Enrylaze® is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma (LBL) in adult and paediatric patients (1 month and older) who developed hypersensitivity or silent inactivation to E. coli-derived asparaginase.

 

Enrylaze® should be prescribed and administered by physicians and healthcare personnel experienced in the use of antineoplastic products. Appropriate resuscitation equipment and other agents necessary to treat anaphylaxis should be available when administering Enrylaze®.

 

Posology

The recommended dose of Enrylaze® is:

-        Every 48 hours

•        25 mg/m² intramuscularly or intravenously

Or

-        Monday/Wednesday/Friday

•        25 mg/m² intramuscularly on Monday and Wednesday, and 50 mg/m² intramuscularly on Friday; or

•        25 mg/m² intravenously on Monday and Wednesday, and 50 mg/m² intramuscularly on Friday; or

•        25 mg/m² intravenously on Monday and Wednesday, and 50 mg/m² intravenously on Friday

Recommended premedication

A consideration to premedicate patients with paracetamol, an H1 receptor blocker, and an H2 receptor blocker 30–60 minutes prior to administration should be made when Enrylaze® is being given intravenously to decrease the risk and severity of infusion related reaction/hypersensitivity reaction.

 

Recommended monitoring

Asparaginase activity can vary between individuals, therefore trough SAA should be monitored. When administered every 48 hours a trough asparaginase activity measurement should be performed at 48 hours post dose. When dosing on a Monday/Wednesday/Friday schedule, trough SAA should be measured 72 hours after the Friday dose and prior to administration of the following Monday dose. The dosing schedule or route of administration should then be individually adapted (see section 4.4).

 

Therapy can be further adjusted according to local treatment protocols.

 

The dose of Enrylaze® is administered in mg/m² and is not administered in units/m², as used for other asparaginase preparations. Enrylaze® is not interchangeable with other crisantaspase products to complete a cycle of treatment.

 

Special populations

Hepatic impairment

Dose adjustment is not required for patients that develop total bilirubin ≤ 3 times the Upper Limit of Normal (ULN) during treatment.

 

Enrylaze® should be withheld if total bilirubin is > 3 times to ≤ 10 times the ULN during treatment, treatment can continue once resolved. In the event of a severe occurrence (total bilirubin > 10 times the ULN), treatment should be stopped and patients not rechallenged (see section 4.4).

 

Dose adjustment is not required for patients with pre-existing mild or moderate hepatic impairment (total bilirubin > 1 to 3 times the ULN or AST greater than the ULN). There are insufficient data in patients with pre-existing severe hepatic impairment to support a dose recommendation.

 

Renal impairment

There are insufficient data in patients with mild, moderate or severe renal impairment to support a dose recommendation.

 

Paediatric population

No dose adjustment is required in paediatric patients.

 

The safety and efficacy of children aged younger than 1 month has not yet been established.

 

Elderly

No dose adjustment is required in elderly patients.

 

Method of administration

Enrylaze® is for intramuscular and/or intravenous use.

 

For intramuscular use, limit the volume of Enrylaze® at a single injection site to 2 mL for patients with a body surface area (BSA) > 0.5 m², for patients with a BSA < 0.5 m² limit the volume to 1 mL. If the volume to be administered is greater than the mentioned limits, use multiple injection sites.

 

For intravenous infusion, it is recommended to administer the dose over 2 hours.

 

For instructions on dilution of the medicinal product before intravenous administration, see section 6.6.

