Proleukin 18 x 10(6) IU powder for solution for injection or for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Proleukin 18 x 106 IU powder for solution for injection or for infusion

aldesleukin

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only and must not be given to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any side effects, consult your doctor or pharmacist, even if they are side effects not listed in this leaflet.

Contents of the leaflet:

1. What Proleukin is and what it is used for
2. What you need to know before using Proleukin
3. How to use Proleukin
4. Possible side effects
5. How to store Proleukin
6. Contents of the pack and other information

1. What Proleukin is and what it is used for

Proleukin is the brand name for aldesleukin. It is a synthetic protein that is 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 cells called lymphocytes, which fight diseases and infections. IL-2 stimulates the production of lymphocytes in the body and enhances the body's defenses.

Proleukin is used to treat kidney cancer that has spread to other organs (also known as metastatic renal cell carcinoma).

2. What you need to know before using Proleukin

Carefully follow all instructions given by your doctor.

Your doctor may perform checks before starting treatment with Proleukin. He or she may carry out a blood test to monitor your blood sugar level and check the function of your kidneys and liver. He or she may also monitor the function of your heart, your respiratory status, and mental state. Your response to treatment will be checked periodically, and necessary actions will be decided accordingly.

Do not use Proleukin

• If you are allergic (hypersensitive) to aldesleukin or to any of the other components of this medicine (listed in section 6).
• If you are required to remain in bed for more than half of the day.
• If less than 24 months have passed since your cancer diagnosis and you have symptoms of cancer, even if the cancer has spread to other organs.
• If you have had heart disease in the past.
• If you have an infection for which you are taking antibiotics.
• If you have low oxygen levels in your blood.
• If you have serious problems with your liver, kidneys, or any other organ.
• If you have seizures (convulsions) or cancer in the brain that has not been properly treated.
• If you have received an organ transplant.
• If you are receiving treatment with medicines called corticosteroids to treat inflammatory reactions or if you might need them during treatment with Proleukin.
• If you have had rheumatoid arthritis, Crohn's disease, or any other disease caused by your immune system.

If any of these apply to you, inform your doctor. You should not receive treatment with Proleukin.

Proleukin should also not be given if blood tests show that:

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

Take special care with Proleukin

• If you have chest pain or an irregular heartbeat. Some patients will have an electrocardiogram (ECG) performed at regular intervals.
• If you have difficulty breathing or start to breathe faster during treatment.
• If you feel extremely 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 take special care:

• If you have fever, chills, cold symptoms, nausea and/or diarrhea.
• If you feel dizzy and notice a rapid heartbeat. 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 a bacterial infection, since treatment with Proleukin increases the risk of infection.
• If you notice mood changes. These generally return to normal after treatment is stopped.
• If you have diabetes. Your blood sugar levels may increase or decrease more than usual.
• If you develop a red, itchy rash or notice that your skin becomes extremely dry during treatment with Proleukin.

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

Use of Proleukin with other medicines

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

Inform your pharmacist if you are taking (or have recently taken) any of the following medicines:

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

Inform your doctor or pharmacist if you are currently using or have recently used any other medicines, including those obtained without a prescription.

Children and adolescents (under 18 years of age)

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

Elderly patients (65 years or older)

Elderly patients may be more susceptible to the adverse effects of Proleukin. Medical staff should exercise special caution when treating elderly patients.

Pregnancy and breastfeeding

• Inform your doctor before starting treatment if you are pregnant, think you might be pregnant, or 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, must use effective contraception while receiving treatment with Proleukin to prevent pregnancy. This applies to most other medicines used to treat cancer.
• Breastfeeding must be discontinued during treatment with Proleukin, as the child may suffer serious 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 medicine.

Driving and use of machines

Do not drive or operate tools or machinery because 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, and is therefore considered essentially “sodium-free”.

3. How to use Proleukin

Proleukin is administered:

• as an intravenous infusion (intravenous drip). This must be carried out in a hospital setting under the supervision of a doctor or nurse experienced in the use of cancer treatments, or
• by direct injection under the skin (subcutaneous injection). This may be given in a hospital, outpatient clinic, or at home, under the supervision of a doctor or nurse.

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

Always follow exactly the instructions provided by your doctor or nurse.

If you use more Proleukin than you should

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

4. Possible adverse effects

Like all medicines, this medicine may cause adverse effects, although not everyone experiences them. The adverse effects of this medicine usually disappear within two days after stopping treatment.

Your doctor may consider it necessary to treat the adverse effects of Proleukin with other medicines.

