SPECTRILA 10000UI powder for concentrate infusion solution medication leaflet

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

Each vial of powder contains 10,000 units of asparaginase*.

After reconstitution, each ml of solution contains 2,500 units of asparaginase.

One unit (U) is defined as the quantity of enzyme required to liberate one µmol ammonia per minute atpH 7.3 and 37 °C.

*Produced in Escherichia coli cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White powder.

Spectrila is indicated as a component of antineoplastic combination therapy for the treatment of acutelymphoblastic leukaemia (ALL) in paediatric patients from birth to 18 years and adults.

Spectrila should be prescribed and administered by physicians and healthcare personnel experienced inthe use of antineoplastic products. It should only be given in a hospital setting where appropriateresuscitation equipment is available.

Spectrila is usually employed as part of combination chemotherapy protocols with other antineoplasticagents (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) bodysurface area (BSA) given every third day.

Treatment may be monitored based on the trough serum asparaginase activity measured three daysafter administration of Spectrila. If asparaginase activity values fail to reach target levels, a switch to adifferent asparaginase preparation could be considered (see section 4.4).

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.

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.

No dose adjustment is necessary in patients with renal 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).

Limited data are available for the treatment of patients older than 65 years of age.

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 sodiumchloride 9 mg/ml (0.9%) solution for infusion. The diluted solution of asparaginase may be infusedover 0.5 to 2 hours.

Asparaginase must not be administered as a bolus dose.

* Hypersensitivity to the active substance, any native (non-pegylated) E. coli-asparaginasepreparation 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 asparaginasetherapy.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should clearly be recorded.

General information and monitoring

The following life-threatening situations may arise during asparaginase treatment in patients of all agegroups:

* acute pancreatitis,

* hepatotoxicity,

* anaphylaxis,

* coagulation disorders including symptomatic thrombosis related to the use of central venouscatheters,

* hyperglycaemic conditions.

Before initiating therapy bilirubin, hepatic transaminases and coagulation parameters (e.g. partialthromboplastin time [PTT], prothrombin time [PT], antithrombin III and fibrinogen) should bedetermined.

After administration of any asparaginase preparation, close monitoring of bilirubin, hepatictransaminases, blood/urinary glucose, coagulation parameters (e.g. PTT, PT, antithrombin III,fibrinogen and D-dimer), amylase, lipase, triglycerides and cholesterol is recommended.

Treatment with asparaginase should be discontinued in patients developing acute pancreatitis. Acutepancreatitis has developed in less than 10% of patients. In rare cases, haemorrhagic or necrotisingpancreatitis occurs. There have been isolated reports of fatal outcomes. Clinical symptoms includeabdominal 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 severehypertriglyceridaemia are at increased risk of developing acute pancreatitis.

These patients should no longer be treated with any asparaginase preparation (see also sections 4.3and 4.8).

In rare cases severe liver impairment has been described, including cholestasis, icterus, hepaticnecrosis and hepatic failure with fatal outcome (see sections 4.8 and 4.5). Liver parameters should bemonitored 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), severehypertriglyceridaemia, hyperglycaemia or coagulation disorder (e.g. sinus vein thrombosis, severebleeding).

Allergy and anaphylaxis

Because of the risk of severe anaphylactic reactions asparaginase should not be administered as abolus 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 andappropriate treatment given, which may include antihistamines and corticosteroids.

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 occurwhich 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 relatedto the use of central venous catheters have been described, too.

Approximately half of the thrombotic events is localised in cerebral vessels. Sinus vein thrombosis canoccur. 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 receptorfunction. The syndrome is generally self-limiting. However, in rare cases it can result in diabeticketoacidosis. Concomitant treatment with corticosteroids contributes to this effect. Serum and urineglucose 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 inhyperuricaemia. Co-administration of other antineoplastic medicinal products contributes to thiseffect. 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 inchildren with a genetic prothrombotic risk factor (factor V G1691A-mutations, prothrombin

G20210A-variation, methylenetetrahydrofolate reductase [MTHFR] T677T-genotype, increasedlipoprotein A, hyperhomocysteinaemia).

Contraceptives

Women of childbearing potential should use effective contraceptive measures while being treated withasparaginase and for 7 months following completion of treatment. Since an indirect interactionbetween components of the oral contraception and asparaginase cannot be ruled out, oralcontraceptives 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-positivepatients.

