Special Warning : אזהרת שימוש

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.

Asparaginase antibodies
The presence of anti-asparaginase antibodies may be associated with low asparaginase activity levels due to potential neutralising activity of these antibodies. In such cases, a switch to a different asparaginase preparation should be considered.


Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to rule out an accelerated reduction of asparaginase activity.

Hypersensitivity
Hypersensitivity reactions to pegaspargase, including life-threatening anaphylaxis, can occur during therapy, including in patients with known hypersensitivity to E. coli derived asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, decreased blood pressure, bronchospasm, dyspnoea, pruritus and rash (see sections 4.3 and 4.8).

As a routine precautionary measure, the patient should be monitored for an hour after administration; resuscitation equipment and other appropriate means for the treatment of anaphylaxis should be available (epinephrine, oxygen, intravenous steroids, etc.). Oncaspar should be discontinued in patients with serious hypersensitivity reactions (see sections 4.3 and 4.8). Depending on the severity of the symptoms, administration of antihistamines, corticosteroids and vasopressors may be indicated as a counter-measure.

Pancreatic effects
Pancreatitis, including haemorrhagic or necrotising pancreatitis with fatal outcomes, has been reported in patients receiving Oncaspar (see section 4.8).

Patients should be informed of the signs and symptoms of pancreatitis which, if left untreated, could become fatal.

If pancreatitis is suspected, Oncaspar should be discontinued; if pancreatitis is confirmed, Oncaspar should not be restarted.

Serum amylase and/or lipase levels should be monitored frequently to identify early signs of pancreatic inflammation. Blood glucose levels should be monitored, as impaired glucose tolerance may occur with concomitant use of Oncaspar with prednisone.

Coagulopathy
Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving pegaspargase (see section 4.8). Oncaspar should be discontinued in patients with serious thrombotic events.

Increased prothrombin time (PT), increased partial thromboplastin time (PTT), hypofibrinogenaemia and antithrombin III decrease can occur in patients receiving pegaspargase. Coagulation parameters should be monitored at baseline and periodically during and after treatment, particularly when other medicinal products with anticoagulant effects (such as acetylsalicylic acid and non-steroidal anti-inflammatory medicinal products) are used simultaneously (see section 4.5), or when concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered. When there is a marked decrease in fibrinogen or antithrombin III (ATIII) deficiency, consider appropriate replacement therapy.

Osteonecrosis
In the presence of glucocorticoids, osteonecrosis (avascular necrosis) is a possible complication of hypercoagulability observed in children and adolescents with a higher incidence seen in girls (see section 4.5 and 4.8). Therefore, a close monitoring in children and adolescents’ patients is recommended in order to detect any clinical signs/symptoms of osteonecrosis. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment as per standard guidelines of treatment of ALL and supportive care principles.

Hepatic effects
Combination therapy with Oncaspar and other hepatotoxic products can result in severe hepatic toxicity.

Caution is required when Oncaspar is given in combination with hepatotoxic products, especially if there is pre-existing hepatic impairment. Patients should be monitored for changes in liver function parameters.

There may be an increased risk of hepatotoxicity in Philadelphia chromosome positive patients, for whom treatment with tyrosine kinase inhibitors (e.g., imatinib) is combined with L-asparaginase therapy. This should be taken into account when considering the use of Oncaspar in these patient populations.

Hepatic veno-occlusive disease (VOD), including severe, life-threatening and potentially fatal cases have been observed in patients treated with Oncaspar in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy (see section 4.8).

Signs and symptoms of VOD include rapid weight gain, fluid retention with ascites, hepatomegaly, thrombocytopenia and rapid increase of bilirubin. The identification of risk factors like pre-existing liver disease or history of VOD is essential for its prevention. Prompt recognition and appropriate management of VOD remain imperative. Patients who experience this condition should be treated according to standard medical practice.

Due to the risk of hyperbilirubinaemia, it is recommended to monitor bilirubin levels at baseline and prior to each dose.

Central nervous system effects
Combination therapy with Oncaspar can result in central nervous system toxicity. Cases of encephalopathy (including reversible posterior leukoencephalopathy syndrome) have been reported (see section 4.8).

Oncaspar may cause central nervous system signs and symptoms manifesting as somnolence, confusion, convulsions. Patients should be closely monitored for such symptoms, especially if Oncaspar is used in association with neurotoxic products (such as vincristine and methotrexate; see section 4.5),

Myelosuppression
Pegaspargase may cause myelosuppression, either directly or indirectly (by altering myelosuppressive effects of other agents such as methotrexate or 6-mercaptopurine). Therefore, use of Oncaspar could increase the risk of infections.

The decrease in the number of circulating lymphoblasts is often quite marked, and normal or too low leukocyte counts are often seen in the first days after the start of therapy. This can be associated with a marked rise in the serum uric acid level. Uric acid nephropathy may develop. To monitor the therapeutic effect, the peripheral blood count and the patient’s bone marrow should be monitored closely.

Hyperammonaemia
Asparaginase facilitates the rapid conversion of asparagine and glutamine to aspartic acid and glutamic acid, with ammonia as the shared by-product of both reactions (see section 5.1). Intravenous administration of asparaginase may therefore cause serum levels of ammonia to rise sharply following administration.

The symptoms of hyperammonaemia are often transient in nature and can include: nausea, vomiting, headache, dizziness and rash. In severe cases, encephalopathy can develop with or without hepatic impairment, especially in older adults, which can be life-threatening or fatal. If symptoms of hyperammonaemia exist, ammonia levels should be monitored closely.

Contraception
Effective non-oral method of contraception must be used during Oncaspar treatment and for at least 6 months after Oncaspar discontinuation. Since an indirect interaction between the oral contraceptives and pegaspargase cannot be ruled out, the use of oral contraception is not considered an acceptable method of contraception (see sections 4.5 and 4.6).

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

Effects on Driving

4.7   Effects on ability to drive and use machines
Oncaspar has a major influence on the ability to drive and use machines. The following adverse reactions have been reported in patients treated with Oncaspar along with other chemotherapy medicinal products: somnolence, confusion, dizziness, syncope, seizure.
Patients should be advised not to drive or operate machines while receiving Oncaspar if they experience these or other adverse reactions which can impair their ability to drive or operate machines (see section 4.4).