SPECTRILA 10000 U POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Spectrila 10,000U powder for concentrate for solution for infusion

asparaginase

Read all of this leaflet carefully before you start receiving this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you experience side effects, ask your doctor or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What is Spectrila and what is it used for
2. What you need to know before you start receiving Spectrila
3. How to use Spectrila
4. Possible side effects
5. Storage of Spectrila
6. Contents of the pack and further information

1. What is Spectrila and what is it used for

Spectrila contains asparaginase, which is an enzyme that interferes with natural substances necessary for the growth of cancer cells. All cells need an amino acid called asparagine to survive. Normal cells can synthesize asparagine themselves, but some cancer cells lack this ability. Asparaginase reduces the amount of asparagine present in leukemic cells and slows down cancer growth.

Spectrila is used to treat children and adults with acute lymphoblastic leukemia (ALL), a type of blood cancer. Spectrila is used as part of a combination treatment.

2. What you need to know before you start receiving Spectrila

Spectrila must not be used

• if you are allergic to asparaginase or any other component of this medicine (listed in section 6),
• if you have or have had pancreatitis (inflammation of the pancreas),
• if you have severe liver function problems,
• if you have a blood coagulation disorder (such as hemophilia),
• if you have had significant bleeding (hemorrhage) or a severe blood clot (thrombosis) during previous treatment with asparaginase

Warnings and precautions

Consult your doctor or nurse before starting treatment with Spectrila.

During treatment with Spectrila, the following potentially life-threatening situations may occur:

• severe pancreatitis (acute pancreatitis),
• liver problems,
• severe allergic reaction causing difficulty breathing or dizziness,
• blood coagulation disorders (bleeding or blood clots),
• high blood sugar levels.

Before and during treatment with Spectrila, your doctor will perform blood tests.

If severe liver problems occur, treatment with Spectrila should be stopped immediately.

If allergy symptoms appear, the intravenous infusion of Spectrila should be stopped immediately. You may be given anti-allergic medication and, if necessary, medication to stabilize circulation. In most cases, your treatment can continue with other medications containing different forms of asparaginase.

Blood coagulation disorders may require you to receive fresh plasma or a type of protein (antithrombin III) to reduce the risk of bleeding or blood clots (thrombosis).

High blood sugar levels may require treatment with intravenous fluids and/or insulin.

The syndrome of posterior reversible leukoencephalopathy (characterized by headache, confusion, seizures, and vision loss) may require medication to reduce blood pressure and, in case of seizures, antiepileptic treatment.

Other medicines and Spectrila

Tell your doctor if you are using, have recently used, or might use any other medicines. This is important because Spectrila can increase the side effects of other medicines due to its effect on the liver, an organ that plays a crucial role in eliminating medicines from the body.

Additionally, it is very important that you inform your doctor if you are taking any of the following medicines:

• Vincristine (used against certain types of cancer) because the simultaneous use of vincristine and asparaginase may increase the risk of certain side effects. To avoid this, vincristine is usually administered between 3 and 24 hours before asparaginase.
• Glucocorticoids (anti-inflammatory medicines that suppress the immune system) because the simultaneous use of glucocorticoids and asparaginase may increase blood clot formation (thrombosis).
• Medicines that reduce blood coagulation, such as anticoagulants (e.g., warfarin and heparin), dipyridamole, acetylsalicylic acid, or medicines to treat pain and inflammation, because the use of these medicines with asparaginase may increase the risk of bleeding.
• Medicines that are metabolized in the liver (e.g., paracetamol, acetylsalicylic acid, tetracycline) because they may increase the risk of side effects.
• Asparaginase may alter the effectiveness of methotrexate or cytarabine (used to treat certain types of cancer):

• Medicines that may have a negative effect on liver function (e.g., paracetamol, acetylsalicylic acid, tetracycline), because parallel treatment with asparaginase may aggravate such negative effects.
• Medicines that may suppress bone marrow function (e.g., cyclophosphamide, doxorubicin, methotrexate), because the simultaneous use of asparaginase may enhance such effects. You may be more prone to infections.
• Other cancer medicines, because they may contribute to the release of excessive uric acid when tumor cells are destroyed by asparaginase.