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 ruleout accelerated reduction of asparaginase activity. Preferably, levels should be measured three daysafter the last asparaginase administration, i.e. usually directly before the next dose of asparaginase isgiven. Low asparaginase activity levels are often accompanied by the appearance of anti-asparaginaseantibodies. In such cases, a switch to a different asparaginase preparation should be considered. Expertadvice should first be sought.

Hypoalbuminaemia

As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases verycommonly in patients treated with asparaginase. Since serum protein is important for the binding andtransport 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 orsevere and prolonged vomiting. In case of hyperammonaemia with severe clinical symptoms,therapeutic and pharmacological measures that rapidly reduce plasma ammonia levels (e.g. proteinrestriction and haemodialysis), reverse catabolic states and increase removal of nitrogen wastes shouldbe initiated and expert advice sought.

Reversible posterior leukoencephalopathy syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) may occur rarely during treatment withany 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 ofthe brain. Symptoms of RPLS essentially include elevated blood pressure, seizures, headaches,changes in mental state and acute visual impairment (primarily cortical blindness or homonymoushemianopsia). It is unclear whether the RPLS is caused by asparaginase, concomitant treatment or theunderlying diseases.

RPLS is treated symptomatically, including measures to treat any seizures. Discontinuation or dosereduction of concomitantly administered immunosuppressive medicinal products may be necessary.

Expert advice should be sought.

Asparaginase may increase the toxicity of other medicinal products through its effect on liver function,e.g. increased hepatotoxicity with potentially hepatotoxic medicinal products, increased toxicity ofmedicinal products metabolised by the liver or bound to plasma proteins and altered pharmacokineticsand pharmacodynamics of medicinal product bound to plasma proteins. Therefore, caution should beexercised in patients receiving other medicinal products metabolised by the liver.

Hepatic parameters should be monitored when potentially hepatotoxic medicinal products are givenconcomitantly with asparaginase (see sections 4.4 and 4.8).

Myelosuppressive agents

During treatment with asparaginase-containing regimens, myelosuppression, potentially affecting allthree myeloid cell lineages (erythrocytes, leukocytes, thrombocytes), and infections can occur.

Concomitant treatment with myelosuppressive medicinal products and those known to causeinfections are major contributing factors and patients should be carefully monitored for signs andsymptoms of myelosuppression and infection (see section 4.8).

Vincristine

The toxicity of vincristine may be additive with that of asparaginase if both agents are administeredconcomitantly. Therefore, vincristine should be given 3 to 24 hours before administration ofasparaginase in order to minimise toxicity.

Glucocorticoids and/or anticoagulants

Concomitant use of glucocorticoids and/ or anticoagulants with asparaginase may increase the risk of achange in coagulation parameters (see section 4.4).

This can promote tendency to bleeding (anticoagulants) or thrombosis (glucocorticoids). Caution istherefore needed when anticoagulants (e.g. coumarin, heparin, dipyridamole, acetylsalicylic acid ornonsteroidal 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 beenshown to attenuate the cytotoxic effect of MTX which requires cell replication for its antineoplasticactivity. This antagonism is observed if asparaginase is administered prior to or concurrently withmethotrexate. Conversely, the antitumour effects of methotrexate are enhanced when asparaginase isadministered 24 hours following methotrexate treatment. This regimen has been shown to reduce thegastrointestinal and haematological effects of methotrexate.

Cytarabine

Laboratory in vitro and in vivo data indicate that the efficacy of high-dose cytarabine is reduced byprior administration of asparaginase. However, when asparaginase was given after cytarabine asynergistic effect was observed. This effect was most prominent with a treatment interval of about120 hours.

Concomitant vaccination with live vaccines increases the risk of serious infection. Immunisation withlive vaccines should therefore take place at the earliest 3 months after completion of the course ofantileukaemic treatment.

Women of childbearing potential have to use effective contraception and avoid becoming pregnantwhile being treated with asparaginase-containing chemotherapy and for 7 months followingcompletion of treatment. Since an indirect interaction between components of the oral contraceptionand asparaginase cannot be ruled out, oral contraceptives are not considered sufficiently safe in suchclinical situation. A method other than oral contraceptives should be used in women of childbearingpotential (see section 4.4).

