LEUSTATIN 1 mg/ml SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

LEUSTATIN 1mg/ml solution for infusion

cladribine

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, as it may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Contents of the package leaflet:

1. What is Leustatin and what is it used for
2. What you need to know before you start using Leustatin
3. How to use Leustatin
4. Possible side effects
5. Storage of Leustatin

Contents of the pack and further information

1. What is Leustatin and what is it used for

Leustatin belongs to a group of medicines called synthetic antineoplastic agents.

Leustatin is indicated:

? for the treatment of active tricholeukemia.

? for the treatment of patients with chronic lymphocytic leukemia of B cells who have not responded or whose disease has progressed during or after treatment with a standard regimen containing at least one alkylating agent.

2. What you need to know before you start using Leustatin

Do not use Leustatin

• if you are allergic (hypersensitive) to cladribine or any of the other ingredients, including those listed in section 6.
• if you are pregnant or think you may be pregnant.

Warnings and precautions

Consult your doctor or pharmacist or nurse before starting to take Leustatin

• This medicine should always be administered under medical supervision, and during its administration, various checks should be carried out to monitor the evolution of the disease and the possible side effects that Leustatin may cause.
• This medicine produces a decrease in the bone marrow's ability to produce blood cells, your doctor may perform careful blood tests even after finishing treatment with Leustatin.
• It should be used with caution if administered after or in combination with other medicines that decrease the bone marrow's ability to produce blood cells.
• Severe infections (e.g., respiratory infections, pneumonia, and skin virus infections) have been reported, even fatal (e.g., generalized infection). To avoid possible infections, patients should be carefully monitored. If infections occur, they should be treated before starting treatment with Leustatin.
• This medicine usually causes fever, especially during the first month, and in the case of tricholeukemia, it is not associated with any type of infection.
• If you have any severe bone marrow injury, regardless of its origin.
• If you have kidney problems.
• If you have liver problems.

At any time during or after treatment, tell your doctor or nurse immediatelyif:

you experience blurred vision, loss of vision, or double vision, difficulty speaking, weakness in an arm or leg, a change in your gait or balance problems, persistent numbness, decreased sensitivity, or loss of sensitivity, memory loss, or confusion. These may be symptoms of a serious and potentially life-threatening brain diseaseknown as multifocal leukoencephalopathy (LMP).

If you had any of these symptoms before starting treatment with cladribine,inform your doctor if you notice any change in these symptoms.

Other medicines and Leustatin

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

The effects of Leustatin on the action of other medicines are not known, your doctor will indicate which ones can be used together with Leustatin, be especially careful with:

• Fludarabine (a medicine used to treat a type of cancer): Patients who have received treatment with fludarabine should not use Leustatin, as no positive outcome is expected after its use.
• Other medicines that decrease the production of blood cells.
• The simultaneous administration of nucleoside analogs (a type of medicine used to treat certain viral diseases) with Leustatin is not recommended.
• Live attenuated vaccines: The use of this type of vaccine with Leustatin is not recommended, as it increases the risk of infections.
• Antiviral agents, adenosine reuptake inhibitors (a type of medicine used to treat certain viral diseases): They should not be administered with Leustatin, as they may alter (increase or decrease) its effects.

Pregnancy, breastfeeding, and fertility

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

Leustatin should not be administered during pregnancy or if you suspect you are pregnant, as there is a potential risk to the fetus.

Both men and women using Leustatin should use effective contraceptives during and up to 6 monthsafter treatment.

It is not known if Leustatin passes into breast milk. Breastfeeding should not be initiated during treatment with Leustatin and up to 6 monthsafter the last dose.

Use in children and adolescents

It should be administered with caution to children and adolescents. The efficacy and safety of Leustatin have not been determined in this age group.

Use in patients over 65 years

Patient over 65 yearsshould be treated after individual evaluation. Their blood tests should be closely monitored, as well as the function of their kidneys and liver. The risk assessment should be done on a case-by-case basis.

Driving and using machines

Due to the patient's physical condition and the possible side effects of Leustatin, driving and the use of hazardous machinery are not recommended.

Leustatin contains sodium

This medicine contains 38.2 mg of sodium (the main component of table/cooking salt) in each vial. This is equivalent to 1.91% of the maximum daily sodium intake recommended for an adult.

