Prospect: information for the patient

Kyprolis 10 mg powder for solution for infusion

Kyprolis 30 mg powder for solution for infusion

Kyprolis 60 mg powder for solution for infusion

carfilzomib

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

• Keep this prospect, as you may need to read it again.
• If you have any questions, consult your doctor or nurse.
• If you experience adverse effects, consult your doctor or nurse, even if they are not listed in this prospect. See section 4.

Kyprolis is a medication that contains the active ingredient carfilzomib.

Carfilzomib works by blocking the proteasome. The proteasome is a system within cells that breaks down proteins when they are damaged or no longer needed. By preventing the breakdown of proteins in cancer cells, which are more likely to contain an abnormal amount of proteins, Kyprolis causes the death of cancer cells.

Kyprolis is used to treat adult patients with multiple myeloma who have had at least one previous treatment for this disease.

Multiple myeloma is a cancer of plasma cells (a type of white blood cell).

Kyprolis will be administered along with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or alone with dexamethasone.Daratumumab, lenalidomide, and dexamethasone are other medications used to treat multiple myeloma.

Your doctor will examine you and review your complete medical history. You will be under strict follow-up during treatment.

Before starting treatment with Kyprolis, and during treatment, blood tests will be performed. This will allow your doctor to verify that you have sufficient blood cells and that your liver and kidneys are functioning correctly. Your doctor or nurse will check that you receive sufficient amounts of fluids.

You must read the leaflet for all the medicines you use in combination with Kyprolis, so that you can understand the information related to these medicines.

Do not use Kyprolis if you are allergicto carfilzomib or to any of the other components of this

medicament (listed in section 6).

Warnings and precautions

Consult your doctor or nurse before starting to use Kyprolis if you have any of the conditions listed below.You may need to undergo additional tests to check that your heart, kidneys, and liver are functioning correctly.

• Heart problems, including a history of chest pain (angina), heart attack, irregular heartbeat, high blood pressure, or if you have ever taken a heart medicine
• Lung problems, including a history of difficulty breathing at rest or during activities (dyspnea)
• Kidney problems, including kidney failure, or if you have ever received dialysis
• Liver problems, including a history of hepatitis, fatty liver, or if you have ever been told that your liver is not functioning correctly
• Unusual bleeding, including easy bruising, bleeding due to a wound, such as a cut that takes longer than expected to stop bleeding; or internal bleeding, such as coughing up blood, vomiting blood, black stools, or bright red stools with blood; or brain bleeding that causes sudden numbness or paralysis on one side of the face, legs, or arms, severe and sudden headache, or difficulty speaking or swallowing (dysphagia). This may indicate a low platelet count (cells that help blood to clot)
• History of blood clots in your veins
• Pain in legs or arms or swelling (which may be symptoms of blood clots in the deep veins of the legs or arms), chest pain, or difficulty breathing (which may be symptoms of blood clots in the lungs)
• Any other serious disease for which you have been hospitalized or received medication.

Symptoms to which you should be alert

You should be aware of certain symptoms while taking Kyprolis to reduce the risk of problems. Kyprolis may worsen some symptoms or produce severe and potentially fatal side effects, such as heart problems, lung problems, kidney problems, tumor lysis syndrome (a potentially fatal disease that occurs when cancer cells break down and release their contents into the blood), reactions to Kyprolis infusion, unusual bleeding or bruising (including internal bleeding), blood clots in your veins, liver problems, certain blood disorders, or a neurological syndrome known as SEPR. See the section ‘Signs and symptoms to which you should be alert’ in section 4.

Inform your doctor if you have ever had or may have hepatitis B virus infection. The reason is that this medicine may cause the hepatitis B virus to become active again. Your doctor will examine you to detect signs of this infection before, during, and some time after completing treatment with this medicine. Inform your doctor immediately if you experience worsening fatigue or if you notice that your skin or the white part of your eyes turn yellow.

At any time during the duration of treatment or after completing it, inform your doctor or nurse immediately if you experience blurred vision, loss of vision, double vision, difficulty speaking, weakness in one arm or leg, a change in the way you walk or balance problems, persistent numbness, decreased sensitivity, or loss of sensitivity, memory loss, or confusion. All of these may be symptoms of a potentially fatal brain disease known as multifocal progressive leukoencephalopathy (MPL). If you had these symptoms before starting treatment with carfilzomib, inform your doctor about any change you experience in these symptoms.

Other medicines and Kyprolis

Inform your doctor if you are taking, have taken recently, or may need to take any other medicine. This includes any medicine obtained without a prescription, such as vitamins or herbal medicines.

Inform your doctor or nurse if you are taking medicines used to prevent pregnancy, such as oral contraceptives or other hormonal contraceptives, because these may not be suitable for use with Kyprolis.

