Paronal

Overdose

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

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.

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 Paronal 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).

Most frequently (very common) observed side effects of Paronal 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 Paronal 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 Paronal 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

Description of selected adverse reactions

Immune system disorders

Paronal 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 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)

No allergic reactions were observed in any of the 12 infants < 1 year of age during treatment with Paronal (study MC-ASP.6/INF).

In case of occurrence of allergic symptoms, administration of Paronal should be discontinued immediately.

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 Paronal 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 (Paronal 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 Paronal (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. 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.

Paediatric population

Data on safety of Paronal 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 (see details below).

United Kingdom

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Ireland

HPRA Pharmacovigilance

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IRL - Dublin 2

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Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

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.

Therapeutic indications

Paronal 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.

Pharmacotherapeutic group

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.

Clinical efficacy and safety

Study in children/adolescents aged 1 - 18 years with de novo ALL

Efficacy and safety of Paronal 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 (Paronal 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 Paronal 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)

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 (Paronal 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 Paronal within the 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.

Pharmacokinetic properties

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

Absorption

Asparaginase is not absorbed by the gastrointestinal tract, thus Paronal 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 Paronal 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 Paronal in 14 children/adolescents

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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

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.

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Hepatotoxicity

In rare cases severe liver impairment has been described, including cholestasis, icterus, hepatic necrosis and hepatic failure with fatal outcome. 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.

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.

Philadelphia chromosome-positive patients

Efficacy and safety of Paronal 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.

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.

Effects on ability to drive and use machines

Paronal has moderate influence on the ability to drive and use machines, especially through its potential effects on the nervous and gastrointestinal systems.

Dosage (Posology) and method of administration

Paronal 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

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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 Paronal. If asparaginase activity values fail to reach target levels, a switch to a different asparaginase preparation could be considered.

Data on efficacy and safety of Paronal in adults are limited.

Data on efficacy and safety of Paronal in the post-induction treatment phases are very limited.

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, Paronal should not be used in patients with severe hepatic impairment.

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:

Method of administration

Paronal is for administration by intravenous infusion only.

The daily amount of Paronal 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.

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.