Spectrila

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SPECTRILA (SPECTRILA)

Composition:

Active substance: asparaginase;

1 vial contains 10,000 IU of asparaginase*;

Excipient: sucrose.

One unit (IU) is defined as the amount of enzyme required to release 1 µmol of ammonia per minute at pH 7.3 and temperature 37 °C.

After reconstitution, 1 ml of solution contains 2500 IU of asparaginase.

* Produced by Escherichia coli cells using recombinant DNA technology.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: white powder.

Pharmacotherapeutic group.

Antineoplastic agents. Other antineoplastic agents. ATC code L01X X02.

Pharmacological Properties.

Pharmacodynamics.

Asparaginase catalyzes the hydrolysis of asparagine into aspartic acid and ammonia. Unlike healthy cells, lymphoblastic tumor cells have very limited capacity to synthesize asparagine due to significantly reduced biosynthesis of asparagine synthetase. Therefore, they depend on asparagine diffusing from the extracellular space. As a result of asparagine depletion caused by asparaginase, protein synthesis in lymphoblastic tumor cells is disrupted, while most healthy cells remain unaffected.

Asparaginase may also be toxic to healthy, rapidly dividing cells that depend to some extent on exogenous asparagine supply.

Due to the concentration gradient of asparagine between intravascular and extravascular compartments, asparagine levels decrease in the extravascular space, including cerebrospinal fluid.

In clinical trials involving children with newly diagnosed acute lymphoblastic leukemia (study MC-ASP./ALL), it was shown that immediately after the end of asparaginase infusion, the mean serum concentration of asparagine decreased (from a premedication concentration of approximately 40 µM to a level below the lower limit of quantification of the bioanalytical method (< 0.5 µM)). The mean serum asparagine concentration remained below 0.5 µM from immediately after the first asparaginase infusion and for at least three days after the last infusion. After this period, serum asparagine levels gradually increased and returned to normal within 1–3 weeks.

In addition to asparagine, asparaginase is also capable of cleaving the amino acid glutamine into glutamic acid and ammonia, although with much lower efficiency. Clinical studies of asparaginase have shown that glutamine levels are only slightly affected, with considerable inter-individual variability. Serum glutamine levels decreased by no more than 50% from the premedication level of approximately 400 µM immediately after asparaginase infusion, but quickly returned to normal within several hours.

Pharmacokinetics.

Absorption

Asparaginase is not absorbed in the gastrointestinal tract; therefore, Spectrila must be administered intravenously.

Distribution

Asparaginase is distributed primarily within the intravascular space. The mean volume of distribution at steady state is 2.47 L.

Asparaginase does not cross the blood-brain barrier in measurable amounts.

The mean maximum serum concentration of asparaginase is 2,324 IU/L (1,625–4,819 IU/L). The maximum serum concentration (Cmax) of asparaginase is reached approximately 2 hours after the end of infusion.

After repeated administration of asparaginase at a dose of 5,000 IU/m² every third day, serum levels of asparaginase range from 108 to 510 IU/L.

Metabolism

The metabolism of asparaginase is not fully known, but it is believed to occur via degradation within the reticuloendothelial system under the influence of serum proteases.

Elimination

The mean terminal half-life of asparaginase is 25.8 ± 9.9 hours, with a range of 14.2 to 44.2 hours.

Preclinical safety data

In preclinical studies of repeated-dose toxicity and pharmacological safety conducted in rats, no special hazard to humans was identified, except for a minor but significant saluretic effect observed at doses lower than the recommended doses for patients with acute lymphoblastic leukemia. Additionally, increased urine pH and relative kidney weight were observed at exposures substantially exceeding the maximum human exposures, indicating limited clinical relevance.

Published studies on asparaginase indicate a negligible mutagenic, carcinogenic, and clastogenic potential of asparaginase.

In certain animal species, including mice, rats, and/or rabbits, administration of asparaginase resulted in an increased incidence of developmental abnormalities (including malformations of the central nervous system, heart, and musculoskeletal system) and fetal death when doses similar to or exceeding the recommended clinical doses (IU/m²) were used.

