Document: 27.08.2009   Gebrauchsinformation (deutsch) change

• 27.08.2009   Gebrauchsinformation (deutsch)
• 23.04.2015   Gebrauchsinformation (deutsch)
• 15.11.2005   Gebrauchsinformation (deutsch)

---

B. PACKAGE LEAFLET

PACKAGE LEAFLET: INFORMATION FOR THE USER

Asparaginase 10000 U medac powder for solution for injection

L-Asparaginase

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.

• If you have any further questions, ask your doctor or pharmacist.

• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What Asparaginase 10000 U medac is and what it is used for

2. Before you use Asparaginase 10000 U medac

3. How to use Asparaginase 10000 U medac

4. Possible side effects

6. Further information

Asparaginase 10000 U medac is a medicinal product (cytostatic agent) which lowers the L-asparagine level in the tumour cells so that the protein synthesis in these cells is inhibited.

Asparaginase 10000 U medac is used as part of an antineoplastic combination therapy of acute lymphatic leukaemia (ALL) in children and adults as well as in non-Hodgkin's lymphomas in children.

Do not use Asparaginase 10000 U medac:

- if you are hypersensitive (allergic) to L-asparaginase

- if you have a pancreatitis or a history of pancreatitis at the time of treatment, as acute haemorrhagic pancreatitis has been observed following asparaginase application.

Take special care with Asparaginase 10000 U medac:

Patients of reproductive age should use contraception or abstain from sexual intercourse during and for up to 3 months after the completion of chemotherapy.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Vincristine

Increased toxicity and an increased risk of anaphylactic reactions may be associated with administration of vincristine concurrently with or immediately before treatment with L-asparaginase.

Prednisone

Concomitant use of prednisone and L-asparaginase may increase the risk of a change in clotting parameters (e.g. a decrease in fibrinogen and ATIII levels).

Methotrexate, cytarabine

Methotrexate and cytarabine may interfere in different ways: prior administration of these substances may synergistically increase the effect of L-asparaginase. Subsequent administration of these substances may antagonistically attenuate the effect of L-asparaginase.

Anticoagulants

The use of L-Asparaginase medac can lead to fluctuating coagulation factors. This can promote tendency to bleeding and/or thrombosis.

Caution is therefore needed when anticoagulants such as coumarin, heparin, dipyridamole, acetylsalicylic acid or nonsteroidal anti-inflammatories are given at the same time.

Vaccination

As a result of the overall situation and taking into consideration the most common combination chemotherapy and the underlying disease, concomitant vaccination with live vaccines increases the risk of serious infection. Immunisation with live vaccines should therefore take place at the earliest 3 months after the completion of the course of antileukaemic treatment.

L-asparaginase may increase the toxicity of other drugs through its effect on liver function.

Using Asparaginase 10000 U medac with food and drink

Do not drink alcohol during therapy with L-asparaginase

Pregnancy and breast-feeding

Aspara­ginase 10000 U medac is contraindicated during pregnancy and breast-feeding.

Driving and using machines

Do not drive or operate machines because this medicine can alter your ability to react even when used as directed. This applies even more so in combination with alcohol.

Important information about some of the ingredients of Asparaginase 10000 U medac

There are no further ingredients.

Treatment with Asparaginase 10000 U medac should be administered only under the supervision of a physician experienced in cytotoxic therapy.

To reduce the risk of a possible IgE-mediated hypersensitivity reaction, a prick test (place 1 drop of the ready-to-use solution on the volar side of the forearm using a tube-like instrument and inject into the epidermis through the drop using a sterile syringe. Avoid bleeding. Wipe away the drop of the preparation after 3 minutes. After a further 20 minutes, observe the reaction: if redness and weals develop, refrain from L-asparaginase treatment) or an intra­cutaneous injection (increasing concentration in an appropriate dilution) should be carried out before treatment is started or resumed.

Since not just IgE-mediated allergic reactions that are detectable by skin testing but also IgG and IgM-mediated sensitisation has been described, the use of an intravenous test dose before intraven­ous administration is also recommended (1000 U i.v. as a short infusion 1 hour before treatment).

Unless otherwise prescribed, the mean in­travenous daily dose in children and adults in the monotherapy is 200 U per kg body weight or 6000 U per m². It can be increased to 1000 U per kg bodyweight or more, depending on the individual clinical response. Higher single doses (1500 U/kg or 45000 U/m² and above) are used, particularly in non-daily, cyclical administration (e.g. twice weekly). In this dose range, intravenous administration is essential.