Men should use effective contraceptive measures and be advised to not father a child while receivingasparaginase and for 4 months following completion of treatment.

There are no data on the use of asparaginase in pregnant women. No reproduction studies in animalswith asparaginase were performed but studies with asparaginase preparations in mice, rats, chickenand rabbits have shown embryotoxic and teratogenic effects (see section 5.3). Based on results fromanimal studies and its mechanism of action, Spectrila should not be used during pregnancy unless theclinical condition of the woman requires treatment with asparaginase.

It is unknown whether asparaginase is excreted into human breast milk. Because potential seriousadverse reactions may occur in breast-feeding infants, Spectrila should be discontinued duringbreast-feeding.

No human data on the effect of asparaginase on fertility are available.

Spectrila has moderate influence on the ability to drive and use machines, especially through itspotential effects on the nervous and gastrointestinal systems (see section 4.8).

The primary toxicity of asparaginase results from immunologic reactions caused by exposure to thebacterial protein. Hypersensitivity reactions range from transient flushing or rash and urticaria tobronchospasm, angioedema and anaphylaxis.

In addition, treatment with asparaginase can result in disturbances in organ systems which exhibit ahigh level of protein synthesis. Decreased protein synthesis can predominantly lead to liverimpairment, acute pancreatitis, decreased insulin production with hyperglycaemia, decreasedproduction of clotting factors (especially fibrinogen and antithrombin III) leading to coagulationdisorders (thrombosis, bleeding), and decreased production of lipoproteins resulting inhypertriglyceridaemia.

Most serious adverse reactions of Spectrila include severe hypersensitivity reactions such asanaphylactic shock (rare), thromboembolic events (common), acute pancreatitis (common), and severehepatotoxicity, e.g. jaundice, hepatic necrosis, hepatic failure (rare).

Most frequently (very common) observed adverse reactions of Spectrila include hypersensitivityreactions, hyperglycaemia, hypoalbuminaemia, nausea, vomiting, diarrhoea, abdominal pain, oedema,fatigue, and change in laboratory parameters (e.g. transaminases, bilirubin, blood lipids, coagulationparameters).

Since Spectrila is usually used in combination therapy with other antineoplastic agents, thedemarcation from undesirable effects of other medicinal products is often difficult.

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 aspost-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 eachfrequency 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 (≥1/10,000to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1

System organ class Frequency and adverse reaction

Infections and infestations Not known

Blood and lymphatic system Commondisorders 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 Very commondisorders Hyperglycaemia, hypoalbuminaemia

Common

Hypoglycaemia, decreased appetite, weight loss

Uncommon

Hyperuricaemia, hyperammonaemia

Rare

Psychiatric disorders Common

Depression, hallucination, confusion

Nervous system disorders Common

Neurological signs and symptoms including agitation, dizzinessand somnolence

Uncommon

Headaches

Rare

Ischaemic stroke, reversible posterior leukoencephalopathysyndrome (RPLS), convulsion, disturbances in consciousnessincluding coma

Very rare

Tremor

Vascular disorders Common

Thrombosis especially cavernous sinus thrombosis or deep veinthrombosis, haemorrhage

Gastrointestinal disorders Very common

Diarrhoea, nausea, vomiting, abdominal pain

Common

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 Very commonadministration site conditions Oedema, fatigue

Common

Pain (back pain, joint pain)

Investigations Very common

Increase in transaminases, blood bilirubin, blood alkalinephosphatase, blood cholesterol, blood triglyceride, very lowdensity lipoprotein (VLDL), lipoprotein lipase activity, bloodurea, 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 deltawave activity)

Spectrila can induce antibodies of different immunoglobulin classes (IgG, IgM, IgE). These antibodiesmay induce clinical allergic reactions, inactivate the enzymatic activity or accelerate the elimination ofasparaginase.

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 administereddoses; however, in very rare cases reactions can occur at the first dose of asparaginase. Mosthypersensitivity 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 followingfrequencies 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 Referenceasparaginase

Number of patients 97 101

Allergic reactions within 12 hours afterasparaginase infusion during induction 2 (2.1%) 5 (5.0%)treatment

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

*Including all allergic reactions within 12 hours after asparaginase infusion and all adverseevents 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 discontinuedimmediately (see section 4.4).

