Package Insert: Information for the User

LEUSTATIN 1mg/ml Infusion Solution

cladribina

Read the entire package insert carefully before starting to use the medication.

-Keep this package insert, as you may need to read it again.

-If you have any doubts, consult your doctor or pharmacist.

-This medication has been prescribed to you and should not be given to others, even if they have the same symptoms, as it may harm them.

-If you consider any of the adverse effects you are experiencing to be severe or if you notice any adverse effect not mentioned in this package insert, inform your doctor or pharmacist.

Contents of the package and additional information

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

Leustatin is indicated for:

?treatment of active tricoleucemia.

?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.

No use Leustatin

• if you are allergic (hypersensitive) to cladribina or any of the other components, including those listed in section6.
• if you are pregnant or suspect that you may be.

Warnings and precautions

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

• This medication must always be administered under medical supervision and during its administration, various controls must be performed to see the evolution of the disease and the possible adverse effects that Leustatin may cause.
• This medication reduces the ability of the bone marrow to produce blood cells, your doctor may perform careful blood tests even after completing the treatment with Leustatin.
• It should be used with caution if administered after or concurrently with other drugs that reduce the ability of the bone marrow 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 must be carefully controlled. If you have infections, they must be treated before starting treatment with Leustatin.
• This medication usually causes fever, especially during the first month, and in the case of tricoleucemia 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,inform your doctor or nurse immediatelyif:

you experience blurred vision, loss of vision or double vision, difficulty speaking, weakness in one arm or leg, a change in your gait or balance problems, persistent numbness, decreased sensitivity or loss of sensitivity, memory loss or confusion. All of these can be symptoms of aserious and potentially fatal brain disease known as multifocal leukoencephalopathy (LMP).

If you had any of these symptoms before starting treatment with cladribina,inform your doctorif you notice any change in these symptoms.

Other medications and Leustatin

Inform your doctor or pharmacist if you are using, have used recently or may need to take any other medication.

We do not know what effects Leustatin may cause on the action of other medications, your doctor will indicate which ones can be used concurrently with Leustatin, be cautious with:

• Fludarabina (medication used for the treatment of a type of cancer): Patients who have received treatment with fludarabina should not use Leustatin as no positive result is expected after its use.
• Other drugs that reduce the production of blood cells.
• We do not recommend the simultaneous administration of nucleoside analogs (a type of medication used for the treatment of certain diseases caused by viruses) with Leustatin.
• Live attenuated vaccines: The use of this type of vaccine with Leustatin is not recommended due to the increased risk of infections.
• Antiviral agents, adenosine reuptake inhibitors (a type of medication used for the treatment of certain diseases caused by viruses): They should not be administered concurrently with Leustatin as they may alter (increase or decrease) its effects.

Pregnancy, breastfeeding and fertility

If you are pregnant or breastfeeding, or if you suspect that you may be pregnant, consult your doctor or pharmacist before using this medication.

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

Both men and women usingLeustatinshould use effective contraceptives during and up to 6months after treatment.

We do not know if Leustatin passes into breast milk. Do not initiate breastfeeding during treatment with Leustatin and up to 6months after 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 people over 65years

Patients over 65years should be treated after individual evaluation. Their blood tests should be closely monitored, as well as their kidney and liver function. The risk assessment should be done on a case-by-case basis.

Driving and operating machinery

Due to the patient's physical condition and the possible adverse effects of Leustatin, it is not recommended to drive and operate hazardous machinery.

Leustatin contains sodium

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

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

Your doctor will inform you of the treatment guidelines and duration for Leustatin depending on the disease you have.

If you use more Leustatin than you should

Immediately consult your doctor or pharmacist if you have used Leustatin in excess.

No specific antidote is known. It is not known if an overdose can be eliminated by any technique that could be similar to some normal bodily process. When an overdose above 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 Toxicological Information Service. Phone (91) 562 04 20.

Like all medicines, Leustatincan cause side effects, although not everyone will experience them.

If you consider that any of the side effects you experience are severe or if you notice any side effect not mentioned in this leaflet, inform your doctor or pharmacist.

Leustatinis a potent antineoplastic agent(substance that prevents the growth of malignant tumor cells)withthe capacity tocause side effects.

Leustatinshould be administered under the supervision of a doctor experienced in the administration of antineoplastic treatments.

Precautions should be taken to prevent bone marrow suppression, including neutropenia(low white blood cell count), anemia(low red blood cell count), and thrombocytopenia(low platelet count). This effect on the bone marrow is generally reversible and appears todepend on the administered dose.

The effect of Leustatinon the bone marrow is more notable during the first month after treatment. Patients with Chronic Lymphocytic Leukemia treated with Leustatinsuffered a more severe suppression of bone marrow function than patients treated with Tricoleucemia.

