects of Spectrila include hypersensitivity reactions, 
hyperglycaemia, hypoalbuminaemia, nausea, vomiting, diarrhoea, abdominal pain, oedema, fatigue, 
and change in laboratory parameters (e.g. transaminases, bilirubin, blood lipids, coagulation 
parameters).   
Since Spectrila is usually used in combination therapy with other antineoplastic agents, the 
demarcation from undesirable effects of other medicinal products is often difficult. 
 
Tabulated list of adverse reactions 
The following adverse reactions, listed in table 1, have been accumulated from clinical trials with 
Spectrila in 125 children with newly diagnosed acute lymphoblastic leukaemia as well as post-
marketing experience with other E. coli-derived asparaginase preparations in children and adults.  
Adverse reactions are ranked under headings of frequency, the most frequent first. Within each 
frequency grouping, adverse reactions are presented in the order of decreasing seriousness.  
 
Frequencies in this table are defined using the following convention:  
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 
to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). 
  
 
Table 1 
System organ class Frequency and symptom 
Infections and infestations Not known 

Infections 
Blood and lymphatic system 
disorders 

Common 
Disseminated intravascular coagulation (DIC), anaemia, 
leukopenia, thrombocytopenia 

Immune system disorders Very common 
Hypersensitivity including flushing, rash, hypotension, 
oedema/angioedema, urticaria, dyspnoea 
 
Common 
Hypersensitivity including bronchospasm  
 
Rare 
Anaphylactic shock 

Endocrine disorders 
 

Very rare 
Secondary hypothyroidism, hypoparathyroidism 

Metabolism and nutrition 
disorders 

Very common 
Hyperglycaemia, hypoalbuminaemia 
 
Common 
Hypoglycaemia, decreased appetite, weight loss 
 
Uncommon 
Hyperuricaemia, hyperammonaemia 
 
Rare 
Diabetic ketoacidosis 

Psychiatric disorders Common 
Depression, hallucination, confusion 

Nervous system disorders Common 
Neurological signs and symptoms including agitation, dizziness 
and somnolence 
 
Uncommon 
Headaches 



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Rare 
Ischaemic stroke, reversible posterior leukoencephalopathy 
syndrome (RPLS), convulsion, disturbances in consciousness 
including coma 
 
Very rare 
Tremor 

Vascular disorders Common 
Thrombosis especially cavernous sinus thrombosis or deep vein 
thrombosis, haemorrhage 

Gastrointestinal disorders Very common 
Diarrhoea, nausea, vomiting, abdominal pain  
 
Common 
Acute pancreatitis 
 
Rare 
Haemorrhagic pancreatitis, necrotising pancreatitis, parotitis 
 
Very rare 
Pancreatitis with fatal outcome, pancreatic pseudocyst  

Hepatobiliary disorders Rare 
Hepatic failure with potentially fatal outcome, hepatic necrosis, 
cholestasis, jaundice  
 
Not known 
Hepatic steatosis 

General disorders and 
administration site conditions 

Very common 
Oedema, fatigue 
 
Common 
Pain (back pain, joint pain) 

Investigations 
 

Very common 
Increase in transaminases, blood bilirubin, blood alkaline 
phosphatase, blood cholesterol, blood triglyceride, very low 
density lipoprotein (VLDL), lipoprotein lipase activity, blood 
urea, ammonia, blood lactate dehydrogenase (LDH),  
Decrease in antithrombin III, blood fibrinogen, blood cholesterol, 
low density lipoprotein (LDL), total protein 
 
Common 
Increase in amylase, lipase, abnormal electroencephalogram 
(EEG) (reduced alpha wave activity, increased theta and delta 
wave activity) 

 
Description of selected adverse reactions 
 
Immune system disorders 
Spectrila can induce antibodies of different immunoglobulin classes (IgG, IgM, IgE). These antibodies 
may induce clinical allergic reactions, inactivate the enzymatic activity or accelerate the elimination of 
asparaginase. 
Allergic reactions can manifest as flushing, rash, pain (joint pain, back pain and abdominal pain), 
hypotension, oedema/angioedema, urticaria, dyspnoea, bronchospasm up to anaphylactic shock. 
The probability of the occurrence of allergic reactions increases with the number of administered 
doses; however, in very rare cases reactions can occur at the first dose of asparaginase. Most 



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hypersensitivity reactions to asparaginase are observed during subsequent treatment phases (re-
induction treatment, delayed intensification). 
 
In a clinical trial in children with newly diagnosed ALL (study MC-ASP.5/ALL), the following 
frequencies of allergic events were observed (table 2). 
 
Table 2: Frequency of patients with allergic reactions (MC-ASP.5/ALL; Safety analysis set) 
 

Treatment group Spectrila Reference asparaginase 
Number of patients 97 101 
Allergic reactions within 12 hours after 
asparaginase infusion during induction treatment 2 (2.1%) 5 (5.0%) 

Any allergic event* within 24 hours after 
asparaginase infusion during induction treatment 16 (16%) 24 (24%) 

   
*Including all allergic reactions within 12 hours after asparaginase infusion and all adverse events with CTCAE terms syncope (fainting), 
hypotension, rash, flushing, pruritus, dyspnoea, injection site reaction or airway obstruction within 24 hours after asparaginase infusion 

 
No allergic reactions were observed in any of the 12 infants < 1 year of age during treatment with 
Spectrila (study MC-ASP.6/INF). 
In case of occurrence of allergic symptoms, administration of Spectrila should be discontinued 
immediately (see section 4.4). 
 



