- Approval Id
- dd398744b586f2a6
- Drug Approval Emc Name
- Enrylaze 10 mg/0.5 ml Solution for injection/infusion
- Drug Name
- Enrylaze 10 mg/0.5 ml Solution for injection/infusion
- Company Name
- Jazz Pharmaceuticals UK Limited
- Company Address
- 80 Charlotte Street, London, W1T 4DF
- Company Telephone
- +44 (0)1865 405 000
- Company Fax
- +44 (0)1748 828 801
- Company Medical Info Direct Line
- 0808 189 0387
- Company Medical Info Email
- [email protected]
- Company Customer Care Direct Line
- +44 (0)1865 405 019
- Company Medical Info Fax
- +44 (0)1748 828 801
- Atc Code
- L01XX02
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Jazz Pharmaceuticals UK Limited 80 Charlotte Street London, W1T 4DF United Kingdom Tel: +44 8081890387 Email: [email protected]
- Authorisation Number
- 8. Marketing authorisation number(s) PLGB 31626/0007
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 30/01/2024
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Jazz Pharmaceuticals UK Limited 80 Charlotte Street London, W1T 4DF United Kingdom Tel: +44 8081890387 Email: [email protected]
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PLGB 31626/0007
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 30/01/2024
- Instruction Composition
- 2. Qualitative and quantitative composition One vial contains 0.5 mL solution of 10 mg of recombinant crisantaspase* The amino acid sequence is identical to native L asparaginase from Erwinia chrysanthemi (also known as crisantaspase). An in-vitro activity assay demonstrated that 1 mg of recombinant crisantaspase approximates 1 000 U of native crisantaspase, consistent with the in-vivo comparisons from clinical trials. Serum asparaginase activity (SAA) exposures (Cmax, concentration at 48h & 72h and AUC) have been shown to be comparable for 25 mg/m2 recombinant crisantaspase and 25 000 U/m2 native crisantaspase, when administered intravenously or intramuscularly in healthy subjects. *recombinant Erwinia chrysanthemi L asparaginase produced in Pseudomonas fluorescens by recombinant DNA technology. For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- 3. Pharmaceutical form Solution for injection/infusion. Clear to opalescent, colourless to slightly yellow solution with a pH of 7.0 ± 0.5 and an osmolality: 290–350 mOsmol/Kg.
- Instruction Clinical Particulars
- 4. Clinical particulars 4.1 Therapeutic indications 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. 4.2 Posology and method of administration 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. 4.3 Contraindications – 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 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 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'. 4.5 Interaction with other medicinal products and other forms of interaction 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. 4.6 Fertility, pregnancy and lactation 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
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties 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% [2
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients Trehalose dihydrate Sodium chloride Sodium hydroxide (for pH adjustment) Disodium phosphate Sodium dihydrogen phosphate monohydrate Polysorbate 80 Water for injection 6.2 Incompatibilities 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. 6.3 Shelf life 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). 6.4 Special precautions for storage 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. 6.5 Nature and contents of container 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. 6.6 Special precautions for disposal and other handling 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.
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition One vial contains 0.5 mL solution of 10 mg of recombinant crisantaspase* The amino acid sequence is identical to native L asparaginase from Erwinia chrysanthemi (also known as crisantaspase). An in-vitro activity assay demonstrated that 1 mg of recombinant crisantaspase approximates 1 000 U of native crisantaspase, consistent with the in-vivo comparisons from clinical trials. Serum asparaginase activity (SAA) exposures (Cmax, concentration at 48h & 72h and AUC) have been shown to be comparable for 25 mg/m2 recombinant crisantaspase and 25 000 U/m2 native crisantaspase, when administered intravenously or intramuscularly in healthy subjects. *recombinant Erwinia chrysanthemi L asparaginase produced in Pseudomonas fluorescens by recombinant DNA technology. For the full list of excipients, see section 6.1.
## Pharmaceutical Form
3. Pharmaceutical form Solution for injection/infusion. Clear to opalescent, colourless to slightly yellow solution with a pH of 7.0 ± 0.5 and an osmolality: 290–350 mOsmol/Kg.
## Clinical Particulars
4. Clinical particulars 4.1 Therapeutic indications 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. 4.2 Posology and method of administration 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. 4.3 Contraindications – 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 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 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'. 4.5 Interaction with other medicinal products and other forms of interaction 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. 4.6 Fertility, pregnancy and lactation 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
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties 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% [2
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients Trehalose dihydrate Sodium chloride Sodium hydroxide (for pH adjustment) Disodium phosphate Sodium dihydrogen phosphate monohydrate Polysorbate 80 Water for injection 6.2 Incompatibilities 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. 6.3 Shelf life 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). 6.4 Special precautions for storage 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. 6.5 Nature and contents of container 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. 6.6 Special precautions for disposal and other handling 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.