3. How to use Leustatin

Follow exactly the administration instructions of Leustatin indicated by your doctor. Consult your doctor or pharmacist if you have doubts.

Your doctor will indicate the guidelines and duration of your treatment with Leustatin depending on the disease you are suffering from.

If you use more Leustatin than you should

If you have used Leustatin more than you should, consult your doctor or pharmacist immediately.

No specific antidote is known. It is not known if an overdose can be eliminated by any technique that may resemble a normal body process. When an overdose higher than the recommended dose is used, treatment with Leustatin should be suspended, careful observation should be performed, and appropriate supportive measures should be taken.

In case of overdose or accidental ingestion, consult the Toxicology Information Service. Telephone (91) 562 04 20.

4. Possible Adverse Effects

Like all medicines, Leustatin can cause adverse effects, although not all people suffer from them.

If you consider that any of the adverse effects you are suffering from is serious or if you notice any adverse effect not mentioned in this prospectus, inform your doctor or pharmacist.

Leustatin is a potent antineoplastic agent (substance that prevents the growth of malignant tumor cells) with the ability to cause adverse effects.

Leustatin should be administered under the supervision of a doctor who has experience in the administration of antineoplastic treatments.

Suppression of bone marrow functions, including neutropenia (low white blood cells), anemia (low red blood cells), and thrombocytopenia (low platelets), should be expected. This effect on the bone marrow is usually reversible and apparently depends on the administered dose.

The effect of Leustatin on the bone marrow is more noticeable during the first month after treatment. Patients with Chronic Lymphocytic Leukemia treated with Leustatin suffered a more severe suppression of bone marrow functions than patients treated for Hairy Cell Leukemia.

Since most episodes of fever occurred in patients with neutropenia (low white blood cells), these patients should be closely monitored during the first month of treatment.

Patients with Hairy Cell Leukemia:

The following adverse effects were seen during clinical trials in patients with Hairy Cell Leukemia and during the marketing of the medicine (regardless of indication).

Adverse effects may occur with certain frequencies, which are defined using the following convention:

• very common: affects more than 1 patient in 10
• common: affects between 1 and 10 patients in 100
• uncommon: affects between 1 and 10 patients in 1,000
• rare: affects between 1 and 10 patients in 10,000
• very rare: affects less than 1 patient in 10,000
• unknown: frequency cannot be estimated from available data

Very Common Adverse Effects (affects more than 1 in 10 people)

• Headache
• Nausea
• Skin rash, including redness in the form of spots or diffuse redness of the skin (erythema), spotted rash (macular exanthem), rash with spots and papules (maculopapular exanthem), rash with papules (papular exanthem), itchy rash (pruriginous exanthem), rash with pus (pustular exanthem), and redness in the form of spots or diffuse redness of the skin (erythematous exanthem)
• Fever, fatigue, and reaction at the administration site, including reaction at the site where the medicine is administered through a tube (catheter) with the appearance of skin infection with blister formation (cellulitis), redness of the skin (erythema), bleeding (hemorrhage), and pain. Also includes reaction at the infusion site with the appearance of redness (erythema), fluid accumulation (edema), and pain.

Common Adverse Effects (affects between 1 and 10 in 100 people)

• Severe generalized infection
• Secondary malignant neoplasms (secondary malignant tumors), primary hematological neoplasms (primary blood tumors)
• Hemolytic anemia (disorder that causes a decrease in the mass of red blood cells) and autoimmune hemolytic anemia (anemia produced when the immune system attacks the body's own red blood cells)
• Anemia, febrile neutropenia (severe decrease in the number of neutrophils in the blood, which can cause fever)
• Allergic reaction
• Confusion, disorientation
• Difficulty sleeping, anxiety
• Dizziness
• Conjunctivitis
• Increased heart rate (tachycardia), heart murmur, insufficient blood flow to the heart (myocardial ischemia)
• Pulmonary interstitial infiltrates (accumulation of foreign substances in the lung tissue)
• Pulmonary infiltration (accumulation of foreign substances in the lung)
• Interstitial lung disease (inflammatory disorder of the lower airways)
• Pneumonitis (inflammation of lung tissue)
• Pulmonary fibrosis (disease characterized by scarring in the lungs)
• Cough, difficulty breathing, including difficulty breathing that appears with physical activity, and wheezing (wheezing), abnormal respiratory sounds, wheezing (rhonchi)
• Vomiting, abdominal pain, including abdominal discomfort and lower and upper abdominal pain, diarrhea, constipation, gas
• Urticaria
• Excessive sweating, bruising, small skin hemorrhages the size of pinheads and red in color (petechiae), itching
• Pain, back pain, muscle pain, joint pain, chest pain, bone pain, pain in the limbs, pain caused by inflammation in a joint