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Immunogenicity 
In the study in children/adolescents aged 1 – 18 years with de novo ALL (study MC-ASP.5/ALL), by 
day 33 of induction treatment 10 patients in the Spectrila group (10.3 %) and 9 in the reference group 
(8.9 %) were measured positive for anti-asparaginase antibodies at least at one time point.  
A comparable proportion of patients in both groups developed anti-asparaginase antibodies before the 
start of the post-induction treatment phase (Spectrila 54.6 % vs. reference E. coli-asparaginase 
52.5 %). The majority of anti-asparaginase antibodies developed in the time gap between the last 
asparaginase infusion on day 33 and start of post-induction treatment at day 79. 
No anti-asparaginase antibodies were detected in any of the 12 infants < 1 year of age during treatment 
with Spectrila (study MC-ASP.6/INF). 
 
Hypothyroidism 
There have been reports of transitory secondary hypothyroidism probably caused by a decrease in the 
serum thyroxin-binding globulin due to asparaginase-induced protein synthesis inhibition.  
 
Hypoalbuminaemia 
As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases very 
commonly in patients treated with asparaginase (see section 4.4). As a consequence of 
hypoalbuminaemia oedema can occur. 
 
Dyslipidemia  
Mild to moderate changes in blood lipid values (e.g. increased or decreased cholesterol, increased 
triglyceride, increased VLDL fraction and decreased LDL, increased lipoprotein lipase activity) are 
very commonly observed in patients treated with asparaginase, which in most cases present without 
clinical symptoms. Concomitant administration of glucocorticoids may be a contributing factor. 
However, in rare cases severe hypertriglyceridaemia (triglycerides > 1,000 mg/dl) has been reported 
which increases the risk of development of acute pancreatitis. Asparaginase-associated 
hyperlipidaemia should be treated depending on its severity and on clinical symptoms. 
 
Hyperammonaemia 
Hyperammonaemia has been reported uncommonly in patients treated with asparaginase-containing 
therapy protocols, especially if patients suffer additionally from hepatic impairment. In very rare 
cases, severe hyperammonaemia has been reported which may induce neurologic disorders such as 
seizures and coma. 
 
Hyperglycaemia and hypoglycaemia 
Changes in endocrine pancreatic function are observed very commonly during treatment with 
asparaginase and manifest predominantly as hyperglycaemia. These events are usually transient.  
In rare cases, diabetic ketoacidosis has been reported. 
Hypoglycaemia mostly without clinical symptoms has been commonly observed in patients treated 
with asparaginase. The mechanism leading to this reaction is unknown. 
 
Nervous system disorders 
Adverse central nervous system reactions observed in patients treated with asparaginase-containing 
therapy protocols include changes in EEG, seizures, dizziness, somnolence, coma and headache.  
The causes of these nervous system disorders are unclear. Hyperammonaemia and sinus vein 
thrombosis may need to be excluded. 
In rare cases, a reversible posterior leukoencephalopathy syndrome (RPLS) has been observed during 
therapy with asparaginase-containing regimens.  
 
Gastrointestinal disorders 
Nausea/vomiting are very commonly observed in patients treated with asparaginase-containing 
treatment regimens but are usually mild. Anorexia, loss of appetite, abdominal cramps, diarrhoea and 
weight loss have also been reported. 
Acute pancreatitis has developed in less than 10 % of patients. In rare cases, haemorrhagic or 
necrotising pancreatitis occurs. There have been isolated reports of fatal outcomes. A few cases of 
asparaginase-induced parotitis have been reported in the literature.  



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Paediatric population 
Data on safety of Spectrila in infants < 1 year of age is limited. 
 
Adults and other special populations 
Qualitatively, the same asparaginase-induced adverse drug reactions are observed in adults and 
children; however, some of these undesirable effects (e.g. thromboembolic events) are known to occur 
with a higher frequency in adult patients compared to the paediatric population. 
 
Because of a higher frequency of comorbidities such as liver and/or renal impairment, patients 
> 55 years of age usually tolerate asparaginase treatment worse than paediatric patients.  
 
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 
 
No case of asparaginase overdose with clinical symptoms has been reported. There is no specific 
antidote. Treatment is symptomatic and supportive. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents; Other antineoplastic agents 
ATC code: L01XX02 
 
Mechanism of action 
Asparaginase hydrolyses asparagine to aspartic acid and ammonia.  In contrast to normal cells, 
lymphoblastic tumour cells have a very limited capacity for synthesising asparagine because of a 
significantly reduced expression of asparagine synthetase. Therefore, they require asparagine which 
diffuses from the extracellular environment. As a result of asparaginase-induced asparagine depletion 
in serum, protein synthesis in lymphoblastic tumour cells is disturbed while sparing most normal cells. 
Asparaginase may also be toxic to normal cells that divide rapidly and are dependent to some degree 
on exogenous asparagine supply.  
Due to the asparagine concentration gradient between the extra- and intravascular space, asparagine 
levels are subsequently also reduced in the extravascular spaces, e.g. the cerebrospinal fluid. 
 