Asparaginase 10000 U medac is usually employed as part of combina­tion chemotherapy protocols with other cytostatics. Special guidelines cover the method of administration, single dose levels and the duration of treatment. The mean dose range for in­tramuscular injection is 100 to 400 U per kg/day or 3000 - 12000 U per m²/day. No more than 5000 U in 2 ml should be administered per injection site. If more than 5000 U per single dose is required, several injection sites should be chosen.

Method of administration

For continuous i.v. drip infusion after dissolution as directed. The amount of L-asparaginase calculated is dissolved in 250 - 500 ml physiologi­cal saline solution and infused over several hours.

To dissolve the powder, 4.0 ml water for injection is injected by syringe not into the substance itself but against the inner wall of the vial. The contents are dissolved by rotating the container without shaking it (avoid creating froth). The ready-to-use solution may be opalescent.

The ready-to-use solution can also be injected intramuscularly without further dilution, depending on the treatment schedule.

Once dissolved (4.0 ml water for injection), the substance can be kept at room temperature for 6 hours.

Duration of administration

Alone or as combination therapy, Asparaginase 10000 U medac should be administered until the treatment cycle has been completed. If side effects or organ damage that constitute a contraindication to Asparaginase 10000 U medac occur, discontinuation of the treatment should be considered.

The following life-threatening situations may arise during L-asparaginase treatment:

- Anaphylaxis,

- Hyperglycaemic conditions, which can be treated with insulin, and

- Clotting changes potentially requiring substitution with fresh plasma in order to reduce the risk of bleeding.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Asparaginase 10000 U medac can cause side effects, although not everybody gets them.

The evaluation of the side effects is based on the following frequency convention:

Very common more than 1 in 10 patients	Common more than 1 in 100 patients
Uncommon more than 1 in 1,000 patients	Rare more than 1 in 10,000 patients
Very rare 1 or less in 10,000 patients including isolated reports

Organ system	Frequency and symptom
Investigations	Common increase in serum amylase
Blood and lymphatic system disorders	Common mild to moderate myelosuppression of all three cell lines. Coagulation defects due to impairment of protein synthesis: bleeding, disseminated intravascular coagulation (DIC) or thromboses. In cases of cerebral manifestation apoplectic stroke, seizures, unconsciousness. Very rare haemolytic anaemia
Nervous system disorders	Common CNS dysfunction such as agitation, depression, hallucinations, confusion and somnolence (slight impaired consciousness); EEG changes (reduced alpha wave activity, increased theta and delta wave activity), possibly due to hyperammonaemia Rare Seizures and severe impaired consciousness up to coma might develop. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Very rare fine tremor of the fingers
Gastrointestinal disorders	Very common mild to moderate gastrointestinal symptoms such as loss of appetite, nausea, vomiting, abdominal cramps, diarrhoea and weight loss Common acute pancreatitis, disturbances in the exocrine pancreas function with diarrhoea. Rare haemorrhagic or necrotising pancreatitis, parotitis Very rare pseudocysts of the pancreas, lethal pancreatitis, pancreatitis with concurrent acute parotitis
Renal and urinary disorders	Rare acute renal failure
Skin and subcutaneous tissue disorders	Very common hypersensitivity reactions of the skin Very rare one case of toxic epidermal necrolysis (Lyell’s syndrome)
Endocrine disorders	Common impairment of the endocrine pancreas function with diabetic ketoacidosis, hyperosmolar hyperglycaemia Very rare transitory secondary hypothyroidism, decrease in thyroxine‑binding globulin, hypoparathyroidism
Metabolism and nutrition disorders	Very common change in blood fat values (e.g. an increase or decrease in cholesterol, increase in triglycerides, increase in the VLDL fraction and decrease in LDL, increased lipoprotein lipase activity), in most cases without clinical symptoms; increase in blood urea nitrogen due to prerenal metabolic imbalance Uncommon increased uric acid levels in the blood (hyperuricaemia), hyperammonaemia
Infections and infestations	Not known infections
General disorders and administration site conditions	Very common pain at the injection site, oedemas Common fever, pain (back pain, joint pain, abdominal pain) Very rare life-threatening hyperpyrexia
Immune system disorders	Very common allergic reactions such as local erythema, urticaria, breathing difficulties Common anaphylactic shock, bronchospasm
Hepatobiliary disorders	Very common changes in hepatic parameters (such as elevation of alkaline phosphatase, serum transaminases, ammonia, LDH and serum bilirubin), fatty liver, hypoalbuminaemia which can among other things lead to oedemas Rare Cholestasis, icterus, hepatic cell necrosis and hepatic failure with potentially fatal outcome

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Blood and lymphatic system disorders:

Haematopoietic disorders:

L-Asparaginase may cause mild to moderate myelosuppression, potentially affecting all three cell lines. Generally speaking, this has no consequences for the treatment. There have been isolated cases of haemolytic anaemia.

