ONIVYDE pegylated liposomal 4.3 mg/ml concentrate for dispersion for infusion

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse.
  This includes any possible side effects not listed in this leaflet. See section 4.

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

ONIVYDE pegylated liposomal is a cancer medicine that contains the active substance irinotecan. This active substance is held in tiny lipid (fatty) particles called liposomes.

Irinotecan belongs to a group of cancer medicines called `topoisomerase inhibitors'. It blocks an enzyme called topoisomerase I, which is involved in the division of cell DNA. This prevents the cancer cells from multiplying and growing, and they eventually die.

The liposomes are expected to accumulate within the tumour and release the medicine slowly over time, thereby allowing it to act for longer.

ONIVYDE pegylated liposomal is used to treat adult patients with metastatic pancreatic cancer (cancer of the pancreas that has already spread elsewhere in the body) whose previous cancer treatment included a medicine called gemcitabine.

ONIVYDE pegylated liposomal is used in combination with other cancer medicines, called 5-fluorouracil and leucovorin.

If you have any questions about how ONIVYDE pegylated liposomal works or why this medicine has been prescribed for you, ask your doctor.

• if you have a history of a severe allergy to irinotecan, or any of the other ingredients of this medicine (listed in section 6)
• if you are breast-feeding.

Talk to your doctor or nurse before you are given ONIVYDE pegylated liposomal

• if you have ever had any liver problems or jaundice
• if you have ever had lung disease or have previously received medicines (colony stimulating factors) to increase your blood count or radiation therapy
• if you are taking other medicines (see section "Other medicines and ONIVYDE pegylated liposomal")
• if you are planning to have a vaccination as many vaccinations must not be given during chemotherapy
• if you are on a controlled sodium diet as this medicine contains sodium

Talk to your doctor or nurse immediately during treatment with ONIVYDE pegylated liposomal

• if you feel sudden shortness of breath, flushing, headache, skin rash or hives (itchy rash with swollen red bumps on the skin that appear suddenly), itching, swelling around the eyes, tightness in the chest or throat during or shortly after your infusion
• if you experience fever, chills or other symptoms of infection
• if you get diarrhoea with frequent liquid stools and cannot control this after 12 to 24 hours of treatment (see below)
• if you get breathlessness or cough
• if you experience signs or symptoms of a blood clot, like sudden pain and swelling in a leg or an arm, sudden onset of coughing, chest pain or difficulty breathing

What to do in case of diarrhoea

As soon as the first liquid stool occurs, start drinking large volumes of rehydration fluids (e.g. water, soda water, fizzy drinks, soup) to avoid losing too much liquid and salts from your body. Contact your doctor immediately to give you a suitable treatment. Your doctor may give you a medicine which contains loperamide to begin treatment at home but it must not be used for longer than 48 consecutive hours. If loose stools persist, contact your doctor.

Blood tests and medical examinations

Before you start treatment with ONIVYDE pegylated liposomal, your doctor will perform blood tests (or other medical examinations) to determine the best starting dose for you. You will need to have further (blood or other) tests during treatment so that your doctor can monitor your blood cells and assess how you are responding to the treatment. Your doctor may need to adjust the dose or your treatment.

ONIVYDE pegylated liposomal is not recommended for use in adolescents and children below the age of 18 years.

Tell your doctor if you are taking, have recently taken or might take any other medicines.

It is especially important that you tell your doctor if you have been given irinotecan in any form earlier.

ONIVYDE pegylated liposomal must not be used instead of other medicines containing irinotecan because it behaves differently when it is contained in the liposomes than when it is given in its free form.

Tell your doctor, pharmacist or nurse if you are already having, or have recently had chemotherapy and/or radiotherapy or treatment with the antifungal medicine flucytosine.

It is also especially important that you tell your doctor if you are also taking the following medicines, since they reduce the level of irinotecan in your body:

• phenytoin, phenobarbital or carbamazepine (medicines used to treat convulsions and falls)
• rifampicin and rifabutin (medicines used to treat tuberculosis)
• St. John's wort (a plant-based medicine used to treat depression and low mood)

It is especially important that you tell your doctor if you are also taking the following medicines, since they increase the level of irinotecan in your body:

• ketoconazole, itraconazole or voriconazole (medicines used to treat fungal infections)
• clarithromycin (an antibiotic medicine used to treat bacterial infections)
• indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir (medicines against HIV infection)
• regorafenib (a medicine against certain forms of cancer)
• telaprevir (a medicine used to treat a liver disease called hepatitis C)
• nefazodone (a medicine used to treat depression, low mood)
• gemfibrozil (medicine used to treat high fat levels in the blood)

Avoid eating grapefruits and drinking grapefruit juice while you are receiving ONIVYDE pegylated liposomal as it may increase the level of irinotecan in your body.

You should not be given ONIVYDE pegylated liposomal if you are pregnant as it may harm the baby. Tell your doctor if you are or think you may be pregnant. Ask your doctor for advice if you are planning to have a baby. If you are given ONIVYDE pegylated liposomal you should not breast-feed until one month after the last dose.