Pharmacodynamic effects 
In a clinical trial in children with de novo ALL (study MC-ASP.4/ALL) it was shown that 
immediately after the end of infusion of asparaginase mean asparagine concentrations in serum 
dropped from the pre-dose concentrations of about 40 µM to below the lower limit of quantification of 
the bioanalytical method (< 0.5 µM). The mean asparagine concentrations in serum remained below 
0.5 µM from immediately after the end of first infusion of asparaginase until at least three days after 
the last infusion. Thereafter, asparagine serum levels increased again and returned to normal values 
within 1 – 3 weeks. 
In addition to asparagine, asparaginase is also able to cleave the amino acid glutamine to glutamic acid 
and ammonia, however with much less efficiency. Clinical trials with asparaginase have shown that 
glutamine levels are only moderately affected with a very high interindividual variability. Immediately 
after the end of infusion of asparaginase, serum levels of glutamine declined by a maximum of 50 % 
from pre-dose levels of about 400 µM but rapidly returned to normal values within a few hours. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.whocc.no/atc_ddd_index/?code=L01XX


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Clinical efficacy and safety 
 
Study in children/adolescents aged 1 – 18 years with de novo ALL  
Efficacy and safety of Spectrila was compared to a native E. coli-asparaginase (reference medicinal 
product) in a randomised double-blinded clinical trial (study MC-ASP.5/ALL; based on ALL 
treatment protocol DCOG ALL10) in 199 children/adolescents aged 1 – 18 years with de novo ALL. 
Patients received 5,000 U/m² asparaginase (Spectrila versus a reference E.coli- asparaginase) at 
days 12, 15, 18, 21, 24, 27, 30, and 33 of induction treatment. After induction treatment, patients 
continued treatment with chemotherapy regimens which included further treatment with 
asparaginases.  
The primary endpoint was the rate of patients with complete asparagine depletion in serum (defined as 
asparagine serum levels below the lower limit of quantification (< 0.5 µM) at all time points measured 
from day 12 up to day 33) during induction treatment. The objective of the study was to demonstrate 
the non-inferiority of Spectrila to the reference E. coli-asparaginase with regard to the primary 
endpoint. 
 
Results of this study are summarised in table 3: 
 
Table 3: Efficacy results (MC-ASP.5/ALL; Full analysis set) 
 
Treatment group Spectrila Reference asparaginase 
Number of patients 98 101 
Complete asparagine depletion in serum 

Yes 93 (94.9 %) 95 (94.1 %) 
No 2 (2.0 %) 2 (2.0 %) 
Not evaluable 3 (3.1 %) 4 (4.0 %) 
Difference (95 % CIa); P valueb 0.8 % (-6.25 %; 8.04 %); P = 0.0028 

Complete asparagine depletion in CSF  
Yesc 82 (83.7 %) 88 (87.1 %) 
No 1 (1.0 %) 6 (5.9 %) 
Not evaluable 15 (15.3 %) 7 (6.9 %) 
Difference (95 % CIa) -3.5 % (-13.67 %; 6.58 %) 

Complete remission rate at end of induction treatment 
Yes 90 (91.8 %) 97 (96.0 %) 
No 2 (2.0 %) 2 (2.0 %) 
Not evaluable / not known 6 (6.1 %) 2 (2.0 %) 
Difference (95 % CIa) -4.2 % (-11.90 %; 2.81 %) 

MRD status at end of induction treatment 
MRD negative 29 (29.6 %) 32 (31.7 %) 
MRD positive 63 (64.3 %) 60 (59.4 %) 
Not evaluable / not known 6 (6.1 %) 9 (8.9 %) 
Difference (95 % CIa) -2.1 % (-14.97 %; 10.84 %) 

CI = confidence interval; CSF = cerebrospinal fluid; MRD = minimal residual disease 
a Unconditional exact confidence interval based on Chan and Zhang 
b Unconditional exact test of non-inferiority for binomial differences based on restricted maximum likelihood estimates 
c Patients were considered as responders if asparagine values in CSF on protocol day 33 were below the lower limit of quantification. 

 
During induction treatment, asparaginase-typical adverse drug reactions like elevated liver 
enzymes/bilirubin (≥ CTCAE Grade III: 44.3 % vs. 39.6 %), haemorrhage or thromboembolism 
(≥ CTCAE Grade II: 2.1 % vs. 4.0 %), and neurotoxicity (≥ CTCAE Grade III: 4.1 % vs. 5.9 %) were 
observed in comparable frequencies in both groups (Spectrila versus reference).  
 