Pregnancy and breastfeeding

For women taking Kyprolis

Do not take Kyprolis if you are pregnant, think you may be pregnant, or intend to become pregnant. Kyprolis treatment has not been evaluated in pregnant women. While taking Kyprolis, and for 30 days after stopping treatment, you must use an appropriate contraceptive method to ensure that you do not become pregnant. You should consult with your doctor or nurse about suitable contraceptive methods.

Inform your doctor or nurse immediately if you become pregnant while receiving Kyprolis.

Do not take Kyprolis if you are breastfeeding. It is unknown whether Kyprolis is excreted in breast milk.

Lenalidomide is expected to be harmful to the fetus. Kyprolis is administered in combination with lenalidomide, so you should follow the Pregnancy Prevention Program (see the lenalidomide leaflet for information on pregnancy prevention and discuss with your doctor, pharmacist, or nurse).

For men taking Kyprolis

While taking Kyprolis, and for 90 days after stopping treatment, you must use a condom, even if your partner is pregnant.

Inform your doctor or nurse immediately if your partner becomes pregnant while receiving Kyprolis or 90 days after stopping treatment.

Driving and operating machinery

While receiving treatment with Kyprolis, you may experience fatigue, dizziness, fainting, and/or low blood pressure. This may affect your ability to drive or operate machinery. Do not drive or operate machinery if you experience these symptoms.

Kyprolis contains sodium

This medicine contains 37 mg of sodium per 10 mg vial. This is equivalent to 1.9% of the maximum daily sodium intake of 2 g recommended for an adult

This medicine contains 109mg of sodium per 30mg vial. This is equivalent to 5.5% of the maximum daily sodium intake of 2g recommended for an adult.

This medicine contains 216mg of sodium per 60mg vial. This is equivalent to 11% of the maximum daily sodium intake of 2g recommended for an adult.

Kyprolis contains cyclodextrin

This medicine contains 500mg of cyclodextrin (sulfobutyl ether beta‑cyclodextrin sodium) in each 10mg vial equivalent to 88mg/kg for an adult of 70kg.

This medicine contains 1,500mg of cyclodextrin (sulfobutyl ether beta‑cyclodextrin sodium) in each 30mg vial equivalent to 88mg/kg for an adult of 70kg.

This medicine contains 3,000mg of cyclodextrin (sulfobutyl ether beta‑cyclodextrin sodium) in each 60mg vial equivalent to 88mg/kg for an adult of 70kg

Your doctor or nurse will administer Kyprolis. The dose will be calculated based on your height and weight (body surface area). Your doctor or nurse will determine the dose of Kyprolis you receive.

You will receive Kyprolis through a vein infusion. The infusion may last up to 30 minutes. Kyprolis is given 2 days in a row each week, for 3 weeks, followed by a week without treatment.

Each 28-day period is a treatment cycle. This means that Kyprolis will be administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. If you receive treatment with Kyprolis in combination with lenalidomide and dexamethasone, the doses on days 8 and 9 of each cycle will not be administered starting from cycle 13.

Most patients will receive treatment while their disease improves or remains stable. However, treatment with Kyprolis should also be discontinued if you experience adverse effects that cannot be controlled.

In combination with Kyprolis, you will also receive lenalidomide and dexamethasone,daratumumab and dexamethasone,or only dexamethasone. You may also receive other medications.

If you take more Kyprolis than you should

This medication will be administered by a doctor or nurse, so it is unlikely that you will receive more than you should. However, if you receive more Kyprolis than you should, your doctor will monitor you for adverse effects.

If you have any doubts about using this medication, consult your doctor or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Signs and symptoms to be aware of

Some side effects can be serious. Inform your doctor immediatelyif

you experience any of the following symptoms:

• Chest pain, difficulty breathing, or swelling in the feet, which can be symptoms of heart problems
• Respiratory difficulties, including difficulty breathing at rest or with activity or cough (dyspnea), rapid breathing, feeling unable to breathe when there is enough oxygen, wheezing (breathing sounds) or cough, which can be signs of pulmonary toxicity
• Very high blood pressure, intense chest pain, severe headache, confusion, blurred vision, nausea and vomiting, or anxiety attack, which can be signs of a condition known as hypertensive crisis
• Difficulty breathing during daily activities or at rest, irregular heartbeat,
• accelerated pulse, fatigue, dizziness, and fainting, which can be signs of a condition known as pulmonary hypertension
• Swelling in the ankles, feet, or hands, loss of appetite, decreased urine output, or abnormal results in blood tests, which can be symptoms of kidney problems or renal insufficiency
• A side effect known as Tumor Lysis Syndrome, which can be caused by the rapid breakdown of tumor cells and produce irregular heartbeats, renal insufficiency, or abnormal results in blood tests
• Fever, chills, or shivering, joint pain, muscle pain, facial congestion, or swelling,of the face, lips, tongue, and/or throat that can cause difficulty breathing or swallowing (angioedema),weakness, difficulty breathing, low blood pressure, fainting, low heart rate, chest tightness, or chest pain that may occur as a reaction to infusion
• Unusual bruising or bleeding, such as a cut that takes longer than usual to stop bleeding; or internal bleeding such as coughing up blood, vomiting blood, black stools, or stools with bright red blood; or cerebral hemorrhage that induces sudden numbness or paralysis on one side of the face, legs, or arms, severe headache, or difficulty seeing or speaking or difficulty swallowing (dysphagia)
• Pain in the legs or arms or swelling (which could be symptoms of the presence of blood clotsin the deep veins of the legs or arms), chest pain, or difficulty breathing (which could be symptoms of the presence of blood clots in the lungs)
• Yellowing of the skin and eyes (jaundice), abdominal pain or swelling, nausea, or vomiting, which could be symptoms of liver problems, including liver failure. If you have ever had a hepatitis B virus infection, treatment with this medicine can cause the hepatitis B virus infection to become reactivated.
• Bleeding, bruising, weakness, confusion, fever, nausea, vomiting, and acute renal failure, which can be signs of a blood disorder known as microangiopathic thrombosis
• Headaches, confusion, seizures (convulsions), vision loss, and high blood pressure (hypertension), which can be symptoms of a neurological disorder known as posterior reversible encephalopathy syndrome (PRES)

Other possible side effects

Frequent side effects (can affect more than 1 in 10 people)

• Severe lung infection (pneumonia)
• Respiratory tract infection (respiratory tract infection)
• Low platelet count, which can cause bruising or bleeding (thrombocytopenia)
• Low white blood cell count, which can decrease your ability to fight infections and be associated with fever
• Low red blood cell count (anemia), which can cause fatigue and weakness
• Changes in blood tests (decreased potassium levels, increased creatinine levels)
• Loss of appetite
• Difficulty sleeping (insomnia)
• Headache
• Numbness, tingling, or decreased sensitivity in the hands and/or feet
• Dizziness
• High blood pressure (hypertension)
• Difficulty breathing
• Cough
• Diarrhea
• Nausea
• Constipation
• Vomiting
• Abdominal pain
• Back pain
• Joint pain
• Pain in the extremities, hands, or feet
• Muscle spasms
• Fever
• Chills
• Swelling of the hands, feet, or ankles
• Weakness
• Fatigue (weakness)

Frequent side effects (can affect up to 1 in 10 people)

• Infusion reactions
• Heart failure and cardiac problems, including rapid, strong, or irregular heartbeats
• Heart attack
• Kidney problems, including renal insufficiency
• Deep vein thrombosis (blood clots in the veins)
• Angina
• Blood clots in the lungs
• Pulmonary edema
• Wheezing (breathing sounds)
• Severe infection, including sepsis
• Lung infection
• Liver problems, including increased liver enzymes in the blood
• Flu-like symptoms (grippe)
• Reactivation of the varicella virus, which can cause a skin rash and pain (herpes zoster)
• Urinary tract infection (infection of the structures that transport urine)
• Cough that may include chest tightness or pain, nasal congestion (bronchitis)
• Sore throat
• Inflammation of the nose and throat
• Runny nose, nasal congestion, or sneezing
• Viral infection
• Gastroenteritis (infection of the stomach and intestines)
• Bleeding in the stomach and intestines
• Changes in blood tests (decreased sodium, magnesium, protein, calcium, or phosphate levels, increased calcium, uric acid, potassium, bilirubin, or C-reactive protein or sugar levels)
• Dehydration
• Anxiety
• Confusion
• Blurred vision
• Cataracts
• Low blood pressure (hypotension)
• Nasal bleeding
• Changes in voice or hoarseness
• Indigestion
• Toothache
• Skin rash
• Bone pain, muscle pain, and chest pain
• Weakness of the muscles
• Muscle pain
• Itching of the skin
• Redness of the skin
• Increased sweating
• Pain
• Pain, swelling, irritation, or discomfort at the site of intravenous injection
• Tinnitus (ringing in the ears)
• Sensation of being unwell or general malaise

Rare side effects (can affect up to 1 in 100 people)

• Bleeding in the lungs
• Colitis caused by the bacteriaClostridium difficile
• Allergic reaction to Kyprolis
• Multi-organ failure
• Reduced blood flow to the heart
• Cerebral hemorrhage
• Cerebral infarction
• Difficulty breathing, rapid breathing, and/or the fingertips of the hands and lips slightly blue (acute respiratory distress syndrome)
• Swelling of the heart lining (pericarditis), symptoms include chest pain, sometimes spreading to the neck and shoulders, sometimes with fever
• Accumulation of fluid in the heart lining (pericardial effusion), symptoms include chest pain or pressure and difficulty breathing
• Obstruction of bile flow from the liver (cholestasis), which can cause itching of the skin, yellowing of the skin, dark urine, and pale stools
• Perforation of the digestive tract
• Cytomegalovirus infection
• Reactivated hepatitis B virus infection (inflammation of the liver)
• Pancreatitis

Reporting side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse,even if it is a possible side effect that does not appear in this leaflet.