Some adverse effects may be serious

Very common (affecting more than 1 in 10 people) or common (affecting up to 1 in 10 people):

• Blood disorders: low white blood cell count (leucopenia) with symptoms such as fever or increased risk of infections; low platelet count in the blood with bruising and spontaneous bleeding (thrombocytopenia); low red blood cell count (anemia) with symptoms such as fatigue and pale skin; blood coagulation disorders with sudden onset of breathing difficulty, bloody sputum, leg pain, or increased tendency to bleed; high levels of a type of white blood cells called eosinophils, which may cause heart or lung problems due to inflammation.
• Heart and circulatory problems: heart attack (myocardial ischemia); heart and blood vessel disorders such as abnormal or insufficient heart pumping force (heart failure); sensation of irregular heartbeat (palpitations); chest pain; low blood pressure (hypotension) or high blood pressure (hypertension) associated with dizziness, blurred vision, or persistent headache; irregular heartbeat (arrhythmia); rapid heartbeat (tachycardia); bluish discoloration of lips, tongue, and skin due to lack of oxygen in the blood (cyanosis).
• Breathing and lung problems: cough; difficulty breathing (dyspnea) or chest discomfort; fluid accumulation in the lungs (pulmonary edema); lack of oxygen in organs (hypoxia); coughing up blood (hemoptysis).
• Acute systemic inflammation, often associated with fever and elevated white blood cell count or decreased white blood cell count and reduced body temperature, along with vomiting, may be signs of blood infection.
• Kidney and urinary problems: low urine output (oliguria), with elevated levels of urea and creatinine in the blood and symptoms such as vomiting, inability to urinate, numbness, low muscle tone, or breathing difficulties; blood in the urine (hematuria); kidney failure associated with fatigue, sleep problems, loss of appetite, vomiting, or leg swelling.
• Digestive problems: bleeding from the stomach, intestine, or rectum (resulting in black stools); vomiting blood (hematemesis); abdominal swelling (ascites); difficulty swallowing (dysphagia); abdominal swelling and discomfort, possible signs of enlarged liver and/or spleen.
• Nervous system problems: sudden loss of consciousness or fainting (syncope); loss of ability to speak.
• Decreased or increased thyroid function (hypo- or hyperthyroidism) with symptoms such as weight gain, weight loss, sweating, or hearing loss; elevated calcium levels in the blood (hypercalcemia) with symptoms such as nausea, vomiting, or constipation.
• Difficulty breathing, fatigue, vomiting, numbness, possible signs of high blood lactate levels (lactic acidosis).
• Feeling cold due to low body temperature (hypothermia); low calcium levels (hypocalcemia) possibly causing muscle weakness, spasms, or tingling in fingers; high potassium levels (hyperkalemia) in the blood associated with cramps, irregular heartbeat, dizziness, and headache.

If you experience any of the above effects, contact your doctor immediately or go to the nearest medical emergency center.

Uncommon (affecting up to 1 in 100 people) or rare (affecting up to 1 in 1,000 people) or frequency not known (cannot be estimated from available data):

• Blood disorders: low white blood cell count with signs and symptoms such as high fever, severe sore throat, and frequent infections (agranulocytosis or neutropenia); blood clot formation (thrombosis); bleeding (hemorrhage).
• Heart problems: irregular heartbeat; heart muscle disease with symptoms such as chest pain, fever, or malaise; loss of consciousness (sudden loss of cardiac function); chest pain or discomfort (abnormal fluid accumulation around the heart).
• Lung problems: sudden onset of breathing difficulties due to blood clots in the lung (pulmonary embolism); extreme difficulty breathing (adult respiratory distress syndrome).
• Severe allergic reactions: anaphylaxis, causing facial and throat swelling and breathing difficulties (Quincke's edema); high fever, skin rash with small blisters, joint pain, and/or eye inflammation (Stevens-Johnson syndrome).
• Digestive and other organ problems: recurrent (severe) intestinal inflammation (Crohn's disease) accompanied by diarrhea, lower abdominal pain, fever, and weight loss; inflammation of the pancreas (pancreatitis) accompanied by severe upper abdominal pain radiating to the back; constipation, abdominal swelling, abdominal pain (intestinal obstruction); upper abdominal pain (cholecystitis); liver failure with abdominal pain, fatigue, yellowing of the skin and eyes, or dark yellow urine; a group of symptoms including severe abdominal pain, nausea, fever, and vomiting (gastrointestinal perforation).
• Nervous system problems: seizures (convulsions); paralysis; coma; vision disorders (optic neuropathy); central nervous system damage with tingling, numbness (paresthesia), or loss of motor control; weakness or paralysis in limbs or face, difficulty speaking (cerebral hemorrhage/stroke/leukoencephalopathy).
• Low glucose levels (hypoglycemia) associated with symptoms such as hunger sensation, sweating, dizziness, palpitations.
• Muscle problems: muscle spasms, red-brown urine, possible signs of muscle disorder (rhabdomyolysis); muscle pain or weakness.

If you experience any of the above effects, contact your doctor immediately or go to the nearest emergency unit.