Study in infants with de novo ALL 
In an uncontrolled clinical trial (study MC-ASP.6/INF), 12 infants (median age [range] at time of first 
infusion: 6 months [0.5 – 12.2 months]) with de novo ALL were treated with Spectrila within the 



14 

INTERFANT-06 protocol. Patients received asparaginase at a dose of 10,000 U/m², adjusted to the 
current age of the patient at the time of administration (< 6 months: 6,700 U/m²; 6 – 12 months: 
7,500 U/m²; > 12 months: 10,000 U/m²) on days 15, 18, 22, 25, 29, and 33 of induction treatment. 
Asparagine depletion in serum was complete in 11 of 12 patients (92%). All 12 patients (100 %) were 
in CR after induction treatment.  
 
5.2 Pharmacokinetic properties 
 
Pharmacokinetic parameters of Spectrila were determined in 7 adult patients after intravenous infusion 
of 5,000 U/m². 
 
Absorption 
Asparaginase is not absorbed by the gastrointestinal tract, thus Spectrila must be given intravenously. 
 
Distribution 
Asparaginase is distributed mainly within the intravascular space. The mean (Standard Deviation, SD) 
of the volume of distribution at steady state (Vdss) was 2.47 l (0.45 l). 
Asparaginase does not seem to penetrate the blood-brain barrier in measurable amounts. 
Median (range) maximum serum concentrations of asparaginase activity were 2,324 U/l (1,625 – 
4,819 U/l). Peak (Cmax) of asparaginase activity in serum was reached with a delay of approximately 
2 hours after the end of the infusion.  
After repeated administration of asparaginase at a dose of 5,000 U/m² every third day, trough 
asparaginase activity levels in serum ranged from 108 to 510 U/l.  
 
Biotransformation 
The metabolism of asparaginase is not known but thought to occur via degradation within the reticulo-
histiocytic system and by serum proteases. 
 
Elimination 
The mean ± SD terminal half-life (elimination half-life) of asparaginase activity in serum was 
25.8 ± 9.9 h, with a range between 14.2 and 44.2 h.  
 
Pharmacokinetic/pharmacodynamic relationship(s) 
In clinical trials with asparaginase, trough asparaginase serum activity levels greater than 100 U/l were 
achieved in the majority of patients which nearly always correlated with a complete depletion of 
asparagine in serum and cerebrospinal fluid (CSF). Even those few patients with trough asparaginase 
serum activity levels of 10 – 100 U/l usually experienced complete asparagine depletion in serum and 
CSF. 
 
Paediatric population 
Pharmacokinetic parameters after administration of 5,000 U/m² of Spectrila were determined in 
14 children/adolescents (age 2 – 14 years) with de novo ALL (study MC-ASP.4/ALL). Results are 
shown in table 4. 
 
Table 4: Pharmacokinetic parameters of Spectrila in 14 children/adolescents 

Parameter Median (range)  
Area under the curve (AUC0-72h) 60,165 (38,627 – 80,764) U*h/l 
Maximum serum concentration (Cmax) 3,527 (2,231 – 4,526) U/l 
Time to Cmax  0 (0 – 2) h 
Half-life  17.33 (12.54 – 22.91) h 
Total clearance 0.053 (0.043 – 0.178) l/h 
Volume of distribution  0.948 (0.691 – 2.770) l 

 



15 

Median trough serum asparaginase activities were measured in 81 children/adolescents with de novo 
ALL three days after infusion of asparaginase (just before the next dose had to be given) during 
induction treatment and ranged from 168 to 184 U/l (study MC-ASP.5/ALL). 
 
Trough serum activity levels were measured in 12 infants (age from birth to 1 year) with de novo ALL 
(study MC-ASP.6/INF). Median (range) serum trough asparaginase activities on days 18, 25, and 33 
were 209 (42 – 330) U/l, 130 (6 – 424) U/l, and 32 (1 – 129) U/l, respectively. The lower median 
activity level on day 33 compared to the former two measurements was in part due to the fact that this 
last serum sample was taken 4 days after the last infusion of asparaginase instead of three days on the 
other occasions.  
 
5.3 Preclinical safety data 
 
Non-clinical repeat-dose toxicity and safety pharmacology studies in rats revealed no special hazard 
for humans, except a slight but significant saluretic effect at doses below the recommended dose for 
ALL/LBL patients. Additionally, the urinary pH value and the relative weight of kidneys were 
increased at exposures considered sufficiently in excess of the maximum human exposure indicating 
little relevance to clinical use.  
 
Evidence from published data with asparaginase renders the mutagenic, clastogenic and carcinogenic 
potential of asparaginase negligible.  
 
Asparaginase caused an increase in the incidence of malformations (including those of the central 
nervous system, heart and skeletal system) and foetal death at doses that are similar to or in excess of 
those proposed clinically (on a U/m² basis) in a number of species including the mouse, rat and/or 
rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose 
 
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 vials 
4 years 
 
Reconstituted and diluted solution 
Chemical and physical in-use stability has been demonstrated for 2 days at 2 °C – 8 °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 and 
would normally not be longer than 24 hours at 2 °C – 8 °C unless reconstitution/dilution has taken 
place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Keep the vial in the outer carton in order to protect from light. 
 