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

Patients with Tricoleucemia:

The following side effects were seen during clinical trials in patients with tricoleucemia and during the commercialization of the drug (regardless of the indication).

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

• Very common: affects more than 1 in 10 patients
• Common: affects between 1 and 10 in 100 patients
• Uncommon: affects between 1 and 10 in 1000 patients
• Rare: affects between 1 and 10 in 10000 patients
• Very rare: affects less than 1 in 10000 patients
• Unknown: the frequency cannot be estimated from available data

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

• Headache
• Nausea
• Skin rash, including redness in the form of patches or diffuse skin (erythema), maculopapular rash (exanthema maculoso), papular rash (exanthema papuloso), pruritic rash (exanthema pruriginoso), pustular rash (exanthema pustuloso), and erythematous rash (exanthema eritematoso)
• Fever, fatigue, and reaction at the site of administration, including reaction at the site where the medication is administered through a tube (catheter) with the appearance of skin infection with blister formation (cellulitis), redness (erythema), bleeding (hemorrhage), and pain. It also includes reaction at the site of infusion with the appearance of redness (erythema), fluid accumulation (edema), and pain.

Common side effects (affects between 1 and 10 in 100 people)

• Severe generalized infection
• Secondary malignant neoplasms (secondary malignant tumors), primary hematological neoplasms (primary tumors of hematological origin)
• Hemolytic anemia (disorder that causes a decrease in the mass of red blood cells) and autoimmune hemolytic anemia (when the autoimmune system attacks the cells of the organism)
• Anemia, febrile neutropenia (severe decrease in the number of white blood cells 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 a foreign substance in the lung)
• Pulmonary interstitial disease (inflammatory disorder of the lower respiratory tract)
• Pneumonitis (inflammation of lung tissue)
• Pulmonary fibrosis (disease characterized by the formation of scars in the lungs)
• Cough, difficulty breathing, including difficulty breathing with physical activity, abnormal respiratory sounds, and wheezing (stertores)
• Vomiting, abdominal pain, including abdominal discomfort and low and high abdominal pain, diarrhea, constipation, gas
• Urticaria
• Excessive sweating, petechiae (small red spots on the skin), pruritus
• Pain, back pain, muscle pain, joint pain, chest pain, bone pain, extremity pain, inflammatory joint pain

-Renal insufficiency (kidneys do not function properly), acute renal insufficiency (rapid and progressive loss of kidney function), and renal dysfunction (kidney malfunction)

• Generalized fatigue (asthenia), general malaise, chills, peripheral edema (fluid accumulation at the surface level), muscle weakness, decreased appetite
• Contusion (small trauma)

Uncommon side effects (affects between 1 and 10 in 1000 people)

• Opportunistic infections
• Prolonged bone marrow suppression with pancytopenia
• Aplastic anemia (disease in which the bone marrow does not function correctly and does not produce enough normal red blood cells)
• Persistent elevation of eosinophils (eosinophilia)
• Developmental and defective formation of cells in the bone marrow(Myelodysplastic syndrome)
• Massive destruction of malignant cells (Tumor lysis syndrome)
• Decreased level of consciousness
• Neurological toxicity, including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, and paraparesia (mild paraplegia)
• Increased bilirubin and transaminases (substances and proteins that are in the organism and that tell us how the liver works)
• Stevens-Johnson syndrome (severe disorder that affects the skin, mucous membranes, and internal organs)

Rare side effects (affects between 1 and 10 in 10000 people)

• Cardiac failure, arrhythmia

Since the drug has been commercially available, the following additional side effects have been reported:

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

Patients with Leucemia Linfocítica Crónica:

The following side effects were seen during clinical trials in patients with Leucemia Linfocítica Crónica and during the commercialization of the drug (regardless of the indication).

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

• Headache
• Fever, fatigue, reaction at the site of administration, including reaction at the site where the medication is administered through a tube (catheter) with the appearance of redness (erythema) and skin infection. It also includes reaction at the site of infusion 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 side 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 tumors of hematological origin)
• Hemolytic anemia (disorder that causes a decrease in the mass of red blood cells) and autoimmune hemolytic anemia (anemia produced when the autoimmune system attacks the red blood cells of the organism)
• Decreased platelet count (thrombocytopenia), which leads to bleeding or small red spots on the skin (petechiae), anemia
• Allergic reaction
• Confusion, disorientation
• Vein wall inflammation (phlebitis)
• Pulmonary interstitial infiltrates (accumulation of foreign substances in the lung tissue)
• Pulmonary infiltration (accumulation of a foreign substance in the lung)
• Pulmonary interstitial disease (inflammatory disorder of the lower respiratory tract)
• Pneumonitis (inflammation of lung tissue)
• Pulmonary fibrosis (disease characterized by the formation of scars in the lungs)
• Cough, difficulty breathing, including difficulty breathing with physical activity, abnormal respiratory sounds, and wheezing (stertores)
• Nausea, diarrhea, vomiting
• Urticaria
• Skin rash, including maculopapular rash (exanthema maculopapuloso), pruritic rash (exanthema pruriginoso), pustular rash (exanthema pustuloso), and erythematous rash (exanthema eritematoso), excessive sweating, purpura (red spots on the skin)
• Pain, joint pain, back pain, bone pain, muscle pain, extremity pain, inflammatory joint pain
• Renal insufficiency (kidneys do not function properly), acute renal insufficiency (rapid and progressive loss of kidney function), and renal dysfunction (kidney malfunction)
• Generalized fatigue (asthenia), muscle weakness, fluid accumulation (edema), localized fluid accumulation (edema localizado), peripheral edema (fluid accumulation at the surface level), abnormal sound, fixed, and bubbling produced by air in the pulmonary conductors (crepitantes)

