KYPROLIS 30 mg POWDER FOR SOLUTION FOR INFUSION

2. What you need to know before you use Kyprolis

Your doctor will examine you and review your complete medical history. You will be closely monitored during treatment.

Before starting treatment with Kyprolis, and during treatment, you will have blood tests. This will check that you have enough blood cells and that your liver and kidneys are working properly. Your doctor or nurse will check that you are getting enough fluids.

You should read the package leaflet of 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 any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Tell your doctor or nurse before you start using Kyprolis if you have any of the conditions listed below.You may need to have additional tests to check that your heart, kidneys, and liver are working properly.

• 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 when performing activities (dyspnea)
• Kidney problems, including kidney failure, or if you have ever had dialysis
• Liver problems, including a history of hepatitis, fatty liver, or if you have ever been told that your liver is not working properly
• Unusual bleeding, including easy bruising, bleeding due to an injury, 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 stools with bright red blood; or brain bleeding that causes sudden numbness or paralysis on one side of the face, arms, or legs, severe headache, or difficulty seeing or speaking or difficulty swallowing (dysphagia). This may indicate a low platelet count (cells that help blood clot)
• A history of blood clots in your veins
• Pain in your legs or arms or swelling (which could be symptoms of blood clots in the deep veins of your legs or arms), chest pain or difficulty breathing (which could be symptoms of blood clots in the lungs)
• Any other serious illness for which you have been hospitalized or received medication.

Symptoms to look out for

You should be aware of certain symptoms while taking Kyprolis to reduce the risk of problems. Kyprolis may worsen some symptoms or cause serious side effects that can be life-threatening, such as heart problems, lung problems, kidney problems, tumor lysis syndrome (a potentially life-threatening disease that occurs when cancer cells break down and release their contents into the blood), reactions to Kyprolis infusion, bruising or unusual bleeding (including internal bleeding), blood clots in your veins, liver problems, certain blood disorders, or a neurological syndrome known as SEPR. See the 'Signs and symptoms to look out for' section in section 4.

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

At any time during or after treatment, tell your doctor or nurse immediately if you experience blurred vision, loss of vision, or double vision, difficulty speaking, weakness in one arm or leg, a change in the way you walk or problems with balance, persistent numbness, decreased sensitivity, or loss of sensitivity, memory loss, or confusion. These can be symptoms of a potentially life-threatening brain disease known as progressive multifocal leukoencephalopathy (PML). If you had these symptoms before treatment with carfilzomib, tell your doctor about any changes you experience in these symptoms.

Other medicines and Kyprolis

Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription, such as vitamins or herbal medicines.

Tell your doctor or nurse if you are taking medicines used to prevent pregnancy, such as oral contraceptives or other hormonal contraceptives, because they 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 plan to become pregnant. Treatment with Kyprolis has not been studied in pregnant women. While taking Kyprolis, and for 30 days after stopping treatment, you must use a suitable contraceptive method to ensure you do not become pregnant. You should discuss suitable contraceptive methods with your doctor or nurse.

If you become pregnant while receiving Kyprolis, tell your doctor or nurse immediately.

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

Lenalidomide is expected to be harmful to the fetus. Kyprolis is given in combination with lenalidomide, so you must follow the Pregnancy Prevention Programme (see the lenalidomide package leaflet for information on pregnancy prevention and talk to 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.

If your partner becomes pregnant while you are receiving Kyprolis or within 90 days after stopping treatment, tell your doctor or nurse immediately.

Driving and using machines

While receiving treatment with Kyprolis, you may experience fatigue, dizziness, fainting, and/or low blood pressure. This may affect your ability to drive or use machines. Do not drive or use machines if you have 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 intake of 2 g of sodium recommended for an adult.

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

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

Kyprolis contains cyclodextrin

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

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

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

3. How to use Kyprolis

Your doctor or nurse will give you Kyprolis. The dose will be calculated according to 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. 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 you will be given Kyprolis on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. If you are receiving treatment with Kyprolis in combination with lenalidomide and dexamethasone, the doses on days 8 and 9 of each cycle will not be given from cycle 13 onwards.

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

In combination with Kyprolis, you will also be given lenalidomide and dexamethasone, daratumumab and dexamethasone, or alone with dexamethasone. You may also receive other medicines.

If you use more Kyprolis than you should

This medicine will be given 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 side effects.

If you are in doubt about the use of this medicine, ask your doctor or nurse.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Signs and symptoms to which you should pay attention

Some adverse effects can be important. 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 of not being able to breathe when there is enough oxygen, wheezing (noises when breathing) or cough, which can be signs of pulmonary toxicity
• Very high blood pressure, severe chest pain, severe headache, confusion, blurred vision, nausea and vomiting or anxiety attacks, which can be signs of a disorder 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 disorder known as pulmonary hypertension
• Swelling in the ankles, feet or hands, loss of appetite, decreased urine output, or abnormal blood test results, which can be symptoms of kidney problems or kidney failure
• An adverse effect called Tumor Lysis Syndrome, which can be due to the rapid breakdown of tumor cells and produce irregular heartbeats, kidney failure or abnormal blood test results
• Fever, chills or tremors, 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 pressure or chest pain can occur as a reaction to perfusion
• Formation of hematomas or unusual 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 hemorrhages that induce sudden numbness or paralysis on one side of the face, legs or arms, severe headache or difficulty seeing or difficulty speaking or difficulty swallowing (dysphagia)
• Pain in the legs or arms or swelling (which could be symptoms of blood clots in the deep veins of the legs or arms), chest pain or difficulty breathing (which could be symptoms of blood clots in the lungs)
• Yellowish coloration 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 may cause the hepatitis B virus infection to become active again.
• Bleeding, hematomas, weakness, confusion, fever, nausea, vomiting and diarrhea and acute kidney failure, which can be signs of a blood disorder known as thrombotic microangiopathy
• Headaches, confusion, seizures (attacks), visual loss and high blood pressure (hypertension), which can be symptoms of a neurological disorder called posterior reversible encephalopathy syndrome (PRES).