Clotting disorders:

Owing to the impairment of protein synthesis, clotting disorders in the form of bleeding and disseminated intravascular clotting (DIC) or thrombosis may occur frequently, and the risk of thrombosis appears to rise with increasing duration after the completion of treatment.

Besides L-asparaginase, however, concomitant treatment with other myelosuppressive drugs or the underlying disease itself may be responsible for these side effects.

Approximately half of all cases of severe bleeding and thrombosis affect cerebral vessels and may, for example, cause apoplectic stroke, seizures, or loss of consciousness.

An increased risk of thrombosis has been described in the ALL-BFM95 study for children with Factor V mutations, APC resistance or reduced serum levels of Protein S, antithrombin III or Protein C. In these patients, the use of central venous catheters should be avoided, if possible, as this may further increase the risk of thromboembolic complications. In induction therapy for ALL, a central venous access should, if possible, be placed only after the completion of L-asparaginase treatment.

Laboratory tests may show clotting disorders and fibrinolysis, e.g. as a decrease in fibrinogen, Factor IX, Factor XI, antithrombin III, Protein C and plasminogen levels and as an increase in the von Willebrand factor, plasminogen activator-1 inhibitor, prothrombin fragment 1 and 2, and fibrinogen fission products (D-dimers).

Thrombocytopenia or sepsis increases the risk of bleeding.

Regular monitoring of the blood clotting profile is necessary. Fibrinogen can be regarded as a parameter of the pro- and anticoagulatory system. As such, in the presence of a marked decrease in the fibrinogen or ATIII level, selective substitution is feasible. ATIII is administered as an infusion, dosage: 100 minus current value in % x kg body weight. Fibrinogen is administered as fresh frozen plasma (FFP) in a dosage of 10 – 15 ml/kg body weight.

Nervous system disorders:

L-asparagianse may cause CNS dysfunction in the form of agitation, depression, hallucinations, confusion and somnolence (slight impaired consciousness) commonly and rarely in the form of severe impaired consciousness up to coma.

EEG changes showing reduced alpha wave activity and increased theta and delta wave activity, may occur. Hyperammonaemia should be ruled out as a possible cause. A fine tremor of the fingers was described in one case.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) may develop rarely. This is characterised in MRT (magnetic resonance tomography) by reversible (days until months) lesions/oedemas mainly located in the posterior part of the brain. Symptoms of RPLS are primarily hypertension, seizures, headache, changed mental status and acute impaired vision. There have been reports about patients who developed RPLS during combined therapy including L-Asparaginase. It is often difficult to distinguish if RPLS was caused by L-Asparaginase, concomitant drugs or the underlying disease.

RPLS has to be treated symptomatically. Hypertension and seizures have to be treated primarily. Furthermore a dose reduction or discontinuation of immunosuppressive therapy has to be recommended.

Gastrointestinal disorders:

Very frequently (in approximately 50 % of patients) mild to moderate gastrointestinal symptoms such as loss of appetite, nausea, vomiting, abdominal cramps, diarrhoea and weight loss are observed.

Acute pancreatitis can occur frequently (in < 10 % of cases). There have been isolated reports of pseudocyst formation (with a delay of up to four months after the last treatment). Therefore, appropriate tests (e.g. ultrasound) should be performed for up to four months after the completion of L-asparaginase treatment. As the precise pathogenesis is not known, only supportive measures can be recommended.

In rare cases, haemorrhagic or necrotising pancreatitis or parotitisoccurs. There have been isolated reports of fatal outcomes.

One case of pancreatitis with concomitant acute parotitis has been described.

Renal disorders:

Acute renal failure has been reported in rare cases.

Skin disorders:

Commonly allergic reactions may manifest cutaneously. One case of toxic epidermal necrolysis (Lyell's syndrome) has been described.

Endocrine disorders:

Changes in endocrine pancreatic function are observed commonly, and are manifested predominantlyas abnormal glucose metabolism. Both diabetic ketoacidosis and hyperosmolar hyperglycaemia have been described which generally respond to exogenous insulin administration.

Reduced insulin synthesis as a result of the L-asparaginase-induced inhibition of protein synthesis on the one hand, and disordered insulin secretion or a reduction in the number of insulin receptors on the other hand, are being discussed as possible causes of this.

The risk factors for hyperglycaemia are age > 10 years, excess weight, and Down's syndrome.

Regular urine and blood sugar tests are therefore indicated on L-asparaginase treatment.

Diarrhoea may be caused by disturbances in exocrine pancreatic function.

There have been isolated reports of transitory secondary hypothyroi­dism and a decrease in the serum thyroxine-binding globulin. Hypoparathyroidism has also been described.

