ENRYLAZE Solution for injection/infusion Ref.[51281] Active ingredients: Asparaginase

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):

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 authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.