Other adverse effects

Very common (affecting more than 1 in 10 people):

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

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

Common (affecting up to 1 in 10 people):

• Infections of the nose, throat, and lungs; stuffy nose (nasal congestion).
• Nosebleeds (epistaxis).
• Dehydration with signs such as dry mouth or thirst.
• Mood changes, e.g., irritability, excitement, and inability to rest (agitation), depression, seeing things that are not real (hallucinations).
• Loss of motor control, itching, and tingling in fingers or feet without cause (paresthesia, neuropathy).
• Loss of taste.
• Lethargy with signs of lack of energy, tiredness, and insomnia.
• Stomach discomfort after meals (dyspepsia); constipation.
• Inflammation of the lips (cheilitis); stomach inflammation causing stomach pain and nausea (gastritis).
• Hair loss (alopecia); itchy rash.
• Muscle pain; joint pain.
• Eye inflammation (conjunctivitis) with itching, redness, and swelling.
• Swelling and redness of a vein (phlebitis).
• Inflammation of mucous membranes (mucositis); swelling with nodules (nodules) at the injection site.
• High blood glucose levels (hyperglycemia) with signs such as excessive thirst, hunger, urination, or fatigue.
• Blood tests indicating changes in liver function, e.g., high bilirubin levels (hyperbilirubinemia) or elevated liver enzymes in the blood (liver transaminases, alkaline phosphatase, or lactate dehydrogenase).
• Fever and cough appearing after use of Proleukin (flu-like illness).
• Low sodium levels (hyponatremia), which may present as fatigue, confusion, or muscle spasms.
• Low phosphate levels (hypophosphatemia), which may present as muscle weakness.

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

Uncommon (affecting up to 1 in 100 people):

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

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

Rare (affecting up to 1 in 1,000 people):

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

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

Cases of blood vessel inflammation (vasculitis) in the skin, brain, and other parts of the body have also been reported.

Reporting of adverse effects:

If you experience any adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Proleukin

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

Do not use this medicine after the expiry date stated on the container after EXP. The expiry date refers to the last day of the month indicated.

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

Keep in the original packaging to protect from light.

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

6. Pack contents and other information

Composition of Proleukin

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

Appearance of the product and contents of the pack

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

Only certain pack sizes may be marketed.

Marketing Authorisation Holder

Iovance Biotherapeutics B.V.

Noma House

Gustav Mahlerlaan 1212

1081LA Amsterdam

Netherlands

Manufacturer

Almac Pharma Services (Ireland) Limited

Finnabair Industrial Estate

Dundalk

Co. Louth

A91 P9KD

Ireland

Date of latest revision of this leaflet: 06/2019

The following information is intended for healthcare professionals only:

Proleukin 18 million IU powder for solution for injection or infusion

aldesleukin

Special storage precautions

Keep out of the sight and reach of children.

Do not use Proleukin after the expiry date stated on the container.

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

Keep in the original packaging to protect from light.

Shelf-life after reconstitution

The reconstituted Proleukin solution may be stored for 24 hours in a 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 syringe and injection needle.
• Inject 1.2 ml of water for injections into the Proleukin vial. Direct the stream of water for injections against the vial wall to avoid excessive foaming.
• Gently swirl to allow the powder to dissolve completely. Do not shake.
• The solution contains 18 million IU or 1.1 mg of Proleukin (aldesleukin) per millilitre.

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

Instructions for the proper use of Proleukin

Subcutaneous administration (s.c.)

• After reconstitution, the product should be used within 24 hours.
• The product should be brought to room temperature before administration and used immediately.
• The appropriate dose can then be withdrawn and administered subcutaneously.
• Proleukin should be injected into subcutaneous tissue. The best injection sites are soft, loose (flaccid) areas, away from joints, nerves, bones, and other important structures.
• The injection site should be rotated regularly if Proleukin is administered subcutaneously. This helps prevent pain and redness at the injection site.

A treatment cycle typically lasts four weeks.

-Week 1

Days 1 to 5: one dose of 18 million IU of Proleukin daily.

Days 6 and 7: no Proleukin treatment.

-Weeks 2, 3 and 4

Days 1 and 2: one dose of 18 million IU daily.

Days 3, 4 and 5: one dose of 9 million IU daily.

Days 6 and 7: no Proleukin treatment.

After a one-week break without Proleukin, a second 4-week cycle should be administered.

If the patient has improved or their condition has stabilised, Proleukin treatment may continue with additional 4-week cycles.

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

Intravenous administration (i.v.)

• Using a sterile syringe, withdraw the appropriate dose of Proleukin solution from the vial.
• Dilute as necessary in up to 500 ml of 50 mg/ml (5%) glucose solution for infusion, containing 1 mg/ml (0.1%) human albumin. Human albumin must be mixed with the glucose solution before adding the reconstituted aldesleukin.
• The appropriate dose can then be administered intravenously as a daily dose of 18 million IU/m² over 24 hours, for 5 consecutive days.

As with all injectable preparations, inspect the solution for particulate matter and discoloration prior to administration. Do not use Proleukin if particles are observed or if the solution is cloudy or more intensely coloured than a faint yellow.

A treatment cycle typically consists of:

• Days 1 to 5: daily dose of 18 million IU/m² body surface area over 24 hours as continuous infusion. The intravenous line should remain in place during treatment.
• Next 2 to 6 days: no Proleukin treatment.
• Then, another 5 consecutive days of continuous infusion.

After a three-week break without Proleukin, a second cycle should follow as described above.

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

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

Each vial is for single use only.

Disposal

Medicines should not be disposed of via wastewater or household waste. Residual solution, vials, syringes, and needles must be disposed of properly. This helps protect the environment.