16 

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Colourless 20 ml glass vial (Type I glass) closed with butylrubber stopper, aluminium seal and plastic 
flip-off cap, containing 10,000 units of asparaginase. 
 
Each pack contains either 1 or 5 vials. Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
To dissolve the powder, 3.7 ml of water for injections are carefully squirted against the inner wall of 
the vial with an injection syringe (do not squirt directly on or into the powder). Dissolution of the 
contents is achieved by slow turning (avoid froth formation due to shaking). The reconstituted solution 
may exhibit a slight opalescence. 
 
The calculated quantity of asparaginase is dissolved further in 50 to 250 ml of sodium chloride 
9 mg/ml (0.9 %) solution for infusion. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
medac Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
Tel.: +49 4103 8006-0 
Fax: +49 4103 8006-100 
E-mail: contact@medac.de 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1072/001 
EU/1/15/1072/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
14 January 2016 
 
 
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. 
 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 



18 

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

 
Name and address of the manufacturer of the biological active substance 
Wacker Biotech GmbH 
Hans-Knoell-Str. 3 
07745 Jena  
Germany 
 
Name and address of the manufacturer(s) responsible for batch release 
medac Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
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 
 
The requirements for submission of periodic safety update reports 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 shall submit the first periodic safety update report 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 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. 

 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



21 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Spectrila 10,000 U powder for concentrate for solution for infusion 
 
Asparaginase 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 10,000 units of asparaginase. 
After reconstitution 1 ml contains 2,500 units of asparaginase.  
 
 
3. LIST OF EXCIPIENTS 
 
Excipient: sucrose. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
 
1 vial 
5 vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Intravenous use after further dilution. 
 
 
 
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: 
 
In-use stability has been demonstrated for 2 days at 2 °C – 8 °C. 
 
 



22 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Keep the vial in the outer carton in order to protect from light. 
 
 
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 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1072/001 (1 vial) 
EU/1/15/1072/002 (5 vials) 
 
 
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: 
 



23 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Spectrila 10,000 U powder for concentrate for solution for infusion 
 
Asparaginase 
 
For intravenous use ONLY. 
Intravenous use after further dilution. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
Store in a refrigerator. 
 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



25 

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. 

 
Package leaflet: Information for the patient 

 
Spectrila 10,000 U powder for concentrate for solution for infusion 

Asparaginase 
 
Read all of this leaflet carefully before you are given 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 Spectrila is and what it is used for 
2. What you need to know before you are given Spectrila 
3. How to use Spectrila 
4. Possible side effects 
5. How to store Spectrila 
6. Contents of the pack and other information 
 
 
1. What Spectrila is and what it is used for 
 
Spectrila contains asparaginase, which is an enzyme that interferes with natural substances necessary 
for cancer cell growth. All cells need an amino acid called asparagine to stay alive. Normal cells can 
make asparagine for themselves, while some cancer cells cannot. Asparaginase lowers asparagine 
level in blood cancer cells and stops the cancer growing. 
 
Spectrila is used to treat adults and children with acute lymphoblastic leukaemia (ALL) which is a 
form of blood cancer. Spectrila is used as part of a combination therapy.  
 
2. What you need to know before you are given Spectrila 
 
Spectrila will not be used: 
• if you are allergic to asparaginase or to any of the other ingredients of this medicine (listed in 

section 6),  
• if you have or previously had inflammation of the pancreas (pancreatitis), 
• if you have severe liver function problems,  
• if you have a blood clotting disorder (such as haemophilia), 
 
Warnings and precautions 
Talk to your doctor or nurse before you are given Spectrila. 
 
The following life-threatening situations could arise during treatment with Spectrila: 
• severe inflammation of the pancreas (acute pancreatitis), 
• liver problems, 
• a serious allergic reaction which causes difficulty in breathing or dizziness, 
• blood clotting disorders (bleeding or formation of blood clots),  
• increased blood sugar values. 
 
Before and during treatment with Spectrila your doctor will carry out blood tests. 



26 

 
If severe liver problems occur, treatment with Spectrila must be interrupted immediately. 
 
If allergic symptoms occur, intravenous infusion of Spectrila must be discontinued immediately. You 
may be given anti-allergic medicines and, if necessary, medicines to stabilise your circulation. In the 
majority of cases, your treatment can be continued by switching to other medicines containing 
different forms of asparaginase. 
 
Blood clotting disorders may require you to receive fresh plasma or a certain type of protein 
(antithrombin III) in order to reduce the risk of bleeding or formation of blood clots (thrombosis). 
 
Increased blood sugar values may require treatment with intravenous fluids and/or insulin. 
 
Reversible posterior leukoencephalopathy syndrome (characterised by headache, confusion, seizures 
and visual loss) may require blood-pressure lowering medicines and in case of seizure, anti-epileptic 
treatment. 
 
Other medicines and Spectrila 
Tell your doctor if you are using, have recently used or might use any other medicines. This is 
important as Spectrila may increase the side effects of other medicines through its effect on the liver 
which plays an important role in removing medicines from the body. 
 