Vaccination

Simultaneous vaccination with live attenuated vaccines may increase the risk of severe infection. Therefore, you should not receive any live attenuated vaccine until at least 3 months after the end of treatment with Spectrila.

Pregnancy and breastfeeding

There are no data on the use of asparaginase in pregnant women. Spectrila should not be used during pregnancy unless the clinical situation of the woman requires the use of asparaginase. It is not known whether asparaginase is present in breast milk. Therefore, Spectrila should not be used during breastfeeding.

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medicine.

If you are a woman, you should use effective contraceptive methods or practice sexual abstinence during chemotherapy and for 7 months after the end of treatment. Since an indirect interaction between the components of oral contraceptives and asparaginase cannot be ruled out, oral contraceptives cannot be considered safe enough. Women of childbearing age should use an effective contraceptive method that is not an oral contraceptive.

If you are a man, you should take adequate precautions to ensure that your partner does not become pregnant during treatment with Spectrila and for 4 months after the last dose.

Driving and using machines

Do not drive or use machines while taking this medicine because it can cause drowsiness, fatigue, or confusion.

3. How to use Spectrila

The preparation and dispensing of Spectrila are carried out by healthcare personnel. Your doctor will decide the dose you will receive. The dose depends on the body surface area, which is calculated from height and weight.

Spectrila is administered through a vein, usually along with other cancer medicines. The duration of treatment depends on the specific chemotherapy regimen used to treat your disease.

Use in adults

The recommended dose of Spectrila for adults is 5,000 U per m² of body surface area every three days.

Use in children and adolescents

The recommended dose in children and adolescents from 1 to 18 years of age is 5,000 U per m² of body surface area every three days.

The recommended doses for infants from 0 to 12 months are as follows:

• Less than 6 months of age: 6,700 U/m² of body surface area
• 6 to 12 months of age: 7,500 U/m² of body surface area

If you receive more Spectrila than you should

If you think you have received too much Spectrila, inform your doctor or nurse as soon as possible.

To date, it has not been described that asparaginase overdose has caused any signs of overdose. If necessary, your doctor will administer symptomatic and supportive treatment to treat your symptoms.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately and stop taking Spectrila if you experience:

• pancreatitis, which causes severe abdominal and back pain,
• severe liver function abnormalities (determined by laboratory tests),
• allergic reactions, including a severe allergic reaction (anaphylactic shock), flushing, skin rash, low blood pressure, swelling of the face and throat, hives, difficulty breathing,
• blood coagulation disorders such as bleeding, disseminated intravascular coagulation (DIC), or blood clots (thrombosis),
• high blood sugar levels (hyperglycemia).

The following is a list of other side effects, ordered by frequency:

Very common side effects (may affect more than 1 in 10 people)

• nausea, vomiting, stomach pain, or diarrhea,
• fluid accumulation (edema),
• feeling of tiredness,
• abnormal laboratory tests, such as changes in blood protein levels, blood lipid levels, or liver enzyme values, or elevated urea levels in the blood.

Common side effects (may affect up to 1 in 10 people)

• mild or moderate reduction in the number of all blood cells,
• allergic reactions, such as wheezing (bronchospasm) or difficulty breathing,
• low blood sugar levels (hypoglycemia),
• loss of appetite or weight,
• depression, hallucinations, or confusion,
• nervousness (agitation) or drowsiness,
• changes in the electroencephalogram (a record of brain electrical activity),
• elevated amylase and lipase levels in the blood,
• pain (back pain, joint pain, stomach pain).

Uncommon side effects (may affect up to 1 in 100 people)

• high uric acid levels in the blood (hyperuricemia),
• high ammonia levels in the blood (hyperammonemia),
• headache.

Rare side effects (may affect up to 1 in 1,000 people)

• diabetic ketoacidosis (complication of uncontrolled blood sugar levels),
• seizures, severe impairment of consciousness that may include coma and stroke,
• syndrome of posterior reversible leukoencephalopathy (disorder characterized by headache, confusion, seizures, and vision loss),
• inflammation of the salivary glands (parotitis),
• cholestasis (obstruction of bile flow from the liver),
• jaundice,
• destruction of liver cells (liver necrosis),
• liver failure that can cause death.

