Source: Health Products and Food Branch (CA) Revision Year: 2019
KIDROLASE (L-asparaginase) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.
KIDROLASE (L-asparaginase) may be used for maintenance or reinduction treatment; however, if a relapse occurs during maintenance treatment with KIDROLASE, reinduction should be attempted with another agent. The incidence of hepatic and pancreatic toxicities and of venous thromboembolic events may be increased in adolescents and young adults compared to children.
Treatment with KIDROLASE may cause glucose intolerance, exacerbate diabetes mellitus and potentially severe hyperglycemia. New onset of glucose intolerance may be irreversible.
In some patients, ketoacidosis has been reported.
Patients must be monitored for developing hyperglycemia and potential complications, especially in patients with uncontrolled diabetes. Administration of insulin and possibly discontinuation of Lasparaginase treatment may be necessary to manage hyperglycemia.
L-asparaginase has been reported to have immunosuppressive activity in animal experiments. This should be considered because KIDROLASE is used concomitantly with other agents that can reduce immune response and increase the risk for infections.
As with other L-asparaginase preparations, development of specific neutralizing antibodies has been reported with repeated dosing and is associated with reduced L-asparaginase activity. Therefore, monitoring L-asparaginase activity levels in serum or plasma and switching to another asparaginase preparation should be considered.
Patients should be evaluated before initiation of therapy and monitored during therapy for potential toxicities of KIDROLASE and the chemotherapy regimen. This should include laboratory monitoring for pancreatic, hepatic, coagulation, metabolic, hematologic, and renal adverse effects (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).
Treatment with L-asparaginase, including KIDROLASE, can cause pancreatitis. L-asparaginase induced pancreatitis can be limited to biochemical and/or radiologic manifestations, progress to pancreatitis with clinical symptoms, and can be severe (see ADVERSE REACTIONS). Fatal outcome of pancreatitis due to L-asparaginase products, including KIDROLASE, has been reported.
Patients must be closely monitored for signs and symptoms of pancreatic toxicity and instructed to promptly report potential symptoms of pancreatitis. If pancreatitis is suspected based on clinical symptoms, serum amylase and lipase should be determined. In patients treated with Lasparaginase, increase of serum amylase and lipase may be delayed, mild or absent. Clinical judgment should be used.
KIDROLASE must be permanently discontinued in case of severe pancreatitis (see CONTRAINDICATIONS).
Hyperglyceridemia, if marked, can contribute to the development of pancreatitis (see ADVERSE REACTIONS).
There have been isolated reports of first onset of clinical pancreatitis and detection of pancreatic pseudocyst formation several months after the last administration of L-asparaginase. Patients must be monitored for late-occurring signs of pancreatitis.
Development of chronic pancreatitis as well as persistent pancreatic insufficiency (exocrine insufficiency with, e.g. malabsorption; persistent glucose intolerance / diabetes mellitus) have been reported with L-asparaginase treatment.
Treatment with L-asparaginase, including KIDROLASE, can cause or worsen hepatic injury/dysfunction (including increase in transaminases and bilirubin, hepatic steatosis and hepatic failure). In addition, L-asparaginase reduces hepatic protein synthesis, leading to, e.g. hypoalbuminemia (see Hematologic in this section and ADVERSE REACTIONS).
Patients must be monitored for hepatic dysfunction (see also DRUG INTERACTIONS).
In case of severe hepatic adverse reactions, KIDROLASE should be discontinued until complete or near complete recovery. Treatment must be re-instituted only under very close monitoring.
Cerebral thrombosis and hemorrhage have been observed in patients treated with KIDROLASE. In some of these patients, events may have been attributable to coagulation disorders such as increases in Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT), hypofibrinogenemia, decreases in antithrombin III, plasminogen and other coagulation factors (VII, IX, X, VIII).
Blood clotting tests (aPTT, KPTT, Fibrinogen and AT III levels) should be carried out before treatment and before each injection of KIDROLASE (L-asparaginase). Replacement therapy should be instituted if fibrinogen is less than 1g/L or ATIII less than 60%. If fibrinogen and AT III cannot be increased, treatment should preferably be suspended and resumed only when the laboratory parameters have returned to normal, and if the potential benefit outweighs the potential risk.
Central Nervous System (CNS) toxicity, including encephalopathy, seizures and CNS depression, as well as development of the Posterior Reversible Encephalopathy Syndrome (PRES), have been reported in patients treated with protocols that contain L-asparaginase (see ADVERSE REACTIONS).
Posterior Reversible Encephalopathy Syndrome may occur rarely during treatment with any asparaginase Symptoms of PRES include elevated blood pressure, seizures, headaches, changes in mental state and acute visual impairment (primarily cortical blindness or homonymous hemianopsia). Symptoms can be nonspecific, and diagnosis requires confirmation by radiological procedures. 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 of KIDROLASE may be necessary if PRES is suspected or diagnosed. Expert advice should be sought.
Since hyperammonemia, if present, may cause or contribute to CNS toxicity, consider measuring serum ammonia in patients with CNS toxicity. In symptomatic patients initiate treatment as appropriate.
Fatal outcome of L-asparaginase-induced CNS toxicity has been reported.
Tumour cell destruction can result in hyperuricemia, tumour lysis syndrome and urate nephropathy. Renal impairment may be caused or aggravated by the chemotherapy regimen. Renal function and serum uric acid levels should be monitored and appropriately managed. If necessary, allopurinol should be administered for as long as required.
Administration of KIDROLASE can cause hypersensitivity reactions (infusion/injection reactions), including reactions presenting as anaphylaxis. Reactions have occurred following the first or subsequent administrations.