In addition, it is especially important to tell your doctor if you are also using any of the following 
medicines: 
• Vincristine (used to treat certain types of cancer) since the simultaneous use of vincristine and 

asparaginase may increase the risk of certain side effects. To avoid this, vincristine is usually 
given 3 – 24 hours before asparaginase. 

• Glucocorticoids (anti-inflammation medicines that dampen down your immune system) since 
the simultaneous use of glucocorticoids and asparaginase may increase the formation of blood 
clots (thrombosis). 

• Medicines that reduce the ability of blood to clot, such as anticoagulants (e.g. warfarin and 
heparin), dipyridamole, acetylsalicylic acid or medicines to treat pain and inflammation, since 
using these medicines with asparaginase may increase the risk of bleeding. 

• Medicines which are metabolised in the liver, because the risk of side effects may increase. 
• Asparaginase may influence the efficacy of methotrexate or cytarabine (used to treat certain 

types of cancer):  
 - if asparaginase is given after these agents their effect may be increased.  

- if asparaginase is given before these agents their effect may be weakened.  
• Medicines which may have a negative effect on liver function since these negative effects may 

be worsened by concomitant treatment with asparaginase. 
• Medicines which may suppress bone marrow function as these effects may be enhanced by 

concomitant use of asparaginase. You may be more susceptible to infections.  
• Other anti-cancer medicines as they may contribute to the release of too much uric acid when 

tumour cells are destroyed by asparaginase. 
 
Vaccination 
Simultaneous vaccination with live vaccines may increase the risk of a serious infection. You should 
therefore not receive vaccination with live vaccines until at least 3 months after the end of treatment 
with Spectrila. 
 
Pregnancy, breast-feeding and fertility 
There are no data on the use of asparaginase in pregnant women. Spectrila should not be used during 
pregnancy unless the clinical condition of the woman requires treatment with asparaginase. 
It is unknown whether asparaginase is present in human breast milk. Therefore, Spectrila must not be 
used during breast-feeding.  
 



27 

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 using this medicine. 
 
If you are sexually mature you must use contraceptives or remain abstinent during chemotherapy and 
for up to 3 months after the end of treatment. Since an indirect interaction between components of the 
oral contraception and asparaginase cannot be ruled out, oral contraceptives are not considered 
sufficiently safe. A method other than oral contraceptives should be used in women of childbearing 
potential. 
 
Driving and using machines 
Do not drive when taking this medicine because it may make you feel drowsy, tired or confused. 
 
 
3. How to use Spectrila 
 
Spectrila is prepared and given by healthcare personnel. Your doctor decides on the dose you receive. 
The dose depends on your body surface area (BSA) which is calculated from your height and weight. 
 
Spectrila is given into a vein. It is usually given with other anti-cancer medicines. The duration of 
treatment depends on the specific chemotherapy protocol that is used to treat your disease. 
 
The recommended dose of Spectrila for adults is 5,000 U per m² body surface area (BSA) given every 
third day. 
 
Use in children and adolescents 
Similarly to adults, the recommended dose in children and adolescents aged 1 – 18 years is 5,000 U 
per m² BSA given every third day. 
 
The recommended dose in infants aged 0 – 12 months is as follows: 
- age less than 6 months:  6,700 U/m² BSA,  
- age 6 – 12 months:   7,500 U/m² BSA,  
 
If you were given more Spectrila than you should 
If you think that you received too much Spectrila, tell your doctor or nurse as soon as possible. 
 
There is no known case of an overdose with asparaginase where patients showed any signs of an 
overdose. If necessary, your doctor will treat your symptoms and will give you supportive care. 
 
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. 
 
Tell your doctor immediately and stop taking Spectrila if you experience: 
• inflammation of the pancreas, which causes severe pain in the abdomen and back, 
• severe liver function abnormalities (determined by laboratory tests),  
• allergic reactions including serious allergic reaction (anaphylactic shock), flushing, rash, low 

blood pressure, swelling of face and throat, hives, shortness of breath, 
• blood clotting disorders such as bleeding, disseminated intravascular coagulation (DIC) or 

formation of blood clots (thrombosis), 
• high blood sugar level (hyperglycaemia). 
 
A list of all other side effects is set out below according to how common they are: 
Very common side effects (may affect more than 1 in 10 people): 
• feeling sick (nausea), being sick (vomiting), stomach ache or watery stools (diarrhoea) 



28 

• accumulation of fluid (oedema) 
• feeling of tiredness 
• abnormal laboratory tests including changes in protein levels in the blood, changes in blood fat 

or in liver enzyme values or high level of urea in the blood 
 
Common side effects (may affect up to 1 in 10 people): 
• mild to moderate reduction in all blood cell counts 
• allergic reactions including wheezing (bronchospasm) or difficulty in breathing  
• low blood sugar level (hypoglycaemia) 
• loss of appetite or weight loss 
• depression, hallucination or confusion 
• nervousness (agitation) or somnolence (sleepiness) 
• changes in the electroencephalogram (a trace of the electrical activity of your brain) 
• high blood levels of amylase and lipase 
• pain (back pain, joint pain, stomach ache) 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• high blood levels of uric acid (hyperuricaemia) 
• high blood levels of ammonia (hyperammonaemia) 
• headache 
 
