Kyprolis

Patient Information Leaflet

Kyprolis 10 mg powder for solution for infusion, 30 mg powder for solution for infusion, 60 mg powder for solution for infusion

carfilzomib
Please read this leaflet carefully before using this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, inform your doctor or nurse. See section 4.

Contents of this leaflet

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

1. What Kyprolis is and what it is used for

Kyprolis is a medicine that contains the active substance carfilzomib.
Carfilzomib works by blocking the proteasome. The proteasome is a system within cells that destroys proteins when they are damaged or no longer needed. By preventing the breakdown of proteins in tumour cells—which typically contain a higher amount of abnormal proteins—Kyprolis causes tumour cells to die.
Kyprolis is used to treat adult patients with multiple myeloma who have received at least one prior therapy for this disease. Multiple myeloma is a cancer that affects plasma cells (a type of white blood cell).
Kyprolis will be given to you in combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasone alone. Daratumumab, lenalidomide and dexamethasone are other medicines used to treat multiple myeloma.

2. What you should know before using Kyprolis

Your doctor will examine and evaluate your complete medical history. During treatment, you will be closely monitored. Before starting Kyprolis and throughout treatment, you will undergo blood tests. These tests are performed to ensure that you have an adequate number of blood cells and that your liver and kidneys are functioning properly. Your doctor or nurse will monitor whether you are receiving enough fluids.
You should read the package leaflet of all the medicines you take in combination with Kyprolis to understand the information about these medicines.
Do not use Kyprolis if you are allergic to carfilzomib or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Before using Kyprolis, speak with your doctor or nurse if you have any of the following conditions. You may need additional tests to check that your heart, kidneys, and liver are functioning properly.

• Heart problems, including a history of chest pain (angina), heart attack, irregular heartbeat, high blood pressure, or if you have ever taken medications for heart conditions
• Lung problems, including a history of shortness of breath at rest or during physical activity (dyspnea)
• Kidney problems, including kidney failure, or if you have ever undergone dialysis
• Liver problems, including a history of hepatitis, fatty liver, or if you have ever been told that your liver is not functioning properly
• Unusual bleeding, including a tendency to bruise easily, prolonged bleeding from wounds (e.g., a cut that takes longer than expected to stop bleeding), internal bleeding such as coughing up blood, vomiting blood, dark tarry stools, blood in stools, or bleeding in the brain causing sudden numbness or paralysis on one side of the face, legs, or arms, sudden severe headache, or problems with vision, speaking, or swallowing. This may indicate that you have a low platelet count (cells that help blood to clot)
• History of blood clots in veins
• Pain or swelling in arms or legs (which may be a sign of deep vein thrombosis), chest pain or shortness of breath (which may be a sign of blood clots in the lungs)
• Any other serious illness for which you have been hospitalized or for which you have received medication

Conditions requiring attention
Be alert for certain symptoms while taking Kyprolis to reduce the risk of complications. Kyprolis may worsen certain conditions or cause serious, potentially fatal side effects, including heart problems, lung problems, kidney problems, tumor lysis syndrome (a potentially fatal condition that occurs when tumor cells break apart and release their contents into the bloodstream), infusion reactions to Kyprolis, unusual bruising or bleeding (including internal bleeding), blood clots in veins, liver problems, certain blood disorders, or a neurological condition known as posterior reversible encephalopathy syndrome (PRES). See "Conditions requiring attention" in section 4.
Inform your doctor if you have ever had a hepatitis B virus infection or if you may currently have one, as this medicine could reactivate the hepatitis B virus. Your doctor will check for signs of this infection before, during, and for some time after treatment with this medicine. Immediately inform your doctor if you feel more tired than usual or if you develop yellowing of the skin or the whites of the eyes.
At any time during or after treatment, immediately inform your doctor or nurse if you experience blurred vision, loss of vision, double vision, difficulty speaking, weakness in one arm or leg, changes in the way you walk, balance problems, persistent numbness, reduced or lost sensation, memory loss, or confusion.
These could all be symptoms of a serious and potentially life-threatening brain condition called Progressive Multifocal Leukoencephalopathy (PML). If you had these symptoms before treatment with carfilzomib, inform your doctor of any changes in these symptoms.

Other medicines and Kyprolis
Inform your doctor if you are taking, have recently taken, or might take any other medicines, including over-the-counter medicines such as vitamin supplements and herbal remedies.
Inform your doctor or nurse if you are taking medications used to prevent pregnancy, such as oral contraceptives or other hormonal contraceptives, as they may not be compatible with use of Kyprolis.

Pregnancy and breastfeeding
For women taking Kyprolis
Do not take Kyprolis if you are pregnant, suspect you may be pregnant, or are planning to have a baby. The use of Kyprolis in pregnant women has not been studied. During treatment with Kyprolis and for 30 days after stopping treatment, you must use an effective method of contraception to prevent pregnancy. You should discuss suitable contraceptive methods with your doctor or nurse.
If you become pregnant during treatment with Kyprolis, inform your doctor or nurse immediately.
Do not take Kyprolis if you are breastfeeding. It is not known whether Kyprolis passes into human breast milk.
Lenalidomide can be harmful to the fetus. When Kyprolis is administered in combination with lenalidomide, the pregnancy prevention program must be followed (see the lenalidomide package leaflet for information on pregnancy prevention and discuss with your doctor, pharmacist, or nurse).

For men taking Kyprolis
While you are 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 taking Kyprolis or within 90 days after stopping treatment, inform your doctor or nurse immediately.

Driving and using machines
During treatment with Kyprolis, you may experience fatigue, dizziness, fainting, and/or low blood pressure. These conditions may impair your ability to drive or operate machinery. Do not drive a vehicle or operate machinery if you experience any of these symptoms.