Clinical characteristics.

Indications.

In combination with antineoplastic therapy for the treatment of acute lymphoblastic leukemia (ALL) in children from birth to 18 years of age and in adults.

Contraindications.

• Hypersensitivity to the active substance, to any natural (non-pegylated) E. coli asparaginase preparation, or to any excipient.
• Pancreatitis.
• Severe hepatic dysfunction (bilirubin level > 3 times the upper limit of normal; transaminase level > 10 times the upper limit of normal).
• Coagulopathy (e.g., hemophilia) in medical history.
• Pancreatitis, severe bleeding, or severe thrombosis following asparaginase treatment in medical history.

Special precautions.

For reconstitution of the powder: using a syringe, 3.7 mL of water for injections is carefully introduced into the vial along the inner wall (do not inject directly onto or into the powder). Reconstitution of the vial contents is achieved by gentle swirling (to avoid foaming caused by shaking). The reconstituted solution may exhibit slight opalescence.

The calculated amount of asparaginase is then dissolved in 50–250 mL of 0.9% sodium chloride solution for infusion.

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

Interaction with other medicinal products and other forms of interaction.

General information

Asparaginase may increase the toxicity of other medicinal products due to its effects on liver function, for example, by increasing hepatotoxicity of potentially hepatotoxic medicinal products, increasing toxicity of drugs metabolized in the liver or bound to plasma proteins, and by altering the pharmacokinetics and pharmacodynamics of drugs bound to plasma proteins. Therefore, caution should be exercised in patients receiving other medicinal products metabolized in the liver.

Thus, when asparaginase is used concomitantly with potentially hepatotoxic medicinal products, liver function parameters should be monitored.

Myelosuppressive medicinal products

Myelosuppression, potentially affecting all three cell lines, may develop during therapy including asparaginase, and infections may occur. Concomitant treatment with myelosuppressive medicinal products known to cause infections are major contributing factors; therefore, patients should be carefully monitored for symptoms of myelosuppression and infection.

Vincristine
The toxicity of vincristine may be augmented by the toxicity of asparaginase when both agents are administered simultaneously. Therefore, vincristine should be administered 3–24 hours before administration of asparaginase to minimize toxicity.

Glucocorticoids and/or anticoagulants

Concomitant use of glucocorticoids and/or anticoagulants with asparaginase may increase the risk of altered blood coagulation properties (see section "Special warnings and precautions for use"). This may promote bleeding (effect of anticoagulants) or thrombosis (effect of glucocorticoids). Therefore, caution is required when anticoagulants (e.g., coumarin, heparin, dipyridamole, acetylsalicylic acid, or nonsteroidal anti-inflammatory drugs) or glucocorticoids are used concomitantly with asparaginase.

Methotrexate

Suppression of protein synthesis due to asparagine depletion induced by asparaginase suggests a reduced cytotoxic effect of methotrexate, which requires cellular replication for its antitumor activity. This antagonism is observed when asparaginase is administered before or simultaneously with methotrexate. Conversely, the antitumor effects of methotrexate are enhanced when asparaginase is administered 24 hours after methotrexate. This treatment schedule favors reduction of gastrointestinal and hematological effects of methotrexate.

Cytarabine
In vitro and in vivo laboratory data show that the efficacy of high-dose cytarabine is reduced when asparaginase is administered prior to cytarabine. However, a synergistic effect was observed when asparaginase was administered after cytarabine. This effect was most pronounced with an interval of approximately 120 hours.

Vaccination
Concomitant vaccination with live vaccines increases the risk of developing serious infection. Therefore, immunization with live vaccines should not be performed earlier than 3 months after completion of antineoplastic therapy.

Special precautions for use.

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number should be clearly documented in the patient's medical records to establish a link between the patient's condition and the batch of the administered medicinal product.

General information and laboratory monitoring

During treatment with asparaginase, the following life-threatening conditions may occur in patients of all age groups:

• Acute pancreatitis;
• Hepatotoxicity;
• Anaphylaxis;
• Coagulation disorders, including symptomatic thrombosis associated with the use of central venous catheters;
• Hyperglycemic states.