In the study in children/adolescents aged 1-18 years with de novo ALL (study MC-ASP.5/ALL), byday 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 thestart 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 asparaginaseinfusion 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 treatmentwith Spectrila (study MC-ASP.6/INF).

There have been reports of transitory secondary hypothyroidism probably caused by a decrease in theserum 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 verycommonly in patients treated with asparaginase (see section 4.4). As a consequence ofhypoalbuminaemia oedema can occur.

Dyslipidemia

Mild to moderate changes in blood lipid values (e.g. increased or decreased cholesterol, increasedtriglyceride, increased VLDL fraction and decreased LDL, increased lipoprotein lipase activity) arevery commonly observed in patients treated with asparaginase, which in most cases present withoutclinical symptoms. Concomitant administration of glucocorticoids may be a contributing factor.

However, in rare cases severe hypertriglyceridaemia (triglycerides > 1,000 mg/dl) has been reportedwhich increases the risk of development of acute pancreatitis. Asparaginase-associatedhyperlipidaemia should be treated depending on its severity and on clinical symptoms.

Hyperammonaemia

Hyperammonaemia has been reported uncommonly in patients treated with asparaginase-containingtherapy protocols, especially if patients suffer additionally from hepatic impairment. In very rarecases, severe hyperammonaemia has been reported which may induce neurologic disorders such asseizures and coma.

Hyperglycaemia and hypoglycaemia

Changes in endocrine pancreatic function are observed very commonly during treatment withasparaginase 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 treatedwith asparaginase. The mechanism leading to this reaction is unknown.

Adverse central nervous system reactions observed in patients treated with asparaginase-containingtherapy protocols include changes in EEG, seizures, dizziness, somnolence, coma and headache.

The causes of these nervous system disorders are unclear. Hyperammonaemia and sinus veinthrombosis may need to be excluded.

In rare cases, RPLS has been observed during therapy with asparaginase-containing regimens.

Nausea/vomiting are very commonly observed in patients treated with asparaginase-containingtreatment regimens but are usually mild. Anorexia, loss of appetite, abdominal cramps, diarrhoea andweight loss have also been reported.

Acute pancreatitis has developed in less than 10% of patients. In rare cases, haemorrhagic ornecrotising pancreatitis occurs. There have been isolated reports of fatal outcomes. A few cases ofasparaginase-induced parotitis have been reported in the literature.

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 andchildren; however, some of these undesirable effects (e.g. thromboembolic events) are known to occurwith 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of asparaginase overdose with clinical symptoms has been reported. There is no specificantidote. Treatment is symptomatic and supportive.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX02

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 asignificantly reduced expression of asparagine synthetase. Therefore, they require asparagine whichdiffuses from the extracellular environment. As a result of asparaginase-induced asparagine depletionin 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 degreeon exogenous asparagine supply.

Due to the asparagine concentration gradient between the extra- and intravascular space, asparaginelevels are subsequently also reduced in the extravascular spaces, e.g. the cerebrospinal fluid.

In a clinical trial in children with de novo ALL (study MC-ASP.4/ALL) it was shown thatimmediately after the end of infusion of asparaginase mean asparagine concentrations in serumdropped from the pre-dose concentrations of about 40 µM to below the lower limit of quantification ofthe bioanalytical method (< 0.5 µM). The mean asparagine concentrations in serum remained below0.5 µM from immediately after the end of first infusion of asparaginase until at least three days afterthe last infusion. Thereafter, asparagine serum levels increased again and returned to normal valueswithin 1-3 weeks.

In addition to asparagine, asparaginase is also able to cleave the amino acid glutamine to glutamic acidand ammonia, however with much less efficiency. Clinical trials with asparaginase have shown thatglutamine levels are only moderately affected with a very high interindividual variability. Immediatelyafter 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.

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 medicinalproduct) in a randomised double-blinded clinical trial (study MC-ASP.5/ALL; based on ALLtreatment 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) atdays 12, 15, 18, 21, 24, 27, 30, and 33 of induction treatment. After induction treatment, patientscontinued treatment with chemotherapy regimens which included further treatment withasparaginases.

The primary endpoint was the rate of patients with complete asparagine depletion in serum (defined asasparagine serum levels below the lower limit of quantification (< 0.5 µM) at all time points measuredfrom day 12 up to day 33) during induction treatment. The objective of the study was to demonstratethe non-inferiority of Spectrila to the reference E. coli-asparaginase with regard to the primaryendpoint.