 

• History of severe hypersensitivity reactions to the active substance • Hypersensitivity to any of the excipients listed in section 6.1 • Severe pancreatitis • History of severe pancreatitis during previous asparaginase therapy • Severe thrombosis during previous asparaginase therapy • Severe haemorrhagic events during previous asparaginase therapy

 

Traceability

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

 

Clinical monitoring

Asparaginase activity

SAA varies substantially between patients, when treatment is administered intravenously. The optimal SAA level is ≥ 0.1 U/mL; if this is not observed the dosing schedule should be individually adapted. When administering Enrylaze® intravenously on a Monday/Wednesday/Friday schedule, trough SAA levels should be measured 72 hours after the Friday dose and prior to the following Monday administration. If SAA levels ≥ 0.1 U/mL are not observed, administration of intramuscular Enrylaze® or switching to a 48‑hour dosing interval (intravenous or intramuscular) should be considered. If SAA levels are monitored at 48‑hour intervals of intravenous Enrylaze® administration and SAA levels ≥ 0.1 U/mL are not observed, administration intramuscularly should be considered (see section 4.2).

 

Hypersensitivity reactions

Grade 3 and 4 hypersensitivity reactions after the use of Enrylaze® have occurred in patients during clinical trials (see sections 4.3 and 4.8). Hypersensitivity reactions may occur more frequently when treatment is administered intravenously in comparison to when treatment is administered intramuscularly.

 

Because of the risk of serious allergic reactions, Enrylaze® should be administered in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. Enrylaze® should be discontinued in patients with severe hypersensitivity reactions (see section 4.3).

 

Pancreatitis

Pancreatitis has been reported in patients treated with Enrylaze® in clinical trials (see section 4.8).

Patients with symptoms compatible with pancreatitis should be evaluated to establish a diagnosis.

 

Enrylaze® should be discontinued in patients that develop necrotising or haemorrhagic pancreatitis.

 

In the case of elevations in lipase or amylase > 2 times the ULN or symptomatic pancreatitis, Enrylaze® should be withheld until the ULN and symptoms subside. After resolution of pancreatitis, treatment with Enrylaze® may be resumed.

 

Glucose intolerance

Cases of glucose intolerance have been reported in patients receiving Enrylaze® in clinical trials (see section 4.8). Glucose levels in patients should be monitored at baseline and periodically during treatment. Insulin therapy should be administered as necessary in patients with hyperglycaemia.

 

Coagulation disorders

Thrombotic and bleeding events, including sagittal sinus thrombosis and pulmonary embolism have been reported with L‑asparaginase therapy. Enrylaze® treatment should be held for a thrombotic or haemorrhagic event until symptoms resolve; after resolution, treatment with Enrylaze® may be resumed.

 

Hepatotoxicity

Therapy that includes Enrylaze® can cause hepatotoxicity as experienced during clinical trials (see section 4.8).

 

Patients should be monitored for signs and symptoms of hepatotoxicity.  Bilirubin and transaminases should be monitored prior to treatment and as clinically required during treatment with Enrylaze®. In the event of severe liver toxicity, treatment with Enrylaze® must be discontinued and supportive care provided.

 

Neurotoxicity

Central nervous system (CNS) toxicity, including encephalopathy, seizures and CNS depression as well as posterior reversible encephalopathy syndrome (PRES) may occur during treatment with any asparaginase therapy.

 

PRES 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 PRES 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 PRES is caused by asparaginase, concomitant treatment or the underlying diseases. PRES 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.

 

Contraception

Contraception should be used during treatment and for 3 months after receiving the final dose of Enrylaze®. Women should also undergo pregnancy testing before therapy with Enrylaze® is initiated. Since an indirect interaction between oral contraceptives and Enrylaze® cannot be ruled out, patients of childbearing potential should use effective non-hormonal contraceptive methods while undergoing treatment (see section 4.6).

 

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say, essentially ‘sodium-free’.

 

 

No interaction studies have been performed.

 

General

The possibility of interactions with medicinal products whose pharmacokinetics or pharmacodynamics are affected by asparaginase-induced changes in the liver function or plasma protein levels should be taken into account when administering asparaginase. Asparaginase may increase toxicity of other medicinal products through its effect on liver function.

 

Vincristine

Administration of asparaginase concurrently or immediately before vincristine may be associated with increased toxicity of vincristine. Asparaginase inhibits hepatic clearance of vincristine.