You can also report them directly through the national notification system included in theAppendix V.Mediante the reporting of side effects, you can contribute to providing more information on the safety of this medicine.

Kyprolis will be stored in the pharmacy.

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

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

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

Do not freeze.

Store the product in the original packaging to protect it from light.

The reconstituted product must be a transparent solution, between colorless and slightly yellowish, and should not be administered if a color alteration or the presence of particles is observed.

Kyprolis is intended for single use only. The disposal of unused medication and all materials that have been in contact with it will be carried out in accordance with local regulations.

Composition of Kyprolis

• The active ingredient is carfilzomib. Each vial contains 10 mg, 30 mg or 60 mg of carfilzomib.

• After reconstitution, 1 ml of solution contains 2 mg of carfilzomib.
• The other components are sulfobutyl ether beta-cyclodextrin sodium, anhydrous citric acid (E330) and sodium hydroxide (see section 2 “Kyprolis contains sodium”).

Appearance of the product and contents of the pack

Kyprolis is supplied in a glass vial as a white to off-white powder for solution for infusion, which is reconstituted (dissolved) before use. The reconstituted solution is a transparent, colourless or slightly yellowish solution.

Each pack contains 1 vial.

Marketing authorisation holder and responsible manufacturer

Amgen Europe B.V.

Minervum 7061,

4817 ZK Breda,

Netherlands

Marketing authorisation holder

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

Netherlands

Manufacturer

Amgen Technology (Ireland) Unlimited Company

Pottery Road

Dun Laoghaire

Co Dublin

Ireland

Manufacturer

Amgen NV

Telecomlaan 5-7

1831 Diegem

Belgium

For further information about this medicinal product, please consult the representative of the marketing authorisation holder in your country.

Last update of the summary of product characteristics

Other sources of information

The detailed information on this medicinal product is available on the website of the European Medicines Agency:http://www.ema.europa.eu.

This website also contains the summary of product characteristics in all languages of the European Union/European Economic Area.

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This information is intended for healthcare professionals only:

Instructions for reconstitution and preparation of Kyprolis powder for solution for infusion for intravenous administration

Carfilzomib is a cytotoxic agent. Therefore, Kyprolis must be handled and prepared with caution. The use of gloves and other protective equipment is recommended.

The vials of Kyprolis do not contain antimicrobial preservatives and are intended for single use only. Appropriate aseptic technique should be applied.

The reconstituted solution contains carfilzomib at a concentration of 2 mg/ml. Read the complete preparation instructions before reconstitution.

1. Calculate the dose (mg/m2) and the number of vials of Kyprolis required, taking into account the patient's basal body surface area (BBSA). Patients with a BBSA greater than 2.2m2should receive a dose based on a BBSA of 2.2m2. No dose adjustment is necessary for weight changes ≤20%.

1. Remove the vial from the refrigerator just before use.
2. Use exclusively a 21 G or larger gauge needle (external diameter of the needle ≤0.8 mm) to reconstitute each vial aseptically by injecting slowly 5 ml (for the 10 mg vial), 15 ml (for the 30 mg vial) or 29 ml (for the 60 mg vial) of sterile water for injection through the stopper and directing the solution towards the INNER WALL OF THE VIAL to minimize foam formation.

1. Gently and slowly rotate and/or invert the vial for approximately 1 minute, or until dissolution is complete. DO NOT AGITATE. If foam forms, allow the solution to settle in the vial until foam decreases (approximately 5 minutes) and the solution is transparent.

1. Visually inspect for particles and colour changes before administration. The reconstituted product should be a transparent, colourless or slightly yellowish solution and should not be administered if colour change or particle presence is observed.

1. Discard any unused portion remaining in the vial.

1. Kyprolis can be administered directly as intravenous infusion or, optionally, in a 50 or 100 ml intravenous bag. It should not be administered as a bolus or pulse intravenous injection.

1. When administered in an intravenous bag, use exclusively a 21 G or larger gauge needle (external diameter of the needle ≤0.8 mm) to extract the calculated dose from the vial and dilute in a 50 or 100 ml intravenous bag with 5% glucose solution.

From a microbiological point of view, the product should be used immediately. If not used immediately, the storage conditions in use and the time period before use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C.

The disposal of unused medicinal product and of all materials that have been in contact with it should be in accordance with local requirements.