Before starting therapy, bilirubin levels, liver transaminases, and coagulation parameters (particularly activated partial thromboplastin time [APTT], prothrombin time [PT], antithrombin III, and fibrinogen) should be determined.

After administration of any asparaginase preparation, careful monitoring of bilirubin, liver transaminases, glucose in urine/blood, coagulation parameters (particularly APTT, PT, antithrombin III, fibrinogen, and D-dimer), amylase, lipase, triglycerides, and cholesterol is recommended.

Acute pancreatitis

If acute pancreatitis develops, treatment with asparaginase should be discontinued. Acute pancreatitis has been observed in less than 10% of patients. Isolated cases of hemorrhagic or necrotizing pancreatitis have been reported. There have been rare reports of fatal outcomes. Clinical symptoms include abdominal pain, nausea, vomiting, and anorexia. Serum amylase and lipase levels are usually elevated, although in some patients they may be normal due to impaired protein synthesis. The risk of developing acute pancreatitis is increased in patients with severe hypertriglyceridemia. Such patients should not continue treatment with asparaginase (see sections "Contraindications" and "Side effects").

Hepatotoxicity

Severe liver function disorders, including cholestasis, jaundice, hepatic necrosis, and liver failure with fatal outcomes, have been rarely reported (see sections "Side effects" and "Interaction with other medicinal products and other forms of interaction"). Liver function parameters should be closely monitored before and during asparaginase therapy.

Treatment with asparaginase should be discontinued in case of severe liver failure (bilirubin level > 3 times the upper limit of normal; transaminase level > 10 times the upper limit of normal), severe hypertriglyceridemia, hyperglycemia, or coagulation disorders (e.g., venous sinus thrombosis, severe bleeding).

Allergic and anaphylactic reactions

Due to the risk of severe anaphylactic reactions, asparaginase should not be administered as an intravenous bolus. A skin test or a small test dose administered intravenously may be performed beforehand. However, neither procedure can reliably predict which patients will develop allergic reactions.

If allergic reactions occur, administration of asparaginase should be immediately discontinued and appropriate treatment initiated, which may include antihistamines and corticosteroids.

Coagulation disorders

Due to protein synthesis inhibition (reduced synthesis of factors II, V, VII, VIII, and IX, proteins C and S, antithrombin III [AT III]) caused by asparaginase, coagulation disorders may develop, manifesting as thrombosis, disseminated intravascular coagulation, or bleeding.

The risk of thrombosis is considered higher than the risk of bleeding. Cases of symptomatic thrombosis associated with the use of central venous catheters have also been described. Approximately half of thrombotic events occur in cerebral vessels. Cerebral venous sinus thrombosis is possible. Ischemic strokes are rare.

Cases of acquired or genetic deficiency of physiological coagulation inhibitors (protein C, protein S, antithrombin) associated with vascular complications have also been reported.

Frequent assessment of coagulation parameters is essential before and during treatment with asparaginase. In case of decreased AT III levels, specialist advice should be sought.

Hyperglycemic states

Asparaginase may cause hyperglycemia due to reduced insulin production. Additionally, it may reduce insulin secretion from pancreatic beta cells and impair insulin receptor function. This so-called self-limiting syndrome. However, in individual cases, it may lead to diabetic ketoacidosis. Concomitant treatment with corticosteroids enhances this effect. Serum glucose and urine glucose levels should be monitored regularly and corrected as clinically indicated.

Antineoplastic agents

Due to tumor cell lysis induced by asparaginase, a large amount of uric acid may be released, leading to hyperuricemia. Concomitant use of other antineoplastic agents enhances this effect. Uric acid nephropathy can be prevented by intensive urine alkalization and administration of allopurinol.

Glucocorticoids

A higher risk of thrombosis during induction therapy with asparaginase and prednisolone has been observed in children with genetic thrombosis risk factors (factor V G1691A mutation, prothrombin gene G20210A mutation, MTHFR T677T genotype, elevated lipoprotein A levels, hyperhomocysteinemia).