Rare (may affect up to 1 in 1,000 people): 
• diabetic ketoacidosis (complication due to uncontrolled blood sugar)  
• seizures, severe impairment of consciousness including coma, and stroke 
• Reversible posterior leukoencephalopathy syndrome (a condition characterised by headache, 

confusion, seizures and visual loss) 
• inflammation of the salivary glands (parotitis) 
• cholestasis (blocked bile flow from the liver) 
• jaundice 
• destruction of liver cells (liver cell necrosis) 
• liver failure which may lead to death 
 
Very rare (may affect up to 1 in 10,000 people): 
• decreased function of the thyroid gland or the parathyroid glands  
• mild tremor (shaking) of the fingers 
• pseudocysts of the pancreas (collections of fluid after acute inflammation of the pancreas) 
 
Not known (frequency cannot be estimated from the available data): 
• infections 
• fatty liver 
 
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 Spectrila 
 
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 carton. The expiry date refers to 
the last day of that month. 
 

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


29 

Store in a refrigerator (2 °C – 8 °C). 
Keep the vial in the outer carton in order to protect from light. 
 
The reconstituted solution is stable for 2 days when stored at 2 °C – 8 °C. If the medicine is not used 
immediately, the user preparing this medicine is responsible for storage times and conditions to ensure 
sterility of the product. Storage would normally not be longer than 24 hours at 2 °C – 8 °C. 
 
 
6. Contents of the pack and other information 
 
What Spectrila contains 
• The active substance is asparaginase. Asparaginase is produced by recombinant DNA 

technology in a microorganism named Escherichia coli. One vial contains 10,000 units of 
asparaginase. After reconstitution, one ml contains 2,500 units of asparaginase. 

 
• The medicine also contains sucrose. 
 
What Spectrila looks like and contents of the pack 
Spectrila is provided as a powder for concentrate for solution for infusion. 
 
The powder is white and it is supplied in a clear glass vial with a rubber stopper and an aluminium seal 
and a plastic flip-off cap. 
 
Spectrila is available in packs containing 1 or 5 vials. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
medac  
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
Tel.: +49-4103-8006-0 
Fax: +49-4103-8006-100 
E-mail: contact@medac.de 
 
 
This leaflet was last revised in MM/YYYY. 
 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
-------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Traceability 
It is strongly recommended that every time Spectrila is administered to a patient, the tradename and 
batch number of the product should clearly be recorded in order to link the patient and the batch of the 
product. 
 
Spectrila should only be used by physicians who are experienced in such treatment protocols. 
 
Recommended control examinations and safety precautions 



30 

Before initiating therapy bilirubin, hepatic transaminases, and coagulation parameters (partial 
thromboplastin time [PTT], prothrombin time [PT], antithrombin, fibrinogen, and D-dimer) should be 
determined. 
 
After administration of asparaginase, close monitoring of bilirubin, hepatic transaminases, of 
blood/urinary glucose, coagulation parameters (PTT, PT, antithrombin III, fibrinogen, and D-dimer), 
amylase, lipase, triglycerides, and cholesterol is recommended.  
 
Acute pancreatitis 
Treatment with asparaginase should be discontinued in patients developing acute pancreatitis. Acute 
pancreatitis has developed in less than 10 % of patients. In rare cases, haemorrhagic or necrotising 
pancreatitis occurs. There have been isolated reports of fatal outcomes. Clinical symptoms include 
abdominal pain, nausea, vomiting and anorexia. Serum amylase and lipase are usually elevated, 
although in some patients they can be normal due to impaired protein synthesis. Patients with severe 
hypertriglyceridaemia are at increased risk of developing acute pancreatitis. These patients should no 
longer be treated with any asparaginase preparation. 
 
Hepatotoxicity 
In rare cases severe liver impairment has been described, including cholestasis, icterus, hepatic 
necrosis and hepatic failure with fatal outcome (see sections 4.8 and 4.5). Liver parameters should be 
monitored closely before and during treatment with asparaginase. 
Treatment with asparaginase should be interrupted if patients develop severe hepatic impairment 
(bilirubin > 3 times the upper limit of normal [ULN]; transaminases > 10 times ULN), severe 
hypertriglyceridaemia, hyperglycaemia or coagulation disorder (e.g. sinus vein thrombosis, severe 
bleeding). 
 
Allergy and anaphylaxis 
Because of the risk of severe anaphylactic reactions asparaginase should not be administered as a 
bolus intravenous injection. If allergic symptoms occur, administration of asparaginase must be 
discontinued immediately and appropriate treatment given, which may include antihistamines and 
corticosteroids. 
 
Coagulation disorders 
Due to the inhibition of protein synthesis (decreased synthesis of factors II, V, VII, VIII, and IX, 
proteins C and S, antithrombin III [AT III]) caused by asparaginase, coagulation disorders can occur 
which can manifest either as thrombosis, disseminated intravascular coagulation (DIC), or bleeding. 
The risk of thrombosis seems to be higher than the risk of bleeding. Symptomatic thromboses related 
to the use of central venous catheters have been described, too. Frequent evaluation of coagulation 
parameters is important before and during asparaginase treatment. Expert advice should be sought in 
cases where AT III is decreased. 
 