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 diseasea Unconditional exact confidence interval based on Chan and Zhangb Unconditional exact test of non-inferiority for binomial differences based on restrictedmaximum likelihood estimatesc Patients were considered as responders if asparagine values in CSF on protocol day 33 werebelow the lower limit of quantification.

During induction treatment, asparaginase-typical adverse drug reactions like elevated liverenzymes/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%) wereobserved 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 firstinfusion: 6 months [0.5-12.2 months]) with de novo ALL were treated with Spectrila within the

INTERFANT-06 protocol. Patients received asparaginase at a dose of 10,000 U/m², adjusted to thecurrent 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%) werein CR after induction treatment.

Pharmacokinetic parameters of Spectrila were determined in 7 adult patients after intravenous infusionof 5,000 U/m².

Asparaginase is not absorbed by the gastrointestinal tract, thus Spectrila must be given intravenously.

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 ofapproximately 2 hours after the end of the infusion.

After repeated administration of asparaginase at a dose of 5,000 U/m² every third day, troughasparaginase activity levels in serum ranged from 108 to 510 U/l.

The metabolism of asparaginase is not known but thought to occur via degradation within thereticulo-histiocytic system and by serum proteases.

The mean ± SD terminal half-life (elimination half-life) of asparaginase activity in serum was25.8 ± 9.9 h, with a range between 14.2 and 44.2 h.

In clinical trials with asparaginase, trough asparaginase serum activity levels greater than 100 U/l wereachieved in the majority of patients which nearly always correlated with a complete depletion ofasparagine in serum and cerebrospinal fluid (CSF). Even those few patients with trough asparaginaseserum activity levels of 10-100 U/l usually experienced complete asparagine depletion in serum and

CSF.

Pharmacokinetic parameters after administration of 5,000 U/m² of Spectrila were determined in14 children/adolescents (age 2-14 years) with de novo ALL (study MC-ASP.4/ALL). Results areshown 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

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) duringinduction 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 33were 209 (42-330) U/l, 130 (6-424) U/l, and 32 (1-129) U/l, respectively. The lower median activitylevel on day 33 compared to the former two measurements was in part due to the fact that this lastserum sample was taken 4 days after the last infusion of asparaginase instead of three days on theother occasions.

Non-clinical repeat-dose toxicity and safety pharmacology studies in rats revealed no special hazardfor humans, except a slight but significant saluretic effect at doses below the recommended dose for

ALL patients. Additionally, the urinary pH value and the relative weight of kidneys were increased atexposures considered sufficiently in excess of the maximum human exposure indicating littlerelevance to clinical use.

Evidence from published data with asparaginase renders the mutagenic, clastogenic and carcinogenicpotential of asparaginase negligible.

Asparaginase caused an increase in the incidence of malformations (including those of the centralnervous system, heart and skeletal system) and foetal death at doses that are similar to or in excess ofthose proposed clinically (on a U/m² basis) in a number of species including the mouse, rat and/orrabbit.

Sucrose

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

Unopened vial4 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 usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 °C-8 °C unless reconstitution/dilution has taken placein controlled and validated aseptic conditions.

Store in a refrigerator (2 °C-8 °C).

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

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Colourless 20 ml glass vial (Type I glass) closed with butylrubber stopper, aluminium seal and plasticflip-off cap, containing 10,000 units of asparaginase.

Each pack contains either 1 or 5 vials. Not all pack sizes may be marketed.

To dissolve the powder, 3.7 ml of water for injections are carefully squirted against the inner wall ofthe vial with an injection syringe (do not squirt directly on or into the powder). Dissolution of thecontents is achieved by slow turning (avoid froth formation due to shaking). The reconstituted solutionmay exhibit a slight opalescence.

The calculated quantity of asparaginase is dissolved further in 50 to 250 ml of sodium chloride9 mg/ml (0.9%) solution for infusion.

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

medac Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 622880 Wedel

Germany

Tel.: +49 4103 8006-0

Fax: +49 4103 8006-100

E-mail: contact@medac.de

EU/1/15/1072/001

EU/1/15/1072/002

Date of first authorisation: 14 January 2016

Date of latest renewal: 24 September 2020

Detailed information on this medicinal product is available on the website of the European Medicines

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