Contraceptives

Women of reproductive age should use effective contraceptive methods during treatment with asparaginase and for 7 months after completion of therapy. Since indirect interaction between components of oral contraceptives and asparaginase cannot be excluded, oral contraceptives are not considered sufficiently effective in such clinical situations.

Other methods, besides oral contraceptives, may be used by women of reproductive age (see section "Special precautions for use").

Men should also use effective contraceptive methods during treatment with asparaginase and for 4 months after completion of therapy.

Patients with Philadelphia chromosome

The efficacy and safety of Spectrila have not been established in patients with the Philadelphia chromosome.

Recommended monitoring tests for patients of all age groups

Asparaginase activity

To avoid accelerated loss of asparaginase activity, serum or plasma asparaginase activity levels should be monitored. It is advisable to measure asparaginase activity levels three days after the last administration, i.e., usually immediately before the next dose of asparaginase. Low asparaginase activity levels are often accompanied by the appearance of antibodies to asparaginase. In such cases, switching to another asparaginase preparation should be considered. Specialist consultation is required.

Hypoalbuminemia

Due to impaired protein synthesis, serum protein levels (particularly albumin) usually decrease in patients receiving asparaginase. Since serum protein is important for binding and transporting certain active substances, serum protein levels should be monitored regularly.

Hyperammonemia

Plasma ammonia levels should be determined in all patients with unexplained neurological symptoms or severe and persistent vomiting. In case of hyperammonemia with severe clinical symptoms, therapeutic and pharmacological measures should be initiated promptly to reduce plasma ammonia levels (e.g., protein intake restriction and hemodialysis), induce reverse catabolism, increase nitrogen waste excretion, and specialist consultation should be sought.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Rarely, reversible posterior leukoencephalopathy syndrome (RPLS) may occur during treatment with asparaginase. On magnetic resonance imaging (MRI), this syndrome is characterized by reversible (from several days to several months) lesions/edema, predominantly in the posterior region of the brain. Symptoms of RPLS include marked elevation of blood pressure, seizures, headache, altered mental status, and acute visual disturbances (primarily cortical blindness or homonymous hemianopsia). It remains unclear whether reversible posterior leukoencephalopathy syndrome is caused by asparaginase use, concomitant therapy, or the underlying disease. In case of RPLS, symptomatic treatment should be provided, including measures to manage any seizures. Discontinuation or dose reduction of concomitantly administered immunosuppressive medicinal products may be necessary. Specialist consultation should be sought.

Use during pregnancy or breastfeeding.

Women of reproductive age/Contraception in men and women

Women of reproductive age should use effective contraceptive methods and avoid pregnancy during treatment with asparaginase and for 7 months after completion of therapy. Since indirect interaction between components of oral contraceptives and asparaginase cannot be excluded, oral contraceptives are not considered sufficiently effective in such clinical situations.

Other methods, besides oral contraceptives, may be used by women of reproductive age (see section "Special precautions for use").

Men should also use effective contraceptive methods during treatment with asparaginase and for 4 months after completion of therapy.

Pregnancy

Data on the use of asparaginase in pregnant women are lacking. Reproductive function studies in animals with asparaginase have not been conducted, but studies with other asparaginase preparations in animals have demonstrated embryotoxic and teratogenic effects (see section "Pharmacological properties"). Given the results of animal studies and the mechanism of action of asparaginase, the drug should not be used during pregnancy unless the woman's clinical condition requires treatment with asparaginase.

Breastfeeding

It is unknown whether asparaginase is excreted in breast milk. Due to the potential for serious adverse reactions in infants, breastfeeding should be discontinued during treatment with Spectrila.

Fertility

Data on the effect of asparaginase on human fertility are lacking.

Ability to affect reaction speed when driving vehicles or operating machinery.

The medicinal product has a moderate effect on the ability to drive vehicles and operate machinery, particularly due to its potential effects on the nervous system and gastrointestinal tract (see section "Side effects").