Hyperglycaemic conditions 
Asparaginase may induce hyperglycaemia as a consequence of decreased insulin production. 
Additionally it may decrease insulin secretion from pancreatic β-cells and impair insulin receptor 
function. The syndrome is generally self-limiting. However, in rare cases it can result in diabetic 
ketoacidosis. Concomitant treatment with corticosteroids contributes to this effect. Serum and urine 
glucose levels should be regularly monitored and managed as clinically indicated. 
 
Antineoplastic agents 
Asparaginase-induced tumour cell destruction may release large amounts of uric acid, resulting in 
hyperuricaemia. Co-administration of other antineoplastic medicinal products contributes to this 
effect. Aggressive alkalinisation of the urine and use of allopurinol can prevent urate nephropathy. 
 
Glucocorticoids 
A higher risk of thrombosis during induction therapy with asparaginase and prednisone was seen in 
children with a genetic prothrombotic risk factor (factor V G1691A-mutations, prothrombin 



31 

G20210A-variation, methylenetetrahydrofolate reductase [MTHFR] T677T-genotype, increased 
lipoprotein A, hyperhomocysteinaemia). 
 
 
 
Contraceptives 
Effective contraception must be used during treatment and for at least 3 months after asparaginase 
discontinuation. Since an indirect interaction between components of the oral contraception and 
asparaginase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such 
clinical situation. 
 
Philadelphia chromosome-positive patients 
Efficacy and safety of Spectrila have not been established in Philadelphia chromosome-positive 
patients. 
 
Asparaginase activity 
Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to rule 
out accelerated elimination of asparaginase activity. Preferably, levels should be measured three days 
after the last asparaginase administration, i.e. usually directly before the next dose of asparaginase is 
given. Low asparaginase activity levels are often accompanied by the appearance of anti-asparaginase 
antibodies. In such cases, a switch to a different asparaginase preparation should be considered. Expert 
advice should first be sought. 
 
Hypoalbuminaemia 
As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases very 
commonly in patients treated with asparaginase. Since serum protein is important for the binding and 
transport function of some active substances, the serum protein level should be monitored regularly. 
 
Hyperammonaemia 
Plasma ammonia levels should be determined in all patients with unexplained neurologic symptoms or 
severe and prolonged vomiting. In case of hyperammonaemia with severe clinical symptoms, 
therapeutic and pharmacological measures that rapidly reduce plasma ammonia levels (e.g. protein 
restriction and haemodialysis), reverse catabolic states and increase removal of nitrogen wastes should 
be initiated and expert advice sought. 
 
Reversible posterior leukoencephalopathy syndrome  
Reversible posterior leukoencephalopathy syndrome (RPLS) may occur rarely during treatment with 
any asparaginase. This syndrome is characterised in magnetic resonance imaging (MRI) by reversible 
(from a few days to months) lesions/oedema, primarily in the posterior region of the brain. Symptoms 
of RPLS essentially include elevated blood pressure, seizures, headaches, changes in mental state and 
acute visual impairment (primarily cortical blindness or homonymous hemianopsia). It is unclear 
whether the RPLS is caused by asparaginase, concomitant treatment or the underlying diseases.  
RPLS is treated symptomatically, including measures to treat any seizures. Discontinuation or dose 
reduction of concomitantly administered immunosuppressive medicinal products may be necessary. 
Expert advice should be sought 
 
Handling 
To dissolve the powder, 3.7 ml of water for injection is carefully squirted against the inner wall of 
the vial with an injection syringe (do not squirt directly on or into the powder). The dissolution of the 
contents is achieved by slow turning (avoid froth formation due to shaking). The ready-to-use solution 
may exhibit a slight opalescence. 
 
The calculated quantity of asparaginase is dissolved further in 50 to 250 ml of sodium chloride 
9 mg/ml (0.9 %) solution for injection. 
 



32 

Method of administration 
For intravenous use only. The daily amount of asparaginase needed per patient can be diluted in a final 
volume of 50 – 250 ml sodium chloride 9 mg/ml (0.9 %) solution for injection.  
 
Duration of administration 
The diluted solution of asparaginase should be infused over 0.5 to 2 hours. 
Asparaginase must not be administered as a bolus dose. 
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 
 
 
 
 
 
 



34 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for asparaginase (centrally 
authorised product), the scientific conclusions of CHMP are as follows:  
 
To aid traceability of rASNase batches and distinction between different ASNase and rASNase 
products, the product information should include in section 4.4 of the SmPC and relevant section of 
the PL a prominent statement that the name and batch number of the administered product should be 
clearly recorded in the patient records.  
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for asparaginase (centrally authorised product) the CHMP 
is of the opinion that the benefit-risk balance of the medicinal product(s) containing asparaginase 
(centrally authorised product) is unchanged subject to the proposed changes to the product 
information. 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMSOF THE MARKETING AUTHORISATION(S)