 

Methotrexate, cytarabine

Non-clinical data indicates that prior or concurrent administration of L‑asparaginase attenuates the effect of methotrexate and cytarabine. Administration of L‑asparaginase after methotrexate or cytarabine results in a synergistic effect. However, the clinical effect of sequence-dependent L‑asparaginase administration on the efficacy of methotrexate and cytarabine is unknown.

 

Glucocorticoids

Administration of asparaginase with or immediately before glucocorticoids (e.g. prednisone) may change coagulation parameters, such as a decrease in fibrinogen and antithrombin III levels.

 

 

Women of childbearing potential/Contraception in males and females

Men and women should use contraception during treatment with Enrylaze® containing chemotherapy. Because the time period following treatment with asparaginase when it is safe to become pregnant or father a child is unknown, effective contraception should be used in men and women for at least 3 months after discontinuation. Since an indirect interaction between oral contraceptives and Enrylaze® cannot be ruled out, patients of childbearing potential should use effective non-hormonal contraceptive methods while undergoing treatment (see section 4.4).

 

Pregnancy

There are no data on the use of recombinant crisantaspase in pregnant women. Based on studies with Erwinia chrysanthemi L‑asparaginase in pregnant animals, recombinant crisantaspase can cause embryonic and foetal harm when administered to a pregnant woman (see section 5.3).

 

Women of childbearing potential should undergo pregnancy testing before initiation of Enrylaze®. Enrylaze® should not be used during pregnancy, unless the clinical condition of the woman requires treatment and justifies the potential risk to the foetus. If the medicinal product is used during pregnancy, or if the patient becomes pregnant while receiving Enrylaze®, the woman should be informed of the potential hazard to the foetus.

 

Breast-feeding

It is not known whether recombinant crisantaspase is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding infants/children, mothers should be advised not to breast-feed during Enrylaze® therapy and for a period of two weeks after the last dose.

 

Fertility

No human data on the effect of recombinant crisantaspase on fertility are available. In a fertility and early embryonic development study in rats with Erwinia chrysanthemi crisantaspase, there were no effect on female or male fertility (margins of human exposure < 1) (see section 5.3).

 

 

Enrylaze® has minor influence on the ability to drive and use machines. This influence is based on the adverse reactions that may occur during treatment (see section 4.8).

 

 

Summary of the safety profile

Serious adverse reactions occurred in 59% of patients who received Enrylaze® in a clinical trial. The most frequent serious adverse reactions were febrile neutropenia (29%), pyrexia (10%), vomiting (8%), sepsis (7%), medicinal product hypersensitivity (6%), nausea (6%), and pancreatitis (5%).

 

The most common adverse reactions were anaemia (52%), vomiting (49%), thrombocytopenia (42%), neutropenia (41%), nausea (38%), febrile neutropenia (32%), fatigue (32%), pyrexia (32%), decreased appetite (29%), transaminase increased (29%), abdominal pain (27%), white blood cell count decreased (27%), headache (25%), diarrhoea (22%), and lymphocyte count decreased (20%).

 

Tabulated list of adverse reactions

Adverse reactions reported in clinical trial are listed in Table 1 by system organ class and by frequency. The frequencies identified are from patients (n=228) who received 6 doses of Enrylaze®, along with a multi-agent chemotherapeutic regimen. Certain adverse reactions listed below, such as reactions resulting from bone marrow suppression, and infections, are known to be associated with multi-agent chemotherapeutic regimens, and the contributory role of Enrylaze® is not clear. In individual cases of adverse reactions, other medicinal products of the regimen may have contributed.