Very rare side effects (may affect up to 1 in 10,000 people)

• decreased function of the thyroid gland or parathyroid glands,
• mild tremor of the fingers,
• pseudocysts in the pancreas (fluid collections resulting from acute pancreatitis).

Frequency not known (cannot be estimated from the available data)

• infections,
• fatty liver.

Reporting of side effects

If you experience any side effects, consult your doctor or nurse, even if they are not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Spectrila

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the carton. The expiry date is the last day of the month stated.

Store in a refrigerator (between 2°C and 8°C).

Keep the vial in the outer packaging to protect it from light.

The reconstituted solution is stable for 2 days if stored between 2°C and 8°C. If the medicine is not used immediately, the storage time and conditions to ensure the sterility of the product are the responsibility of the user who prepares this medicine. Storage should not normally exceed 24 hours at 2°C to 8°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container contents and additional information

Spectrila composition

• The active ingredient is asparaginase. A vial of powder contains 10,000 units of asparaginase. Once reconstituted, one milliliter of the solution contains 2,500 units of asparaginase.

• The other component is sucrose.

Product appearance and container contents

Spectrila is supplied as a powder for concentrate for solution for infusion.

The powder is white and is supplied in a transparent glass vial with a rubber stopper, aluminum cap, and plastic flip-off cap (flip-off cap).

Spectrila is available in packs containing 1 or 5 vials.

Only some pack sizes may be marketed.

Marketing authorization holder and manufacturer

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

Tel.: +49-4103-8006-0

Fax: +49-4103-8006-100

e-mail: contact@medac.de

Date of last revision of this prospectus: {MM/YYYY}.

Other sources of information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.

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This information is intended solely for healthcare professionals:

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product must be clearly recorded.

Spectrila should only be used by physicians with experience in therapeutic protocols of this type.

Recommended control tests and safety precautions

Prior to initiating treatment, it is necessary to determine bilirubin and hepatic transaminase concentrations, as well as coagulation parameters (partial thromboplastin time [PTT], prothrombin time [PT], antithrombin, fibrinogen, and D-dimer).

After administration of any asparaginase preparation, it is recommended to perform rigorous monitoring of bilirubin and hepatic transaminase concentrations, blood and urine glucose, coagulation parameters (PTT, PT, antithrombin III, fibrinogen, and D-dimer), amylase, lipase, triglycerides, and cholesterol.

Acute pancreatitis

Treatment with asparaginase should be discontinued if the patient develops acute pancreatitis, which has occurred in less than 10% of patients. In rare cases, hemorrhagic or necrotizing pancreatitis may occur. Isolated cases with a fatal outcome have been reported. Clinical symptoms included abdominal pain, nausea, vomiting, and anorexia. Serum amylase and lipase concentrations are usually elevated, although in some patients they may be normal due to altered protein synthesis. The risk of developing acute pancreatitis is higher in patients with severe hypertriglyceridemia. These patients should not continue to be treated with any asparaginase preparation.

Hepatotoxicity

In rare cases, severe hepatic failure with cholestasis, jaundice, hepatic necrosis, and hepatic failure with a fatal outcome (see sections 4.8 and 4.5) have been described. Hepatic parameters should be closely monitored before and during treatment with asparaginase.

Treatment with asparaginase should be interrupted if the patient develops severe hepatic failure (bilirubin > 3 times the upper limit of normal [ULN]; transaminases > 10 times the ULN), severe hypertriglyceridemia, hyperglycemia, or coagulation disorder (e.g., venous sinus thrombosis, severe bleeding).

Allergy and anaphylaxis

Due to the risk of severe anaphylactic reactions, asparaginase should not be administered by rapid intravenous injection. If allergic symptoms appear, asparaginase administration should be discontinued immediately and appropriate treatment administered, which may include antihistamines and corticosteroids.

Coagulation disorders

Due to the inhibition of protein synthesis (decrease in the synthesis of factors II, V, VII, VIII, and IX, proteins C and S, antithrombin III [AT III]) caused by asparaginase, coagulation disorders may occur, which can manifest as thrombosis, disseminated intravascular coagulation (DIC), or bleeding. The risk of thrombosis appears to be higher than that of bleeding. Symptomatic thrombosis related to the use of central venous catheters has also been described. It is essential to frequently monitor coagulation parameters before and during treatment with asparaginase.