Prior to taking this medicine talk with your doctor about the possible risk with this medicine and the options that may preserve your ability to have children.

During your ONIVYDE pegylated liposomal treatment and for seven months after you should choose an effective birth control method which suits you to prevent pregnancy in this period of time. Males should use condoms during ONIVYDE pegylated liposomal treatment and for 4 months thereafter.

Tell your doctor if you are breast-feeding. You must not be given ONIVYDE pegylated liposomal if you are breast-feeding as this may be harmful to your baby.

ONIVYDE pegylated liposomal may influence your ability to drive and use machines (as you may be sleepy, dizzy and exhausted with the use of ONIVYDE pegylated liposomal). You should avoid driving, using machines or performing other tasks that need full attention if you feel sleepy, dizzy and exhausted.

This medicine contains 33.1 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 1.65% of the recommended maximum daily dietary intake of sodium for an adult.

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

• Low levels of white blood cells (neutropenia and leukopenia),
• Low level of red blood cells (anaemia)
• Low level of blood platelets (thrombocytopenia)
• Diarrhoea (loose or watery and frequent stools)
• Nausea and vomiting
• Pain in the stomach or in the gut area
• Sore mouth
• Loss of weight
• Loss of appetite
• Loss of body fluid (dehydration)
• Low level of salts (electrolytes) in the body (e.g. of potassium, magnesium)
• Unusual hair loss
• Tiredness
• Dizziness
• Swelling and fluid retention in the soft tissues (peripheral oedema)
• Soreness and swelling of the digestive tract lining (mucosal inflammation)
• Fever
• Generalised weakness

Common (may affect up to 1 in 10 people)

• Chills
• Infections, for example fungal infections in the mouth (oral candidiasis), fever with low counts of white blood cells (febrile neutropenia), infections related to the administration of the product into a vein
• Inflammation of the stomach and the guts (gastroenteritis)
• Systemic body inflammation, caused by infection (sepsis)
• Potentially life-threatening complication of whole body inflammation (septic shock)
• Infection of the lungs (pneumonia)
• Low level of white blood cells subtype, called lymphocytes with important function for the immune system (lymphopenia)
• Decrease in some salts (electrolytes) in the body (e.g. phosphate, sodium)
• Low blood sugar (hypoglycaemia)
• Sleeplessness
• Bad taste in the mouth
• A syndrome called cholinergic syndrome with sweating, salivation and abdominal cramping
• Low blood pressure (hypotension)
• Formation of a blood clot in a deep vein (deep vein thrombosis) or blockage of the main artery of the lung or one of its branches (pulmonary embolism), or blockage due to a blood clot elsewhere in the blood stream (embolism)
• Voice impairment, hoarse or excessively breathy voice
• Shortness of breath
• Inflammation in the gut
• Piles (haemorrhoids)
• Increases in liver enzymes (alanine aminotransferase or aspartate aminotransferase) in laboratory blood tests
• Increase in bilirubin levels (an orange-yellow pigment, waste product of the normal breakdown of the red blood cells) in other laboratory measurements related to liver function
• Increase in other laboratory measurements (increased international normalised ratio) related to the blood clotting system function
• Abnormally low blood levels of albumin (major protein in the body)
• Itching
• Sudden problems with kidney function which may lead to rapid deterioration or loss of the kidney function
• Abnormal reaction to the infusion causing symptoms like shortness of breath, flushing, headache, tightness in the chest or throat
• Abnormal fluid retention in the body causing swelling in the affected tissues (oedema)

Uncommon (may affect up to 1 in 100 people)

• Systemic body inflammation, caused by infection of the gall bladder and bile ducts (biliary sepsis)
• Allergic reaction to ONIVYDE pegylated liposomal (the active substance or the excipients)
• Diminished availability of oxygen to the body tissues
• Inflammation of the oesophagus (food pipe)
• Formation or presence of a blood clot within a blood vessel - vein or artery (thrombosis)
• Inflammation of the lining of the rectum (the end of the large intestine)
• Hive (swollen red bumps)
• Skin rash
• Type of rash, characterised by appearance of a flat, red area on the skin covered with bumps (maculo-papular rash)
• Change in the colour of the nail plates

Not known (frequency cannot be estimated from the available data)

• Reddening of the skin

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

• The active substance is irinotecan. One 10 ml vial of concentrate contains 43 mg irinotecan anhydrous free base (as sucrosofate salt in a pegylated liposomal formulation).
• The other ingredients are: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); cholesterol, N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoly-sn-glycero-3-phosphoethanolamine (MPEG-2000-DSPE); sucrose octasulphate; 2- [4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES buffer); sodium chloride and water for injections.
  ONIVYDE pegylated liposomal contains sodium, if you are on a controlled sodium diet, see section 2.

ONIVYDE pegylated liposomal is supplied as a white to slightly yellow opaque isotonic liposomal dispersion in a glass vial.

Each pack contains one vial with 10 ml of concentrate.