 

Frequencies are defined as: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Table 1: Adverse reactions in patients receiving Enrylaze® with multi-agent chemotherapy (Study JZP458-201)

 

System organ class	Frequency	Adverse reaction
Infections and infestations	Common	Sepsis
Blood and lymphatic system disorders	Very common	Anaemia, Thrombocytopenia, Neutropenia, Febrile neutropenia
Immune system disorders	Very common	Drug hypersensitivity
	Common	Anaphylactic reaction, Hypersensitivity
Metabolism and nutrition disorders	Very common	Decreased appetite, Hyperglycaemia, Hypoalbuminemia
	Common	Hypertriglyceridemia, Hypoglycaemia, Hyperammonaemia
Psychiatric disorders	Very common	Anxiety
	Common	Irritability
Nervous system disorders	Very common	Headache
	Common	Dizziness
	Uncommon	Superior sagittal sinus thrombosis
Vascular disorders	Common	Hypotension
	Uncommon	Jugular vein thrombosis, Deep vein thrombosis
Respiratory, thoracic and mediastinal disorders	Common	Pulmonary embolism
Gastrointestinal disorders	Very common	Vomiting, Nausea, Abdominal pain, Diarrhoea
	Common	Pancreatitis
Skin and subcutaneous tissue disorders	Common	Rash maculo-papular, Pruritus, Rash, Urticaria, Rash erythematous,
Musculoskeletal and connective tissue disorders	Very common	Pain in extremity
General disorders and administration site conditions	Very common	Fatigue, Pyrexia
	Common	Injection site pain, Injection site reaction
Investigations	Very common	Transaminases increased, White blood cell count decreased, Lymphocyte count decreased, Weight decreased, Blood bilirubin increased
	Common	Blood creatinine increased , Activated partial thromboplastin time prolonged, Blood fibrinogen decreased, Antithrombin III decreased
Injury, poisoning and procedural complications	Very common	Contusion
	Common	Infusion-related reaction

 

Description of selected adverse reactions

Hypersensitivity

Hypersensitivity reactions were reported adverse reactions in the Enrylaze® clinical trial. The incidence of medicinal product hypersensitivity was 11% and it was severe in 8% of patients. The incidence of anaphylactic reaction was 2%, and it was severe in all patients. Overall hypersensitivity reactions observed more frequently in patients who received Enrylaze® intravenously. The frequency of hypersensitivity reactions leading to discontinuation was 10% (see section 4.4).

 

Pancreatitis

Cases of pancreatitis including life threatening cases have been reported in the Enrylaze® clinical trial. The incidence of pancreatitis was 7%; the incidence of serious events of pancreatitis was 5%; the incidence of life-threatening pancreatitis was 1%. One patient developed pancreatic pseudocyst after acute pancreatitis, which resolved without sequelae. The frequency of pancreatitis in Study JZP458‑201 which led to discontinuation was 5% (see section 4.4).

 

Adults and other special populations

Although the safety profile of adults above 25 years of age has not been studied, some adverse reactions, such as hepatotoxicity, thrombosis, and pancreatitis, have been reported more frequently in adults with acute lymphoblastic leukemia receiving other asparaginases than in paediatric patients.

 

Immunogencity

It has been reported that there is no to little cross reactivity between crisantaspase and other E. coli derived asparaginase.

 

As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity assays are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as assay methodology, sample handling, timing of sample collection, concomitant treatment, and underlying disease. For these reasons, comparison of the incidence of antibodies to Enrylaze® with the incidence of antibodies to other products may be misleading.

 

Analysis of patients receiving Enrylaze® by either intramuscular injection (n=167) or intravenous infusion (n=61) showed that 116 of 228 (51%) patients had confirmed positive anti-drug antibodies (ADA) toward Enrylaze®, 8 (7%) of these were ADA positive at pre dose 1.

 

A total of 23 (20%) patients who had ADAs experienced hypersensitivity reactions of which 6 (5%) had neutralising antibodies. Of the negative ADA patients 7/112 (6%) experienced a hypersensitivity reaction.

 

During the course of treatment 73 (63%) patients became ADA negative at least once.

 

Intravenous infusion

·             A total of 34 (56%) patients were found to be ADA positive.