Uncommon side effects (affects between 1 and 10 in 1000 people)

• Opportunistic infections
• Prolonged bone marrow suppression with pancytopenia
• Aplastic anemia (disease in which the bone marrow does not function correctly and does not produce enough normal red blood cells)
• Persistent elevation of eosinophils (eosinophilia)
• Developmental and defective formation of cells in the bone marrow(Myelodysplastic syndrome)
• Massive destruction of malignant cells (Tumor lysis syndrome)
• Decreased level of consciousness
• Neurological toxicity, including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, and paraparesia (mild paraplegia)
• Conjunctivitis
• Increased bilirubin and transaminases (substances and proteins that are in the organism and that tell us how the liver works)
• Stevens-Johnson syndrome (severe disorder that affects the skin, mucous membranes, and internal organs)

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

Since the drug has been commercially available, the following additional side effects have been reported:

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

Reporting of side effects

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

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

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

Store in the original packaging to protect it from light.

Do not use this medication after the expiration date shown on the packaging after CAD. The expiration date is the last day of the month indicated.

Composition ofLeustatin

• The active ingredient is cladribina. Each vial (10milliliters) contains 10milligrams of cladribina.
• The other components are sodium chloride and water for injection.
• Acid phosphoric or/dibasic sodium phosphate E339 is added to adjust the pH to a range of 5.5 - 8.0.

Appearance of the product and contents of the package

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

Each package contains seven vials of Leustatin.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

Atnahs Pharma Netherlands B.V.

Copenhagen Towers

Ørestads Boulevard 108, 5.tv

DK-2300 Copenhagen S

Denmark

Responsible for manufacturing

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

Last review date of this leaflet:October2021.

Other sources of information

The detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) (http://www.aemps.gob.es/).

INFORMATION FOR HEALTHCARE PROFESSIONALS ONLY:

Dosage

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

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

Administration

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

Leustatin is stable until the expiration date indicated on the package, when stored in conditions of adequate refrigeration between 2°C and 8°C, protected from light, and in closed vials. Freezing does not damage the solution. In the event of freezing, it must be thawed naturally at room temperature. LEUSTATIN MUST NOT BE HEATED OR MICROWAVED. If once thawed it is returned to the refrigerator, the vial of Leustatin is stable until its expiration date. IT MUST NOT BE RE-FROZEN.

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

Parenteral medications must be visually examined before administration for the presence of particles or discoloration, if the solution or package allows it. When Leustatin is exposed to low temperatures, it may precipitate; this can be resolved by allowing the solution to come to room temperature and agitating it vigorously. LEUSTATIN MUST NOT BE HEATED, NOR MICROWAVED.

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

The possible risks associated with cytotoxic agents are well established, so when handling, preparing, and administering Leustatin, the corresponding precautions must be taken. It is recommended to use disposable gloves and protective clothing. In the event that the skin or mucous membranes come into contact with Leustatin, the affected surface must be washed immediately with plenty of water.

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

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

The solutions containing Leustatin must not be mixed with other intravenous medications or additives, nor must they be administered simultaneously through a common intravenous route, as compatibility tests have not been performed.

If the same intravenous route is used for a sequential infusion of different medications, this route must be washed with a compatible diluent before and after the infusion of Leustatin.

It is not recommended to use 5% dextrose as a diluent, as it increases the degradation of cladribina.

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

Tricoleucemia:Preparation of a daily dose for intravenous administration: Before each daily infusion and before introducing it into the infusion bag, Leustatin must pass through a sterile, disposable, and hydrophilic 0.22µm filter for syringe. Add the calculated dose (0.09milligrams/kilogram or 0.09milliliters/kilogram) of Leustatin through the sterile filter to an infusion bag containing between 100 and 500milliliters of Sodium Chloride 0.9% for injection, Ph. Eur. The infusion must be made continuously for 24hours. This must be repeated every day for a total of 7consecutive days.

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