Label: information for the user

Proleukin 18 x 106UI powder for injectable solution or for infusion

aldesleukina

Read this label carefully before starting to use this medication, as it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed only to you and should not be given to others even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this label.

1. What is Proleukin and how it is used

2. What you need to know before starting to use Proleukin

3. How to use Proleukin

4. Possible adverse effects

5. Storage of Proleukin

6. Contents of the package and additional information

Proleukin is the commercial name ofaldesleukina.It is a synthetic protein, very similar to a protein produced by the body, called interleukin-2 (IL-2). This protein is part of the immune system. IL-2 activates a type of white blood cell called lymphocytes, which fight diseases and infections. IL-2 stimulates the production of lymphocytes in the body and increases the body's defenses.

Proleukin is used to treat kidney cancer that has spreadto other organs (also calledmetastatic renal cell carcinoma).

Follow carefully all the instructions given by your doctor.

Your doctor may perform checks before starting treatment with Proleukin. They may perform a blood test to control your blood sugar level and check the function of your kidneys and liver. They may also check the functioning of your heart, your respiratory condition, and your mental state. They will check your response to treatment at regular intervals and decide what action is necessary.

Do not use Proleukin

• If you areallergic(hypersensitive) to aldesleukin or any of the other components of this medication (including those listed in section 6).
• If you muststay in bedfor more than half the day.
• If it has beenless than 24 monthssince you were diagnosed with cancer and you have cancer symptoms,even ifthe cancer has spread to other organs.
• If you have hadheart disease in the past.
• If you have ainfection for which you are taking antibiotics.
• If you havelow oxygen levels in your blood.
• If you haveserious problems with your liver, kidneysor any other organ.
• If you haveseizures(convulsions) orbrain cancerthat has not been properly treated.
• If you have received atransplant of an organ.
• If you are receiving treatment with medications calledcorticosteroidsto treat inflammatory reactions or if you may need them during treatment with Proleukin.
• If you have hadrheumatoid arthritis, Crohn's diseaseor any other disease caused by your immune system.

If you find yourself in any of these cases,inform your doctor.You should not receive treatment with Proleukin.

Also, Proleukin should not be administered to you if blood tests show that:

• You have a low level of white blood cells, platelets, or red blood cells.
• You have creatinine or bilirubin levels outside the normal range.

Be especially careful with Proleukin

• If you havechest pain or an irregular heart rhythm. In some patients, an electrocardiogram (ECG) will be performed at regular intervals.
• If you havedifficulty breathingor startbreathing more quicklyduring treatment.
• If you feelextremely tired or drowsy, as this may be a sign that you are losing consciousness.

If you experience any of these symptoms,inform your doctor immediately.

Also, be careful:

• If you havefever, chills, cold, nausea, and/or diarrhea.
• If you feeldizzy and notice a rapid heart rate. This may be a sign of low blood pressure, which is usually observed between 2 and 12 hours after administration of Proleukin.
• If you have abacterial infection, as treatment with Proleukin increases the risk of infection.
• If you noticechanges in your mood. These usually return to normal after interrupting treatment.
• If you havediabetes. Your blood sugar levels may increase or decrease more than usual.
• If you have ared rash on your skin and that produces intense itchingor if you notice that yourskin is extremely dryduring treatment with Proleukin.

If any of the above symptoms are severe,inform your doctor.

Use of Proleukin with other medications

Some medications may reduce the effect of Proleukin, or increase its adverse effects.

Inform your pharmacistif you are using any of the following medications (or have used them recently).

• Chemotherapy medications, called tamoxifen, interferon alfa, cisplatin, vinblastine, and/or dacarbazine, used to treat cancer.
• Medications called glucocorticoids (a type of steroid), used to treat inflammatory reactions.
• Medications called beta blockers, used to treat high blood pressure.
• Medications that affect the heart, central nervous system, liver, kidneys, or bone marrow. Consult your doctor if you are unsure about which ones are.
• Contrast liquids used in a Computerized Tomography (CT) scan.

Inform your doctor or pharmacist if you are using or have used recently other medications, even those purchased without a prescription.

Children and adolescents (under 18 years)

Proleukin is not recommended for children and adolescents under 18 years.

Older adults (65 years or older)

Older adults may be more susceptible to the adverse effects of Proleukin. Medical staff should exercise special caution when treating older adults.

Pregnancy and breastfeeding

• Inform your doctor before starting treatmentif you are pregnant, if you think you may be pregnant, or if you are trying to become pregnant. Your doctor will discuss with you the risks and benefits of using Proleukin during pregnancy.
• Patients, both men and women, should use effective contraceptive methodswhile receiving treatment with Proleukin, to prevent pregnancy. This applies to most other medications used to treat cancer.
• Discontinue breastfeeding during treatmentwith Proleukin, as there is a possibility that the baby may experience severe adverse effects.