·             1 patient was ADA positive at pre dose 1.

·             33 patients developed ADA toward Enrylaze® following administration of Enrylaze®. 18 of these patients subsequently became ADA negative at least once during the study.

·             12 (35%) experienced hypersensitivity reactions during the study, and of these patients 2 had neutralising antibodies. Of the negative ADA patients 4/27 (15%) experienced a hypersensitivity reaction.

 

Intramuscular injection

·             A total of 82 (49%) patients were found to be ADA positive.

·             7 patients were ADA positive at pre dose 1.

·             75 patients developed ADA toward Enrylaze® following administration of Enrylaze®. 55 of these patients subsequently became ADA negative at least once during the study.

·             11 (13%) patients experienced hypersensitivity reactions, and of these patients 4 had neutralising antibodies. Of the negative ADA positive patients 7/85 (8%) experienced a hypersensitivity reaction.

 

The presence of ADA does not appear to correlate with the occurrence of hypersensitivity reactions. SAA levels were not impacted for applicable ADA positive patients as they maintained SAA levels ≥ 0.1 U/mL at all available 48- and 72‑hour time points during Course 1. No impact on the pharmacokinetics of Enrylaze® was observed and ADA status was not found to be a significant factor in population pharmacokinetic analysis.

 

Paediatric population

The majority of the patients in Study JZP458‑201 were children < 18 years old 197/228 (86%) and therefore a comparison of frequency and severity in adverse reactions versus other age groups is not suitable.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 side effect(s)

 

 

• The National Pharmacovigilance Centre (NPC):

 

- SFDA Call Center: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa/

 

 

 

 

No case of Enrylaze® overdose with clinical symptoms has been reported and there is no specific antidote. Treatment is symptomatic and supportive.

 

 

Pharmacotherapeutic group: Other antineoplastic agents ATC code: L01XX02.

 

Mechanism of action

Asparaginase is an enzyme that catalyses the conversion of the amino acid L‑asparagine into L‑aspartic acid and ammonia. The pharmacological effect of Enrylaze® is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore is dependent on an exogenous source of asparagine for survival.

 

Clinical efficacy and safety

The efficacy and safety of Enrylaze® was determined in the clinical trials, an open-label, two-part, multi-cohort, multi-centre, multi-agent chemotherapeutic trial that treated 228 adult and paediatric patients with ALL or LBL who developed hypersensitivity to a long-acting E. coli-derived asparaginases. The median age of patients was 10 years (range, 1 to 25 years).

 

Prior long-acting E. coli-derived asparaginase treatments included pegaspargase for all patients apart from one who received other type of E. coli-derived asparaginase. In Study JZP458‑201, 190 (83%) patients experienced a hypersensitivity (Grade ≥ 3) to a long-acting E. coli-derived asparaginases, 15 (7%) patients experienced silent inactivation, and 23 (10%) patients experienced an allergic reaction with inactivation. The number of courses of Enrylaze® received ranged from 1 to 15.

 

Patients received 6 doses of Enrylaze®, either intramuscularly at 25 mg/m² or 37.5 mg/m² three times a week (Monday/Wednesday/Friday), or 25 mg/m² on Monday and Wednesday then 50 mg/m² on Friday by intravenous infusion or an intramuscular injection as a replacement for each dose of E. coli derived asparaginase remaining on a patient’s treatment plan.

 

The determination of efficacy was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) levels ≥ 0.1 U/mL. Serum trough asparaginase activity ≥ 0.1 U/mL has been demonstrated to correlate with asparagine depletion that predicts clinical efficacy (see section 5.2).

 

Observed NSAA levels during the clinical trials for indicated dosing schedules are presented in Table 2.