Method of Administration and Dosage

Spectrila should be prescribed only by physicians experienced in the use of antineoplastic agents. The drug should be administered only in a hospital setting equipped with appropriate resuscitation equipment. Spectrila is typically used within combined chemotherapy protocols with other antineoplastic agents (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adults and Children Aged 1 Year and Older

The recommended dose of asparaginase for intravenous administration is 5000 IU/m² body surface area (BSA), administered every third day of treatment.

Treatment should be monitored by measuring asparaginase activity in blood serum, assessed three days after administration. If serum asparaginase activity does not reach desired levels, switching to another asparaginase medicinal product may be considered (see section "Special Warnings and Precautions for Use").

Children from Birth to 12 Months of Age

Due to limited data, the recommended doses for infants are as follows:

• Children under 6 months of age: 6700 IU/m² body surface area (BSA);
• Children aged 6 to 12 months: 7500 IU/m² body surface area (BSA).

Data on the efficacy and safety of Spectrila in adult patients are limited. Data on the efficacy and safety of Spectrila during the post-induction phase of treatment are very limited.

Special Populations

Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Hepatic Impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment. However, the medicinal product should not be administered to patients with severe hepatic impairment.

Geriatric Patients

Data on treatment of patients aged over 65 years are limited.

Method of Administration

Spectrila is administered only by intravenous infusion.

The daily dose of Spectrila for a single patient should be diluted to a final volume of 50–250 mL with 0.9% sodium chloride solution. The diluted asparaginase solution should be administered by intravenous infusion over 0.5–2 hours.

Asparaginase must not be administered as a bolus injection.

Children

Data on the safety of Spectrila in children under 1 year of age are limited; see sections "Pharmacological Properties" and "Method of Administration and Dosage."

Overdose

Cases of overdose have not been reported.

Treatment: There is no known specific antidote. Treatment is symptomatic and supportive.

Adverse reactions.

Summary of safety profile

The main toxicity of asparaginase results from immunological reactions caused by exposure to a bacterial protein. Hypersensitivity reactions include transient skin flushing or rash, urticaria, bronchospasm, angioedema, and anaphylaxis.

In addition, treatment with asparaginase may lead to organ system disorders characterized by high levels of protein synthesis. Reduced protein synthesis may primarily result in liver dysfunction, acute pancreatitis, decreased insulin secretion and hyperglycemia, reduced secretion of blood coagulation factors (particularly fibrinogen and antithrombin III), leading to coagulation disorders (thrombosis, hemorrhage), as well as decreased production of lipoproteins, resulting in hypertriglyceridemia.

The most serious adverse reactions associated with the use of Spectrila include severe hypersensitivity reactions such as anaphylactic shock (rare), thromboembolic events (common), acute pancreatitis (common), and severe hepatotoxicity, such as jaundice, hepatic necrosis, and liver failure (rare).

The most frequently observed adverse reactions (very common) include hypersensitivity reactions, hyperglycemia, hypoalbuminemia, nausea, vomiting, diarrhea, abdominal pain, edema, fatigue, and changes in laboratory parameters (e.g., transaminases, bilirubin, blood lipids, coagulation parameters).

Since Spectrila is usually administered in combination with other antineoplastic agents, it is often difficult to distinguish adverse reactions associated with the use of other medicinal products.

Summary table of adverse reactions

The information on adverse reactions listed in Table 1 was collected from clinical trials of Spectrila involving 125 children with newly diagnosed acute lymphoblastic leukemia, as well as from post-marketing surveillance data on other E. coli asparaginase preparations used in children and adults.

The frequency of adverse reactions is categorized as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated based on available data).