• Kidney failure (kidneys stop functioning properly), acute kidney failure (rapid and progressive loss of kidney function), and kidney dysfunction (kidney malfunction)
  • Generalized feeling of fatigue (asthenia), general malaise, chills, fluid accumulation at the surface level (peripheral edema), muscle weakness, decreased appetite
  • Minor trauma (bruise)

Uncommon Adverse Effects (affect between 1 and 10 in 1,000 people)

• Infections that occur when defenses are low (opportunistic infections)
• Prolonged scarcity of all blood cell elements due to bone marrow suppression (bone marrow suppression with prolonged pancytopenia)
• Disease in which the bone marrow does not function correctly and does not produce enough normal red blood cells (aplastic anemia)
• Persistent elevation of eosinophils (hypereosinophilia)
• Incomplete and defective development of cells formed in the bone marrow (myelodysplastic syndrome)
• Massive destruction of cancer cells (tumor lysis syndrome)
• Decreased level of consciousness
• Nervous system disorder (neurotoxicity), including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, and paraparesis (mild paralysis)
• Increased bilirubin and transaminases (substances and proteins that indicate liver function)
• Stevens-Johnson syndrome (severe disorder that affects the skin, mucous membranes, and internal organs)

Rare Adverse Effects (affect between 1 and 10 in 10,000 people)

• Heart failure, alteration of heart rhythm (arrhythmia)

Since the medicine has been commercially available, the following additional adverse effects have been reported:

As a consequence of the prolonged suppression of the immune system associated with the use of nucleoside analogs like Leustatin, cases of neoplasms have been observed. Primary hematological malignant tumors are also a risk factor for secondary malignant neoplasms.

Patients with Chronic Lymphocytic Leukemia:

The following adverse effects were seen during clinical trials in patients with Chronic Lymphocytic Leukemia and during the marketing of the medicine (regardless of indication).

Very Common Adverse Effects (affects more than 1 in 10 people)

• Headache
• Fever, fatigue, reaction at the administration site, including reaction at the site where the medicine is administered through a tube (catheter) with the appearance of redness (erythema) and skin infection. Also includes reaction at the infusion site with the appearance of skin infection with blister formation (cellulitis), redness (erythema), irritation, fluid accumulation (edema), pain, infection, and inflammation of the vein wall (phlebitis).

Common Adverse Effects (affects between 1 and 10 in 100 people)

• Severe generalized infection
• Pneumonia, presence of bacteria in the blood (bacteremia), skin infection with blister formation (cellulitis), localized infection
• Secondary malignant neoplasms (secondary malignant tumors), primary hematological neoplasms (primary blood tumors)
• Hemolytic anemia (disorder that causes a decrease in the mass of red blood cells) and autoimmune hemolytic anemia (anemia produced when the immune system attacks the body's own red blood cells)
• Decrease in blood platelets (thrombocytopenia), which leads to bleeding or small skin hemorrhages the size of pinheads and red in color (petechiae), anemia
• Allergic reaction
• Confusion, disorientation
• Inflammation of the vein wall (phlebitis)
• Pulmonary interstitial infiltrates (accumulation of foreign substances in the lung tissue)
• Pulmonary infiltration (accumulation of foreign substances in the lung)
• Interstitial lung disease (inflammatory disorder of the lower airways)
• Pneumonitis (inflammation of lung tissue)
• Pulmonary fibrosis (disease characterized by scarring in the lungs)
• Cough, difficulty breathing, including difficulty breathing that appears with physical activity, abnormal respiratory sounds, wheezing (rhonchi)
• Nausea, diarrhea, vomiting
• Urticaria
• Skin rash, including spotted rash (maculopapular exanthem), itchy rash (pruriginous exanthem), and rash with pus (pustular exanthem), and redness in the form of spots or diffuse redness of the skin (erythema), excessive sweating, formation of red spots on the skin (purpura)
• Pain, joint pain, back pain, bone pain, muscle and bone pain, pain in the limbs
• Kidney failure (kidneys stop functioning properly), acute kidney failure (rapid and progressive loss of kidney function), and kidney dysfunction (kidney malfunction)
• Generalized feeling of fatigue (asthenia), muscle weakness, fluid accumulation (edema), localized fluid accumulation (localized edema), superficial fluid accumulation (peripheral edema), abnormal sound, fixed and bubbling produced by air in the pulmonary ducts (crepitus)