 

Table 2: Observed NSAA levels ≥ 0.1 U/mL during the clinical trials

 

Time Point	Intramuscularly 25 (MW)/ 50 (F) mg/m2	Intravenously 25 (MW)/ 50 (F) mg/m2
Last 48‑hour	95.9% [90.4%, 100.0%]	89.8% [82.1%, 97.5%]
Last 72‑hour	89.8% [81.3%, 98.3%]	40.0% [26.4%, 53.6%]

MW=Monday, Wednesday

MWF=Monday, Wednesday, Friday

 

The other recommended dosing schedules are based on interpolation from pharmacokinetic (PK) and response rates observed with the very similar investigated regimens.

 

Paediatric population

No clinically significant difference is expected in probability of achieving a therapeutic NSAA ≥ 0.1 U/mL based on age (1 month to 39 years) following the proposed Body surface area (BSA)‑based dosing regimens.

 

 

 

The PK of Enrylaze® was determined based on SAA. Patients received 6 doses of Enrylaze® at various doses intramuscularly on Monday, Wednesday and Friday or 25 mg/m² administered intramuscularly or intravenously on Monday and Wednesday and 50 mg/m² on Friday as a replacement for each dose of a long-acting E. coli-derived asparaginase remaining on their original treatment plan. Recombinant crisantaspase maximum SAA (C_max) and area under the SAA-time curve (AUC) increase approximately proportionally over a dose range from 12.5 to 50 mg/m². The trough SAA at 48‑hour (C_trough,48) or 72‑hour (C_trough,72) post the last dose for recombinant crisantaspase are summarised in Table 3.

 

Table 3: Enrylaze® pharmacokinetic parameters based on SAA

 

PK Parametera	Mean (95% CI) after last dose
	25/25/50 mg/m2 Monday, Wednesday, Friday		25/25/50 mg/m2 Monday, Wednesday, Friday
	Intramuscularly		Intravenously
Ctrough,48 (U/mL)	N =49	0.66 (0.54‑0.77)	N = 59	0.25 (0.20‑0.29)
Ctrough,72 (U/mL)	N=49	0.47 (0.35‑0.59)	N =50	0.10 (0.07‑0.13)

 

^a: C_trough,48: Trough SAA at 48 hour post the last 25 mg/m² dose in cycle 1; C_trough,72: Trough SAA at 72 hour post the last 50 mg/m² dose in cycle 1.

 

Absorption

The median T_max of recombinant crisantaspase is 16 hours following intramuscular administration. The mean absolute bioavailability for intramuscular administration is 38%.

 

Distribution

Following intravenous administration, the geometric mean (%CV) volume of distribution of recombinant crisantaspase is 1.75 L/m² (14%).

 

Biotransformation

Recombinant crisantaspase is expected to be metabolized into small peptides by catabolic pathways.

 

Elimination

Following intravenous administration, the geometric mean (%CV) clearance of recombinant crisantaspase is 0.14 L/hour/m² (20%).

 

The geometric mean (%CV) half-life is 8.6 hours (13%) following intravenous administration and 18.8 hours (11%) following intramuscular administration.

 

Special populations

Renal and hepatic impairment

There was no dedicated study on renal or hepatic impairment with Enrylaze®.

 

During treatment dose adjustment is not required for patients with total bilirubin ≤ 3 times the Upper Limit of Normal; there is limited data with Enrylaze® in patients with total bilirubin > 3 times to ≤ 10 times the ULN.

 

Dose adjustment is not required for patients with pre-existing mild or moderate hepatic impairment (total bilirubin > 1 to 3 times the ULN or AST > than the ULN). There are insufficient data in patients with pre-existing severe hepatic impairment to support a dose recommendation.There are insufficient data in patients with mild, moderate or severe renal impairment to support a dose recommendation.

 

Age, weight, body surface area and sex

There were no clinically significant differences in the pharmacokinetics of Enrylaze® based on weight (9 to 131 kg) or sex (n=138 male; n=88 female) after the dose was adjusted by body surface area (BSA).

 

The volume of distribution and clearance of recombinant crisantaspase increase with increasing BSA (0.44 to 2.53 m²).