Table 1

Organs and systems	Adverse reactions by frequency
Infections and infestations	Frequency unknown: infections.
Disorders of the blood and lymphatic system	Common: disseminated intravascular coagulation (DIC), anemia, leukopenia, thrombocytopenia.
Immune system disorders	Very common: hypersensitivity reactions, including skin flushing, rash, arterial hypotension, swelling/angioedema, urticaria, dyspnea. Common: hypersensitivity reactions, including bronchospasm. Uncommon: anaphylactic shock.
Endocrine disorders	Rare: secondary hypothyroidism, hypoparathyroidism.
Metabolism and nutrition disorders	Very common: hyperglycemia, hypoalbuminemia. Common: hypoglycemia, decreased appetite, weight loss. Uncommon: hyperuricemia, hyperammonemia. Rare: diabetic ketoacidosis.
Psychiatric disorders	Common: depression, hallucinations, confusion.
Nervous system disorders	Common: neurological symptoms including agitation, dizziness, and somnolence. Uncommon: headache. Rare: ischemic stroke, reversible posterior leukoencephalopathy syndrome (RPLS), seizures, disturbances of consciousness including coma. Rare: tremor.
Vascular disorders	Common: thrombosis, particularly cavernous sinus thrombosis or deep vein thrombosis, hemorrhage.
Gastrointestinal disorders	Very common: diarrhea, nausea, vomiting, abdominal pain. Common: acute pancreatitis. Rare: hemorrhagic pancreatitis, necrotizing pancreatitis, parotitis. Rare: pancreatic pseudocysts, pancreatitis with potentially fatal outcome.
Hepatobiliary disorders	Rare: liver failure with potentially fatal outcome, hepatocellular necrosis, cases of cholestasis, jaundice. Frequency unknown: fatty degeneration of the liver.
General disorders and administration site conditions	Very common: edema, fatigue. Common: pain (in back, in joints).
Investigations	Very common: increased levels of transaminases, bilirubin, alkaline phosphatase, cholesterol, triglycerides, very low-density lipoproteins (VLDL), lipoprotein lipase, urea, ammonia, lactate dehydrogenase in blood. Decreased levels of antithrombin III, fibrinogen, cholesterol, low-density lipoproteins (LDL), total protein in blood. Common: increased levels of amylase, lipase, deviations in electroencephalogram (EEG) findings (reduced alpha-wave activity, increased zeta- and delta-wave activity).

Description of individual adverse reactions

Immune system disorders

Spectrila may induce antibodies of various immunoglobulin classes (IgG, IgM, IgE). These antibodies may cause clinical allergic reactions, inactivate enzymatic activity, or accelerate the elimination of asparaginase.

Allergic reactions may manifest as skin redness, rash, pain (joint pain, back pain, abdominal pain), arterial hypotension, swelling/angioneurotic edema, urticaria, dyspnea, bronchospasm, and anaphylactic shock.

The likelihood of allergic reactions increases with the number of administered doses; however, in very rare cases, reactions may occur after administration of the first dose of asparaginase. The majority of hypersensitivity reactions to asparaginase occur during subsequent treatment phases (reinduction therapy, delayed intensification).

Allergic reactions were observed in clinical trials involving children with newly diagnosed acute lymphoblastic leukemia (trial MC-ASP.5/ALL) (see Table 2).

Table 2

Frequency of allergic reaction manifestations in patients (MC ASP.5/ALL; safety analysis results)

Treatment group	Spectrila	Comparator drug (asparaginase)
Number of patients	97	101
Allergic reactions occurring within 12 hours after asparaginase infusion during induction therapy	2 (2.1%)	5 (5.0%)
Any allergic reaction*, occurring within 24 hours after asparaginase infusion during induction therapy	16 (16%)	24 (24%)

* Including all allergic reactions occurring within 12 hours after asparaginase infusion and all adverse reactions occurring within 24 hours after infusion, according to the criteria for assessing the frequency of adverse reaction development: namely, loss of consciousness (syncope), hypotension, rash, erythema, pruritus, dyspnea, injection site reactions, or airway obstruction.

During treatment with Spectrila, no allergic reactions were observed in any of the 12 children under 1 year of age (study MC-ASP.6/INF).

In the event of allergic reactions, administration of Spectrila must be immediately discontinued.

Immunogenicity

In an immunogenicity study involving children aged 1–18 years with newly diagnosed acute lymphoblastic leukemia (study MC-ASP.5/ALL), anti-asparaginase antibodies were detected simultaneously on day 33 of induction therapy in 10 patients in the Spectrila treatment group (10.3%) and 9 patients in the control group (8.9%).