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

Driving and operating machinery

Do not drive or operate tools or machinerybecause Proleukin has adverse effects that may affect your ability to perform these activities.

Proleukin contains sodium

Proleukin contains less than 23 mg of sodium per 1 ml, so it is considered essentially “sodium-free”.

Proleukin is administered:

• as an intravenous infusion through a vein(intravenous perfusion).It should be performed in a hospital, under the supervision of an experienced doctor or nurse in the use of cancer medications, or
• by subcutaneous injection directly under the skin(subcutaneous injection). This can be administered in a hospital, in an outpatient clinic, or at home, under the supervision of a doctor or nurse.

Before or during treatment with Proleukin, your doctor may perform regular blood tests and chest X-rays to monitor your organs and blood cell count.

Follow exactly the instructions indicated by your doctor or nurse.

If you use more Proleukin than you should

If you have been given or think you have been given too much Proleukin, or if you believe so, contact your doctor or nurse immediately. You may experience some adverse reactions described in section 4.

Like all medicines, this medicine can cause side effects, although not everyone will experience them. The side effects of this medicine usually disappear after two days of stopping treatment.

Your doctor may consider treating Proleukin side effects with other medicines.

Some side effects can be serious

Very common(may affect more than 1 in 10 people) orcommon(may affect up to 1 in 10 people):

• Blood disorders: low white blood cell count (leucopenia) with symptoms of fever or increased risk of infections; low platelet count in the blood with bruises and spontaneous bleeding (trombocytopenia); low red blood cell count (anemia) with symptoms such as fatigue and pale skin; blood clotting disorders in the blood with sudden onset of difficulty breathing, bloody sputum, leg pain or easy bleeding; high count of a type of white blood cell called eosinophils that can cause heart or lung problems due to inflammation.
• Heart and circulatory problems: heart attack (myocardial infarction); heart and blood vessel disorders, such as abnormal or insufficient heart pumping force (heart failure), abnormal heart palpitations; chest pain; low blood pressure (hypotension) or high blood pressure (hypertension) associated with dizziness, blurred vision or constant headache; irregular heart rhythm (arrhythmia); rapid heart rate (tachycardia); blue discoloration of the lips, tongue and skin due to lack of oxygen in the blood (cyanosis).
• Respiratory and lung problems: cough; difficulty breathing (breathlessness) or chest discomfort; fluid accumulation in the lungs (pulmonary edema); organ deficiency due to lack of oxygen (hypoxia); coughing up blood (hemoptysis).
• Systemic inflammation, often associated with fever and elevated or decreased white blood cell count and decreased body temperature, are possible signs of blood infection.
• Renal and urinary problems: low urine production (oliguria), with high levels of urea and creatinine in the blood with symptoms such as vomiting, inability to urinate, numbness, low muscle tone or respiratory difficulties; blood in the urine (hematuria); kidney insufficiency associated with fatigue, sleep problems, loss of appetite, vomiting or leg cramps.
• Gastrointestinal problems: stomach, intestine and rectal bleeding (causing black stools); vomiting blood (hematemesis); abdominal swelling (ascitis); difficulty swallowing (disphagia); abdominal swelling and discomfort, possible signs of liver and/or spleen enlargement.
• Nervous system problems: sudden loss of consciousness or fainting (syncope); loss of ability to speak.

• Decreased or increased thyroid function (hypothyroidism or hyperthyroidism) with symptoms such as weight gain, weight loss, sweating or hearing loss; high calcium levels in the blood (hypercalcemia) with symptoms such as dizziness (nausea), vomiting or constipation.
• Difficulty breathing, fatigue, vomiting, numbness, possible signs of high blood lactic acid levels.
• Sensation of cold due to low body temperature (hypothermia); low calcium levels (hypocalcemia) with possible muscle weakness, spasms or tingling in fingers; high potassium levels (hyperkalemia) in the blood associated with muscle cramps, irregular heart rhythm, dizziness and headache.

If you experience any of the mentioned side effects,contact your doctor immediatelyor go to the nearest medical emergency center.