 

Age impacts absorption rate constant whereas younger subjects have higher absorption rate constant value, leading to earlier T_max.

 

Race

Black or African American patients (n=24) had 25% lower clearance which may increase SAA exposure compared to population average (n=226). No dose adjustment is needed in African American population. There were no clinically significant differences in clearance between Hispanic (n=73) and Non-Hispanic (n=139) patients.

 

Neutralising antibodies

As with other asparaginase preparations, development of specific neutralising antibodies were identified with repeated dosing.

 

 

In a study, recombinant crisantaspase was administered intravenously to groups of rats for up to 14 consecutive days. Adverse effects in naïve animals, which were typical for asparaginases, were noted at exposures greater than 3.6 times the maximum human exposure.

 

Carcinogenicity, mutagenicity, and reproductive toxicity studies have not been conducted with Enrylaze®.

 

In embryofoetal development studies in rats and rabbits, Erwinia chrysanthemi L‑asparaginase produced maternal toxicity, increased resorptions, post implantation loss, embryofoetal toxicity, and/or gross abnormalities at exposures lower than those observed clinically (margins of exposure < 1).

 

In rat fertility and pre- and post-natal development studies with Erwinia chrysanthemi L‑asparaginase, there were no adverse effects on fertility or development, but the exposures were lower than those observed clinically (margins of exposure < 1).

 

 

Trehalose dihydrate

Sodium chloride

Sodium hydroxide (for pH adjustment)

Disodium phosphate

Sodium dihydrogen phosphate monohydrate

Polysorbate 80

Water for injection

 

 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. This includes infusion of other medicinal products using the same infusion line as Enrylaze®.

 

Unopened vial 3 years. In-use stability data From a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Intramuscular preparation Chemical and physical in-use stability for intramuscular preparations in a polypropylene syringe has been demonstrated for up to 8 hours at room temperature (15 °C–25 °C) or 24 hours when refrigerated (2 °C–8 °C). Intravenous preparation Chemical and physical in-use stability for intravenous preparations has been demonstrated for up to 12 hours at room temperature (15 °C–25 °C) or 24 hours when refrigerated (2 °C–8 °C). The storage times start from withdrawing the required volume from the unopened vials. The storage time in the polyethylene inner lined intravenous bag includes the 2 hour administration time (see section 6.6).

Store in a refrigerator (2 °C–8 °C) in an upright position.

 

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

 

Do not freeze.

 

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

 

 

2 mL Type 1 clear borosilicate glass vial sealed with a halobutyl rubber stopper and aluminium overseal and a violet plastic cap.

 

Pack size: 3 vials.

 

Precautions

Compatibility has been demonstrated in the following materials. No other materials have been studied.

·             Syringes made of polypropylene

·             Intravenous infusion sets made of PVC, polyolefin, polyamide, and ethylene vinyl acetate

 

Preparation instructions

·             Determine the posology, and number of vials of Enrylaze® based on the individual patient’s BSA as outlined in section 4.2. More than one vial may be needed for a full dose

·             Remove the appropriate number of vials of Enrylaze® from the refrigerator

o      Do not shake the vials

o      Each vial should be inspected for particles. If particles are observed and/or the liquid in the vial is not clear, the vial must not be used

·             Withdraw the required volume of Enrylaze® into a syringe

 

Subsequent steps for intravenous infusion preparation

·             The prepared dose of Enrylaze® in the syringe should be further diluted in an infusion bag containing 100 mL of sodium chloride 9 mg/mL (0.9%) solution for injection

·             The intravenous infusion prepared dose should be a clear liquid free from visual particulates.

o      If particles are observed in the intravenous infusion prepared dose, the solution must not be used

o      The start of storage mentioned starts from withdrawing the required volume from the vial (see section 6.3)

o      The 12- or 24‑hour storage time includes the recommended 2‑hour infusion time

 

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