Metabolism disorders:

Non-dose-dependent increases in blood urea nitrogen occur occasionally and almost always indicate a prerenal metabolic imbalance Occasionally increased serum uric acid levels (hyperuricaemia) and hyperammonaemia may occur.

A change in blood fat values (e.g. an increase or decrease in cholesterol, increase in triglycerides, increase in the VLDL fraction and decrease in LDL, increased lipoprotein lipase activity) have been observed, in most cases without clinical symptoms and without the need to switch treatment. The changes may also be associated with concomitant glucocorticoid administration.

In the presence of extremely elevated values (e.g. triglycerides > 2000 mg/dl), close monitoring is advisable because of the increased risk of pancreatitis.

Infections and infestations:

Infections may occur due to combined chemotherapy including L-Asparaginase.It is often difficult to distinguish from the effect of the underlying illness and that of concomitant medication.

General disorders:

Febrile reactions, in most cases subsiding spontaneously, can occur 2 - 5 hours after injection. Pain (joint pain, back pain and abdominal pain) has been commonly observed in connection with allergic reactions and pancreatitis. Life-threateningly high fever (hyperpyrexia) has been observed in rare cases.

Immune system disorders:

The formation of specific antibodies to the foreign protein L-asparaginase is very frequent; this may cause clinical hypersensitivity reactions, and may lead to the inactivation of L-asparaginase.

Allergic reactions have been observed very commonly after administration of L-asparaginase during treatment and may take the form of local erythema, urticaria, pain at the injection site,fever, myalgia, dyspnoea, bronchospasm, tachycardia, fall in blood pressure, extending to anaphylactic shock(in up to 10 % anaphylactic shock and bronchospasms may occur).

The probability of hypersensitivity reactions increases with the number of doses administered. In rare cases, however, allergic reactions may occur at the first administration of L-asparaginase.

In some patients, neutralising antibodies to L-asparaginase may be formed without the appearance of clinical symptoms of hypersensitivity. However, these antibodies may lead to more or less rapid inactivation and therefore accelerated L-asparaginase elimination ("silent inactivation"). It is therefore advisable to measure the L-asparaginase level.

Prior intracutaneous testing does not exclude the risk of anaphylactic reactions.

If allergic symptoms occur, the drug should be discontinued immediately. Depending on the severity of the clinical picture, the administration of antihistamine agents, cortisone and, if necessary, circulation-stabilising substances, is indicated as a counter-measure.

In the majority of cases, treatment can be continued by switching to a different L-asparaginase preparation.

Hepatobiliary disorders:

Changes in liver parameters are very common. A non-dose-dependent increase in alkaline phosphatase, serum transaminases, LDH, ammonia (hyperammonaemia) and serum bilirubin has been observed. A fatty liver can be observed very frequently. There have been rare reports of cholestasis, icterus, liver cell necrosis and hepatic failure with fatal outcome.

The impairment of protein synthesis may lead to a decline in serum proteins. Serum albumin levels undergo a non-dose-dependent decrease during treatment in the majority of patients. The ₂and fractions appear to be most often affected, whereas the ₁fraction is unchanged. As the serum albumin level is important for the binding and transport function of some drugs, the serum albumin level should be monitored, particularly if combination therapy is used. Oedema may occur as a result of hypoalbuminaemia.

During or after the end of L-asparaginase treatment, the serum amylase level may increase. In such cases, no further L-asparaginase should be administered.

5. HOW TO STORE ASPARAGINASE 10000 U MEDAC

Keep out of the reach and sight of children.

Do not use after the expiry date stated on the label and carton.

Discard any unused product after opening.

Once dissolved (4.0 ml water for injection) the substance can be kept at room temperature for 6 hours.

Store in a refrigerator (2 °C – 8 °C).

Keep the vial in the outer carton in order to protect from light.

6. FURTHER INFORMATION

What Asparaginase 10000 U medac contains

The active substance is L-asparaginase.

There are no further ingredients.

What Asparaginase 10000 U medac looks like and contents of the pack

1 vial of Asparaginase 10000 U medac with 43.2 - 49.0 mg powder for solution for injection contains 167 µkat L-asparaginase (E. C. 3.5.1.1), equivalent to 10000 U.

(1 U L-asparaginase releases 1 µmol ammonia from L-asparagine in 1 minute at 37 °C.)

Asparaginase 10000 U medac is available in packages of:

1 vial

5 vials (German labelling) or

5 vials (German-English labelling)

Not all pack sizes will be marketed.

Marketing Authorisation Holder and Manufacturer

medac

Gesellschaft für klinische Spezialpräparate mbH

Fehlandtstr. 3

D-20354 Hamburg

Phone: +49-41 03-80 06-0

Fax.: +49-41 03-80 06-100

This leaflet was last approved in August 2009.