An equal proportion of patients in both groups developed anti-asparaginase antibodies by the start of post-induction therapy (in the Spectrila group – 54.6%, compared to the E. coli asparaginase comparator group – 52.5%). Most anti-asparaginase antibodies developed between the last asparaginase infusion on day 33 and the start of post-induction therapy on day 79.

No anti-asparaginase antibodies were detected in any of the 12 children under 1 year of age during treatment with Spectrila (study MC-ASP.6/INF).

Hypothyroidism

Cases of transient secondary hypothyroidism have been reported, likely due to decreased serum thyroxine-binding globulin resulting from protein synthesis suppression caused by asparaginase.

Hypoalbuminemia

In patients treated with asparaginase, serum protein levels (particularly albumin) typically decrease due to impaired protein synthesis (see section "Special precautions for use"). Hypoalbuminemia may lead to edema.

Dyslipidemia

Changes in blood lipid levels of mild to moderate severity (e.g., increased or decreased cholesterol levels, elevated triglycerides, increased very low-density lipoprotein (VLDL), decreased low-density lipoprotein (LDL), increased lipoprotein lipase activity) are very common in patients treated with asparaginase and are mostly asymptomatic. Concomitant use of glucocorticoids may contribute to these changes. However, in rare cases, severe hypertriglyceridemia (triglyceride levels > 1000 mg/dL) may increase the risk of acute pancreatitis. Asparaginase-induced hyperlipidemia should be managed according to its severity and clinical symptoms.

Hyperammonemia

Cases of hyperammonemia have been infrequently reported in patients receiving asparaginase, particularly in those with hepatic insufficiency. In very rare cases, severe hyperammonemia may lead to neurological disorders such as seizures and coma.

Hyperglycemia and hypoglycemia

Alterations in pancreatic function, predominantly manifesting as hyperglycemia, are very common during asparaginase treatment. These reactions are usually transient. Diabetic ketoacidosis has been reported in rare cases.

Hypoglycemia typically developed without clinical symptoms in patients receiving asparaginase. The mechanism leading to this reaction is unknown.

Nervous system disorders

Adverse reactions affecting the central nervous system observed in patients treated with asparaginase include EEG abnormalities, seizures, dizziness, somnolence, coma, and headache.

The causes of these neurological disorders remain unclear. Hyperammonemia and venous sinus thrombosis cannot be excluded.

In isolated cases, reversible posterior leukoencephalopathy syndrome has been observed during asparaginase therapy.

Gastrointestinal disorders

Nausea/vomiting are very common in patients treated with asparaginase, although usually of mild severity. Anorexia, loss of appetite, abdominal pain, diarrhea, and weight loss have also been reported.

Acute pancreatitis developed in less than 10% of patients. Hemorrhagic or necrotizing pancreatitis has been observed in rare cases. There have been isolated reports of fatal outcomes. Several cases of asparaginase-induced parotitis have been reported.

Children

Data on the safety of Spectrila in children under 1 year of age are limited.

Adults

The same asparaginase-related adverse reactions are observed in adults and children in quantitative terms; however, some of these adverse reactions (e.g., thromboembolic events) occur more frequently in adult patients compared to children. Due to a higher prevalence of comorbidities such as hepatic and/or renal insufficiency, patients over 55 years of age generally tolerate asparaginase treatment less well than children.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Reconstituted and diluted solution

The chemical and physical stability of the solution is maintained for 2 days at 2–8 °C. From a microbiological standpoint, the solution should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions, which should not exceed 24 hours at 2–8 °C, unless dilution was performed under controlled and validated aseptic conditions.

Storage conditions.

Store in a refrigerator (2–8 °C).

Store in a dry, light-protected, and child-resistant place.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products.

Packaging.

10,000 IU of asparaginase in vials made of colorless glass, closed with butyl rubber stoppers and aluminum flip-off caps; 1 or 5 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Medac Gesellschaft für klinische Spezialpräparate mbH.

Manufacturer's address and place of business.

Theaterstraße 6, 22880 Wedel, Germany.