Less common(may affect up to 1 in 100 people) orrare(may affect up to 1 in 1,000 people) orunknown frequency(cannot be estimated from available data):

• Blood disorders: low white blood cell count with signs and symptoms of high fever, severe sore throat, and frequent infections (agranulocytosis or neutropenia); blood clots in the blood (thrombosis); bleeding (hemorrhage).
• Heart problems: irregular heart rhythm; heart muscle disease with symptoms such as chest pain, fever or discomfort; sudden loss of consciousness (sudden loss of cardiac function); chest pain or discomfort (pericardial effusion).
• Pulmonary problems: sudden onset of breathing difficulties due to blood clots in the lungs (pulmonary embolism); severe difficulty breathing (adult respiratory distress syndrome).
• Severe allergic reactions: anaphylaxis, which includes facial and throat swelling and difficulty breathing (Quincke's edema); high fever, skin rash with small blisters, joint pain and/or eye inflammation (Stevens-Johnson syndrome).
• Gastrointestinal and other organ problems: recurrent intestinal inflammation (Crohn's disease) with symptoms such as diarrhea, abdominal pain, fever and weight loss; pancreatitis with severe abdominal pain radiating to the back; constipation, abdominal swelling, abdominal pain (intestinal obstruction); abdominal pain (cholecystitis); liver failure with abdominal pain, fatigue, yellow skin and eyes or dark urine; a group of symptoms consisting of severe abdominal pain, nausea, fever, vomiting (gastrointestinal perforation).
• Nervous system problems: seizures (convulsions); paralysis; coma; vision disturbances (ocular neuropathy); central nervous system damage with numbness, tingling (paresthesia) or loss of motor control; weakness or paralysis in limbs or face, difficulty speaking (stroke/brain hemorrhage/leukoencephalopathy).
• Low blood glucose (hypoglycemia) associated with symptoms such as hunger, sweating, dizziness, palpitations.
• Muscle problems: muscle spasms, reddish-brown urine, possible signs of muscle damage (rhabdomyolysis); muscle pain or weakness.

If you experience any of the described side effects,contact your doctor immediatelyor go to the nearest emergency unit.

Other side effects

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

• Loss of appetite (anorexia).
• Difficulty sleeping (insomnia).
• Anxiety; confusion; dizziness; headache; drowsiness (somnolence).
• Cough.
• Nausea with or without vomiting; diarrhea; mouth sores with inflammation (stomatitis).
• Skin redness (erythema); skin rash; exfoliation; itching, sweating.
• Reactions at the injection site, such as pain and inflammation.
• Flu-like symptoms (fever, chills, discomfort, fatigue); pain; weight loss; weight gain.
• Fluid accumulation (edema).

If any of the described side effects become severe,inform your doctor or pharmacist.

Common(may affect up to 1 in 10 people):

• Upper respiratory tract infections, sore throat and lung infections; nasal congestion.
• Nosebleeds (epistaxis).
• Dehydration with signs such as dry mouth or feeling thirsty.
• Changes in mood, e.g. irritability, excitement and inability to rest (agitation), depression, seeing things that are not real (hallucinations).
• Loss of motor control, tingling and numbness in fingers or toes without cause (paresthesia, neuropathy).
• Loss of taste.
• Lethargy with signs of lack of energy, fatigue and insomnia.
• Abdominal discomfort after meals (indigestion); constipation.
• Lip inflammation (cheilitis); stomach inflammation causing abdominal pain and nausea (gastritis).
• Hair loss (alopecia); skin rash.
• Muscle pain; joint pain.
• Eye inflammation (conjunctivitiswith itching, redness and swelling).
• Vein inflammation (phlebitis).
• Mucous membrane inflammation (mucositis); swelling with nodules at the injection site.
• High blood glucose (hyperglycemia) with symptoms such as excessive thirst, hunger, urination or fatigue.
• Blood test indicating a change in liver function, e.g. high bilirubin levels (hyperbilirubinemia) or liver enzymes in the blood (transaminases, alkaline phosphatase or lactate dehydrogenase).
• Fever and cough appearing after Proleukin use (influenza-like illness).
• Low sodium levels (hyponatremia), which can manifest as fatigue, confusion, muscle spasms.
• Low phosphate levels (hypophosphatemia), which can manifest as muscle weakness.

If any of the described side effects become severe,inform your doctor or pharmacist.

Less common(may affect up to 1 in 100 people):

• Allergic reactions (hypersensitivity) causing itchy eyes, runny nose, skin rash or pain.
• Muscle weakness (myasthenia).
• Skin discoloration (vitiligo).

If any of the described side effects become severe,inform your doctor or pharmacist.

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

• Diabetes.
• Skin rash with small blisters (vesiculobullous rash).
• Tissue damage (necrosis) at the injection site.

If any of the described side effects become severe,inform your doctor or pharmacist.

Also, cases of blood vessel inflammation (vasculitis) in the skin, brain, and rest of the body have been reported.

Reporting of adverse reactions:

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

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

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

Store unopened vials in the refrigerator (between 2°C and 8°C). Do not freeze.

Store in the original packaging to protect it from light.