Uncommon Adverse Effects (affect between 1 and 10 in 1,000 people)

• Infections that occur when defenses are low (opportunistic infections)
• Prolonged scarcity of all blood cell elements due to bone marrow suppression (bone marrow suppression with prolonged pancytopenia)
• Disease in which the bone marrow does not function correctly and does not produce enough normal red blood cells (aplastic anemia)
• Persistent elevation of eosinophils (hypereosinophilia)
• Incomplete and defective development of cells formed in the bone marrow (myelodysplastic syndrome)
• Massive destruction of cancer cells (tumor lysis syndrome)
• Decreased level of consciousness
• Nervous system disorder (neurotoxicity), including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, and paraparesis (mild paralysis)
• Conjunctivitis
• Increased bilirubin and transaminases (substances and proteins that indicate liver function)
• Stevens-Johnson syndrome (severe disorder that affects the skin, mucous membranes, and internal organs)

Months or even years after treatment with Leustatin, herpes infections (herpetic retinitis: retinal infection caused by the herpes virus, herpes zoster) have been observed.

Since the medicine has been commercially available, the following additional adverse effects have been reported:

As a consequence of the prolonged suppression of the immune system associated with the use of nucleoside analogs like Leustatin, cases of neoplasms have been observed. Primary hematological malignant tumors are also a risk factor for secondary malignant neoplasms.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Leustatin

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

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

Store in the original packaging to protect it from light.

Do not use this medicine after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

6. Container Content and Additional Information

Composition ofLeustatin

• The active ingredient is cladribine. Each vial (10 milliliters) contains 10 milligrams of cladribine.
• The other components are sodium chloride and water for injectable preparations.
• Phosphoric acid or/and disodium phosphate E339 is added to adjust the pH to a range of 5.5 - 8.0.

Appearance of the Product and Container Content

Leustatin is presented in vials of buffered, sterile solution, containing 10 milligrams (1 milligram/milliliter) of 2-chloro-2'-deoxy-β-D-adenosine (cladribine) for dissolution and subsequent continuous intravenous infusion.

Each container contains seven vials of Leustatin.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Atnahs Pharma Netherlands B.V.

Copenhagen Towers

Ørestads Boulevard 108, 5.tv

DK-2300 Copenhagen S

Denmark

Manufacturer

Eurofins Analytical Services Hungary Kft.

Kerulet, Anonymus Utca 6/IV, IV Kerulet,

Budapest, 1045, Hungary

Janssen Pharmaceutica N.V.

Turnhoutseweg 30, B-2340 Beerse

Belgium

Local Representative:

Pharmanovia A/S

Copenhagen Towers

Ørestads Boulevard 108, 5.tv

DK-2300 Copenhagen S

Denmark

Date of Last Revision of this Prospectus:October 2021.

Other Sources of Information

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/).

INFORMATION ONLY FOR THE MEDICAL OR HEALTH PROFESSIONAL:

Dosage

Hairy Cell Leukemia: The recommended treatment for hairy cell leukemia is a single cycle of Leustatin, administered by continuous intravenous infusion for 7 consecutive days at a dose of 0.09 milligrams/kilogram/day (3.6 milligrams/square meter/day). Deviation from this dosing regimen is not recommended. If a patient with hairy cell leukemia does not respond to initial treatment with Leustatin, it is unlikely that they will benefit from subsequent cycles. However, limited experience suggests that additional cycles may be beneficial in patients whose relapse occurred after an initial response to Leustatin administration.