In cases where a decrease in AT III occurs, it is recommended to consult an expert.

Hyperglycemia

Asparaginase may cause hyperglycemia as a consequence of decreased insulin production. It may also reduce insulin secretion in pancreatic beta cells and alter insulin receptor function. The syndrome is usually self-limiting. However, in rare cases, it may cause diabetic ketoacidosis. Concomitant treatment with corticosteroids contributes to this effect. Blood and urine glucose concentrations should be regularly monitored and treated as clinically indicated.

Antineoplastic drugs

The destruction of tumor cells induced by asparaginase can release large amounts of uric acid, leading to hyperuricemia. The simultaneous administration of other antineoplastic drugs enhances this effect. Intensive urine alkalization and administration of allopurinol may prevent urate nephropathy.

Glucocorticoids

A higher risk of thrombosis has been observed during induction treatment with asparaginase and prednisone in children with a prothrombotic genetic risk factor (factor V G1691A mutation, prothrombin G20210A variation, methylenetetrahydrofolate reductase [MTHFR] T677T genotype, increased lipoprotein(a), hyperhomocysteinemia).

Contraceptives

Women of childbearing age must use effective contraceptive methods during treatment and up to 7 months after completing treatment with asparaginase. Since an indirect interaction between the components of oral contraceptives and asparaginase cannot be ruled out, oral contraceptives cannot be considered sufficiently safe in this clinical situation. Men should use effective contraceptive methods and be advised not to father a child while receiving asparaginase and for 4 months after completing treatment.

Patients with Philadelphia chromosome-positive

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

Asparaginase activity

Measurement of asparaginase activity level in serum or plasma may be performed to rule out accelerated elimination of asparaginase activity. Preferably, levels should be measured three days after the last administration of asparaginase, i.e., usually just before administering the next dose. Low asparaginase activity levels are often accompanied by the appearance of anti-asparaginase antibodies. In these cases, consideration should be given to changing to a different type of asparaginase preparation. It is recommended to consult an expert.

Hypoalbuminemia

As a consequence of reduced protein synthesis, serum protein concentration (especially albumin) frequently decreases in patients treated with asparaginase. Since serum protein is important for the binding and transport function of some active substances, serum albumin levels should be regularly monitored.

Hyperammonemia

Plasma ammonia concentration should be measured in all patients with unexplained neurological symptoms or prolonged or intense vomiting. In case of hyperammonemia with severe clinical symptoms, therapeutic and pharmacological measures should be initiated to rapidly reduce plasma ammonia concentration (e.g., protein restriction and hemodialysis), reverse the catabolic state, and increase the elimination of nitrogenous waste, and an expert should be consulted.

Posterior reversible leukoencephalopathy syndrome

Posterior reversible leukoencephalopathy syndrome (PRLS) may rarely occur during treatment with asparaginase. This syndrome is characterized by the appearance on magnetic resonance imaging (MRI) of reversible lesions/edema (lasting from a few days to months), mainly in the posterior region of the brain. Symptoms of PRLS are essentially elevated blood pressure, seizures, headaches, altered mental status, and visual acuity loss (mainly cortical blindness or homonymous hemianopsia). It is unknown whether PRLS is caused by asparaginase, concomitant treatments, or underlying diseases.

PRLS is managed with symptomatic treatment, including measures for seizure treatment. Interruption or dose reduction of concomitantly administered immunosuppressive medications may be necessary. It is recommended to consult an expert.

Preparation

To dissolve the powder, gently pour 3.7 ml of water for injectable preparations against the inner wall of the vialwith a hypodermic syringe (do not pour directly onto or into the powder). Dissolve the contents with gentle rotation (do not shake to avoid foam formation). The ready-to-use solution may show slight opalescence.

The calculated amount of asparaginase is dissolved in 50 to 250 ml of 9 mg/ml (0.9%) sodium chloride solution for infusion.

Method of administration

Exclusive use by intravenous route. The daily amount of asparaginase required per patient can be diluted in a final volume of 50 to 250 ml of 9 mg/ml (0.9%) sodium chloride solution for infusion.

Duration of administration

The diluted asparaginase solution should be infused over 0.5 to 2 hours.

Asparaginase should not be administered by rapid intravenous injection.

Elimination

Elimination of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.