Your doctor, nurse, or pharmacist knows how to store Proleukin correctly.

Composition of Proleukin

• The active ingredient is aldesleukin, containing 18 million International Units (UI) (1.1 mg) per milliliter of reconstituted solution as recommended.
• The other components are mannitol (E421), sodium lauryl sulfate, dihydrogen sodium phosphate dihydrate, and dihydrogen sodium phosphate dihydrate.

Appearance of the product and contents of the package

Proleukin is a white, sterile powder available in vials of 1 or 10.

Only some package sizes may be commercially available.

Marketing Authorization Holder

Iovance Biotherapeutics B.V.

Noma House

Gustav Mahlerlaan 1212

1081LA Amsterdam

Netherlands

Responsible for manufacturing

Almac Pharma Services (Ireland) Limited

Finnabair Industrial Estate

Dundalk

Co. Louth

A91 P9KD

Ireland

Last review date of this leaflet: 06/2019

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The following information is intended only for healthcare professionals:

Proleukin 18 million UI powder for injectable solution or for intravenous infusion

aldesleukina

Special precautions for storage

Keep out of the sight and reach of children.

Do not use Proleukin after the expiration date appearing on the package.

Store unopened vials in the refrigerator (between 2°C and 8°C). Do not freeze.

Store in the original packaging to protect it from light.

Expiration date after reconstitution

The reconstituted Proleukin solution can be stored for 24 hours in the refrigerator (2°C-8°C) if not used immediately.

The diluted Proleukin solution must be used within 48 hours after reconstitution, including the duration of the infusion.

How to prepare and administer Proleukin

- Use a sterile injection syringe and a needle for injection.

- Inject 1.2 ml of water for injection into the Proleukin vial. Direct the water for injection against a wall of the vial to avoid excessive foam formation.

- Gently swirl to allow the powder to dissolve completely. Do not agitate.

The solution contains 18 million UI or 1.1 mg of Proleukin (aldesleukina) per milliliter.

The solution is now prepared for subcutaneous administration or must be further diluted for intravenous infusion.

Instructions for the proper use of Proleukin

Subcutaneous administration (s.c.)

- Once reconstituted, the product must be used within 24 hours.

- The product must be brought to room temperature before administration and used immediately.

- Then the appropriate dose can be withdrawn and injected subcutaneously.

- Proleukin must be injected into the subcutaneous tissue. The best areas for injection are soft and pliable (flaccid) areas, away from joints, nerves, bones, and other important structures.

- The injection site should be changed regularly if Proleukin is administered subcutaneously. This helps prevent pain and redness at the injection site.

Course of treatmentusually lasts four weeks.

-Week 1

Days 1 to 5: a dose of 18 million UI of Proleukin per day.

Days 6 and 7: no treatment with Proleukin.

-Weeks 2, 3, and 4

Days 1 and 2: a dose of 18 million UI per day.

Days 3, 4, and 5: a dose of 9 million UI per day.

Days 6 and 7: no treatment with Proleukin

After a week without administering Proleukin, a second cycle of 4 weeks should be administered.

If the patient has improved or their condition has stabilized, treatment with Proleukin can continue with additional cycles of 4 weeks.

Depending on the response to treatment, a higher or lower dose may be suggested.

Intravenous administration (i.v.)

-With a sterile syringe, withdraw the appropriate dose of the Proleukin solution from the vial.

-Dilute as needed to 500 ml of infusion solution of glucose 50 mg/ml (5%), containing 1 mg/ml (0.1%) of human albumin. Human albumin must be mixed with the glucose solution before adding the reconstituted aldesleukina.

-Then the appropriate dose can be administered intravenously, delivering a daily dose of 18 million UI/m2in 24 hours, for 5 days.

As with all injectable preparations, check for the presence of particles or if discoloration occurs before administration. Do not use Proleukin if particles are observed in the solution or if the solution is turbid or has a color greater than a light yellow.

Course of treatmentusually consists of:

-Days 1 to 5: a daily dose of 18 million UI/m2of body surface area in 24 hours as continuous infusion. The vein will be maintained in the vein during treatment.

-In the next 2 to 6 days: no treatment with Proleukin.

-Then, another 5 consecutive days of continuous infusion.

After three weeks without administering Proleukin, a second cycle should be followed as described above.

If the patient has improved or their condition has stabilized after completing two cycles, treatment with Proleukin can continue as five days of treatment every 4 weeks. Up to four maintenance cycles can be administered.

Depending on the response to treatment, a higher or lower dose may be suggested.

Each vial is for single use.

Elimination

Medicines should not be disposed of through the drains or in the trash. The remains of the solution, vials, syringes, and needles should be disposed of properly. This will help protect the environment.