Hypersensitivity Reactions include
Since the intradermal test is unreliable in detecting the sensitivity of the patients – reactions have been observed after a negative intradermal test and vice-versa – and these reactions regress rapidly with I.V. corticotherapy, it is advisable to administer corticosteroids for a day or 2 before initiating reinduction treatment. Furthermore, at the time of injection, the appropriate material required to treat anaphylactic shock should be readily available.
When intermittent administration has been used, anaphylactic reactions to L-asparaginase were 3 times more frequent when administered I.V. than when injected I.M. Consequently, the I.M. route is recommended for intermittent administration. (See DOSAGE AND ADMINISTRATION).
Hypersensitivity reactions can begin during or immediately following administration. In the majority of patients, local and non-local reactions occur within the first 24 hours. Later onset of reactions has been reported two days or later after IM administration. Once a patient has received L-asparaginase as part of a treatment regimen, retreatment with the same agent at a later time (e.g. use during a later consolidation phase) is associated with an increased risk of hypersensitivity and anaphylactic reactions.
Women of childbearing potential must avoid pregnancy during cancer chemotherapy and for a period of time thereafter.
Men are advised not to father a child during cancer chemotherapy and for a period of time thereafter.
Refer to current practice guidelines for the duration to avoid conceiving following treatment with KIDROLASE.
L-asparaginase has been shown in animals to possess embryotoxic and teratogenic activity; therefore, it should not be used in pregnant patients or lactating women unless the potential benefit to the patient outweighs the risk to the fetus or breast feeding child.
Clinical trials with KIDROLASE (L-asparaginase) were conducted prior to 1970, and some patient subpopulations participating in those trials might have differed from the patients for whom KIDROLASE is used today. Furthermore, some of the concomitant chemotherapeutics would have been different than would be administered to those patients today, and the survival rates would have been very different for some of the subpopulations of patients in the clinical trials that were conducted. All of these factors would have an influence upon the adverse event profile. Therefore, the adverse reaction profile observed in those studies might have differed from what would be observed now in any recent clinical trial, including the frequencies of these adverse events. However, the following information represents the best possible understanding of the Adverse Reactions that have been observed based on the collective clinical experience with KIDROLASE.
The two most common adverse effects are:
Adverse effects of a clinical or biological nature observed in the course of clinical trials as well as those reported in the literature in patients treated with L-asparaginase can be classified as follows:
Nausea and vomiting generally appear at the beginning of treatment. They may be due directly to the drug itself or be secondary to elevation of BUN and blood uric acid. These adverse effects are rather frequent but rarely severe enough to necessitate withdrawal of treatment.
Diarrhea and abdominal pain have been observed infrequently but the precise cause is unknown. In rare instances, intestinal perforation has occurred although it has been impossible to establish the exact relationship with L-asparaginase.
Thromboembolic events resulting from the effects of asparaginase on clotting protein synthesis are the second most common class of adverse effects. They may be fatal or result in sequelae based on their location. The disease itself and the presence of a central venous catheter contribute to increasing thromboembolic risk (see WARNINGS AND PRECAUTIONS, Hematologic).
Coagulation disorders includeincluding increases in Prothrombin Time (PT) and Thromboplastin Time with hypofibrinogenemia, decreases in antithrombin III, plasminogen and other clotting factors (VII, IX, X and VIII) leading to possible bleeding and thrombotic complications. In consideration of coagulation changes during L-asparaginase treatment, hemostatic function should be checked periodically.
Coagulopathy, antithrombin III decreases, plasminogen, Protein C, Protein S, and fibrinogen resulting from the inhibition of protein synthesis were observed.
Bone marrow failure is exceptional with L-asparaginase and its hematological toxicity is not increased by its association with other antileukemic drugs; nevertheless, the usual blood and bone marrow determinations should be done.
Abnormalities of hepatic function are quite frequent and may, warrant interruption of treatment.
Most characteristics are the following:
To mitigate these adverse effects, it is recommended that hepatic function tests be performed at least once a week during L-asparaginase therapy and that the treatment be stopped should any significant changes occur.
Furthermore, before attempting reinduction with KIDROLASE, hepatic function should be checked to avoid giving L-asparaginase to any patient whose lab values are abnormal.
A posterior reversible encephalopathy syndrome (PRES) has been observed during therapy with asparaginase-containing regimens (see WARNINGS AND PRECAUTIONS, Neurologic).
Encephalopathy can be a consequence of hyperammonemia, sometimes associated with clinical signs of metabolic encephalopathy such as consciousness disorders with confusion, stupor, or coma, resulting from excessive ammonia production induced by the action of KIDROLASE on endogenous asparagine and glutamine. Seizures may be associated with cases of thrombosis or metabolic encephalopathy.
The hypersensitivity reactions are the most frequent undesirable effects. Within one-half to one hour following the injection of L-asparaginase, cases of hypersensitivity reactions have been observed. These consisted of cutaneous manifestations, oedema or, in a small number of patients, an anaphylactic reaction. Immediate hypersensitivity reactions include urticaria, laryngeal oedema, bronchospasm, hypotension and even anaphylactic shock. The anaphylactic reaction can be seen after the first injection but it occurs mainly between the 5th and the 9th administration. In case of a hypersensitivity reaction, treatment must be immediately and definitively stopped (see CONTRAINDICATIONS).
Patients receiving other agents which have potential life threatening interactions with KIDROLASE should be taken into consideration when administering KIDROLASE (Drug-Drug Interactions below).
Due to the increased risk of thrombosis in tumoral diseases, anticoagulant treatment is frequently administered. If oral anticoagulants are given, the high within-patient variability of coagulability in the course of the disease and the potential interaction between oral anticoagulants and anticancer chemotherapy require that INR (or PT) testing be done frequently.
Interactions with food have not been established.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
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