Other possible adverse effects

Very common adverse effects (which may affect more than 1 person in 10)

• Severe lung infection (pneumonia)
• Respiratory tract infection (infection of the airways)
• 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 tiredness
• Changes in blood tests (decrease in blood levels of potassium, increase in blood levels of creatinine)
• Decreased 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
• Stomach 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 (tiredness)

Common adverse effects (which may affect up to 1 in 10 people)

• Perfusion reactions
• Heart failure and heart problems including rapid, strong or irregular heartbeats
• Heart attack
• Kidney problems, including kidney failure
• Blood clots in the veins (deep vein thrombosis)
• Hot flashes
• Blood clots in the lungs
• Fluid in the lungs
• Wheezing (noises when breathing)
• Severe infection, including infection in the blood (sepsis)
• Lung infection
• Liver problems, including increased liver enzymes in the blood
• Flu-like symptoms (flu)
• Reactivation of the varicella virus that can cause a skin rash and pain (herpes zoster)
• Urinary tract infection (infection of the structures that carry urine)
• Cough that may include chest pressure or pain, nasal congestion (bronchitis)
• Sore throat
• Inflammation of the nose and throat
• Runny nose, nasal congestion or sneezing
• Viral infection
• Stomach and intestine infection (gastroenteritis)
• Bleeding in the stomach and intestines
• Changes in blood tests (decrease in blood levels of sodium, magnesium, proteins, calcium or phosphates, increase in blood levels of calcium, uric acid, potassium, bilirubin or C-reactive protein or sugar)
• Dehydration
• Anxiety
• Feeling of confusion
• Blurred vision
• Cataracts
• Low blood pressure (hypotension)
• Nosebleeds
• Changes in voice or hoarseness
• Indigestion
• Toothache
• Skin rash
• Bone pain, muscle pain and chest pain
• Muscle weakness
• Sore muscles
• Itching of the skin
• Redness of the skin
• Increased sweating
• Pain
• Pain, swelling, irritation or discomfort at the injection site
• Ringing in the ears (tinnitus)
• Feeling of being sick or general malaise

Uncommon adverse effects (which may affect up to 1 in 100 people)

• Bleeding in the lungs
• Inflammation in the colon produced by the bacteria Clostridium difficile
• Allergic reaction to Kyprolis
• Multi-organ failure
• Reduced blood flow to the heart
• Cerebral hemorrhage
• Stroke
• Difficulty breathing, rapid breathing and/or blue discoloration of the fingertips and lips (acute respiratory distress syndrome)
• Swelling of the heart lining (pericarditis), symptoms include pain behind the sternum, sometimes spreading to the neck and shoulders, occasionally with fever
• Fluid accumulation in the heart lining (pericardial effusion), symptoms include chest pain or pressure and difficulty breathing
• A blockage of bile flow from the liver (cholestasis), which can cause itching of the skin, yellowish coloration of the skin, dark urine and very pale stools
• Perforation of the digestive tract
• Cytomegalovirus infection
• Reactivated hepatitis B virus infection (viral inflammation of the liver)
• Pancreatitis

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, pharmacist or nurse,even if it is a possible adverse effect that is not listed in this prospectus.

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

5. Storage of Kyprolis

Kyprolis will be stored in the pharmacy.

Keep this medicine out of sight and reach of children.

Do not use this medicine 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 the refrigerator (between 2°C and 8°C).

Do not freeze.

Keep the product in its original packaging to protect it from light.

The reconstituted product must be a transparent solution, between colorless and slightly yellowish, and must 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 medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

6. Package contents and additional information

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 package contents

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

Each package contains 1 vial.

Marketing authorization holder and manufacturer

Amgen Europe B.V.

Minervum 7061,

4817 ZK Breda,

Netherlands

Marketing authorization 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

You can request more information about this medicine by contacting the local representative of the marketing authorization holder.

Date of last revision of this prospectus

Other sources of information

Detailed information about this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu.

On the European Medicines Agency website, this prospectus can be found in all the languages of the European Union/European Economic Area.

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This information is intended only for healthcare professionals:

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

Carfilzomib is a cytotoxic agent. Therefore, Kyprolis should 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. Adequate 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 needed based on the patient's basal body surface area (BSA). Patients with a BSA greater than 2.2 m2 should receive a dose based on a BSA of 2.2 m2. No dose adjustments are necessary for weight changes ≤ 20%.

1. Remove the vial from the refrigerator just before use.

1. Use only a 21 G or larger gauge needle (needle outer diameter of 0.8 mm or less) to reconstitute each vial aseptically by slowly injecting 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 injectable preparations through the stopper and directing the solution to the INNER WALL OF THE VIAL to minimize foam formation.

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

1. Visually inspect for particles and color changes before administration. The reconstituted product must be a transparent solution, between colorless and slightly yellowish, and must not be administered if a color alteration or the presence of particles is observed.

1. Discard any unused portion remaining in the vial.

1. Kyprolis can be administered directly as an intravenous infusion or optionally in an intravenous bag. It must not be administered as an intravenous push or bolus.

1. When administering in an intravenous bag, use only a 21 G or larger gauge needle (needle outer diameter of 0.8 mm or less) to withdraw the calculated dose from the vial and dilute in an intravenous bag of 50 or 100 ml with 5% glucose injectable solution.

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

The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.