Chronic Lymphocytic Leukemia: In patients with Chronic Lymphocytic Leukemia, the recommended treatment consists of a continuous infusion of Leustatin for 2 hours on days 1 to 5 in 28-day cycles, at a dose of 0.12 milligrams/kilogram/day (4.8 milligrams/square meter/day). It is recommended that patients who respond to treatment with Leustatin receive a maximum of 6 monthly cycles, and those who do not respond receive no more than 2 cycles of treatment.

Method of Administration

Prior to administration, Leustatin must be diluted. Since the medication does not contain any antimicrobial preservative or bacteriostatic agent, aseptic techniques and environmental precautions should be observed in the preparation of the Leustatin solution.

Leustatin is stable up to the expiration date indicated on the container, when stored under adequate refrigeration conditions between 2°C and 8°C, protected from light, and in closed vials. Freezing does not spoil the solution. If frozen, it should be thawed naturally at room temperature. LEUSTATIN SHOULD NOT BE HEATED OR PLACED IN A MICROWAVE. If, after thawing, it is put back in the refrigerator, the Leustatin vial is stable until its expiration date. IT SHOULD NOT BE RE-FROZEN.

Once diluted, solutions containing Leustatin should be administered immediately or stored in the refrigerator between 2°C and 8°C before administration, for a period not exceeding 8 hours.

Parenteral drugs should be visually inspected for particles or discoloration before administration, whenever the solution or container allows. When Leustatin is exposed to low temperatures, it may precipitate; this can be resolved by letting the solution come to room temperature and shaking it vigorously. LEUSTATIN SHOULD NOT BE HEATED OR PLACED IN A MICROWAVE.

Care should be taken to ensure the sterility of prepared solutions. Once diluted, Leustatin solutions should be administered immediately or stored in the refrigerator between 2°C and 8°C before administration, for a period not exceeding 8 hours. Leustatin vials are for single use only. The unused portion should be discarded properly.

The potential risks associated with cytotoxic agents are well demonstrated, so when handling, preparing, and administering Leustatin, corresponding precautions should be taken. It is recommended to use disposable gloves and protective clothing. If the skin or mucous membranes come into contact with Leustatin, the affected area should be washed immediately with plenty of water.

If the administered medication accidentally extravasates, it is unlikely to cause local tissue damage. If extravasation occurs, administration should be suspended and resumed in another vein. Other local measures are: elevating the arm and applying ice to reduce swelling.

Given the scarcity of existing compatibility data, it is advised to use the recommended diluents and infusion systems.

Solutions containing Leustatin should not be mixed with other drugs or intravenous additives, nor should they be administered simultaneously through a common intravenous line, as compatibility tests have not been performed.

If the same intravenous line is used for sequential infusion of different drugs, the line should be flushed with a compatible diluent before and after Leustatin infusion.

The use of 5% dextrose as a diluent is not recommended, as it increases the degradation of cladribine.

The additives used in the mixture of Leustatin are physically and chemically stable for at least 24 hours, provided they are kept at room temperature, in a normal place with fluorescent lighting, and in most PVC containers commonly used for infusions.

Hairy Cell Leukemia:Preparation of a single daily dose for intravenous administration: prior to each daily infusion and prior to introduction into the infusion bag, Leustatin must pass through a sterile, disposable, hydrophilic filter for a 0.22 µm syringe. Add the calculated dose (0.09 milligrams/kilogram or 0.09 milliliters/kilogram) of Leustatin through the sterile filter to an infusion bag containing between 100 and 500 milliliters of Sodium Chloride 0.9% for injection, Ph. Eur. The infusion should be continuous for 24 hours. It should be repeated every day for a total of 7 consecutive days.

Chronic Lymphocytic Leukemia:Preparation of a single daily dose for intravenous administration: prior to each daily infusion and prior to introduction into the infusion bag, Leustatin must pass through a sterile, disposable, hydrophilic filter for a 0.22 µm syringe. Add the calculated dose (0.12 milligrams/kilogram or 4.8 milligrams/square meter) of Leustatin through the sterile filter to an infusion bag containing between 100 and 500 milliliters of Sodium Chloride 0.9%, Ph. Eur. The infusion should be continuous for 2 hours. It should be repeated daily for a total of 5 consecutive days. The use of 5% dextrose as a diluent is not recommended, as it increases the degradation of cladribine.