Kyprolis contains sodium
This medicine contains 37 mg of sodium per 10 mg vial, equivalent to 1.9% of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult.
This medicine contains 109 mg of sodium per 30 mg vial, equivalent to 5.5% of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult.
This medicine contains 216 mg of sodium per 60 mg vial, equivalent to 11% of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult.

Kyprolis contains cyclodextrin
This medicine contains 500 mg of cyclodextrin (sodium sulfobutylether beta-cyclodextrin) per 10 mg vial, equivalent to 88 mg/kg for a 70 kg adult.
This medicine contains 1,500 mg of cyclodextrin (sodium sulfobutylether beta-cyclodextrin) per 30 mg vial, equivalent to 88 mg/kg for a 70 kg adult.
This medicine contains 3,000 mg of cyclodextrin (sodium sulfobutylether beta-cyclodextrin) per 60 mg vial, equivalent to 88 mg/kg for a 70 kg adult.

3. How to use Kyprolis

Kyprolis will be administered by a doctor or nurse. The dose will be calculated based on your height and weight (body surface area). The doctor or nurse will calculate the dose of Kyprolis you will receive.
Kyprolis will be given as an intravenous infusion. The infusion may last up to 30 minutes.
Kyprolis is administered on two consecutive days each week for 3 weeks, followed by 1 week without treatment.
Each 28-day period is considered a treatment cycle. This means that Kyprolis will be administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Doses administered on day 8 and day 9 of each cycle will no longer be given starting from cycle 13 if you are being treated with Kyprolis in combination with lenalidomide and dexamethasone.
Most patients will continue to receive treatment until the disease progresses or remains stable. However, treatment with Kyprolis may also be suspended if you experience adverse reactions that cannot be managed.
Along with Kyprolis, you will also receive either lenalidomide and dexamethasone, daratumumab and dexamethasone, or dexamethasone alone. You may also be given other medications.
If you are given too much Kyprolis
Since this medicine is administered by a doctor or nurse, it is unlikely that you will receive an overdose. However, if this should happen, the doctor will monitor you for any adverse effects.
If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Conditions to watch for
Some side effects can be serious. Immediately contact your doctor if you notice any of the following symptoms:

• Chest pain, shortness of breath or swelling in the feet, which may be symptoms of heart problems
• Difficulty breathing, including shortness of breath at rest or during physical activity, or cough (dyspnea), rapid breathing, feeling of not getting enough air, wheezing, or cough, which may be signs of lung toxicity
• Very high blood pressure, severe chest pain, severe headache, confusion, blurred vision, nausea and vomiting, or severe anxiety, which may be signs of a condition known as hypertensive crisis
• Shortness of breath during daily activities or at rest, irregular heartbeat, rapid heartbeat, fatigue, dizziness and fainting, which may be signs of a condition known as pulmonary hypertension
• Swelling in the ankles, feet or hands, loss of appetite, reduced amount of urine or abnormal blood test results, which may be symptoms of kidney problems or kidney failure
• A side effect called tumour lysis syndrome, which may be caused by the rapid destruction of tumour cells and may lead to irregular heartbeat, kidney failure or abnormal blood test results
• Fever, chills or shivering, joint pain, muscle pain, flushing or swelling of the face, lips, tongue and/or throat, which may cause difficulty breathing or swallowing (angioedema), weakness, shortness of breath, low blood pressure, fainting, slowed heart rate, chest tightness or chest pain, which may occur as an infusion reaction
• Unusual bruising or bleeding, for example a cut that takes longer than usual to stop bleeding, internal bleeding such as coughing up blood, vomiting blood, black tarry stools, or bright red blood in the stools, or bleeding in the brain leading to sudden numbness or paralysis of one side of the face, legs or arms, sudden severe headache or problems with vision, speaking or swallowing
• Pain or swelling in the legs or arms (which may be a symptom of blood clots in the deep veins of the legs or arms), chest pain or shortness of breath (which may be a symptom of blood clots in the lungs)
• Yellowing of the skin and eyes (jaundice), abdominal pain or swelling, nausea or vomiting, which may be symptoms of liver problems, including liver failure. If you have ever had a hepatitis B virus infection, treatment with this medicine may cause reactivation of hepatitis B virus infection
• Bleeding, bruising, weakness, confusion, fever, nausea, vomiting and diarrhoea, and acute kidney failure, which may be possible signs of a blood disorder known as thrombotic microangiopathy
• Headache, confusion, seizures (convulsions), vision loss and high blood pressure (hypertension), which may be possible symptoms of a neurological condition known as reversible posterior encephalopathy syndrome (PRES)

Other possible side effects

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

• Severe lung infection (pneumonia)
• Respiratory tract infection (airway infection)
• Low platelet count, which may cause increased tendency to bruise or bleed (thrombocytopenia)
• Low white blood cell count, which may reduce the body’s ability to fight infections and may be accompanied by fever
• Low red blood cell count (anaemia), which may cause tiredness and fatigue
• Changes in blood test results (low potassium levels in blood, increased creatinine levels in blood)
• Reduced appetite
• Difficulty sleeping (insomnia)
• Headache
• Numbness, tingling, or reduced sensation in the hands and/or feet
• Dizziness
• High blood pressure (hypertension)
• Shortness of breath
• Cough
• Diarrhoea
• Nausea
• Constipation
• Vomiting
• Stomach ache
• Back pain
• Joint pain
• Pain in limbs, hands or feet
• Muscle spasms
• Fever
• Chills
• Swelling of hands, feet or ankles
• Feeling of weakness
• Tiredness (fatigue)

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

• Infusion reaction
• Heart failure and heart problems, including rapid, strong or irregular heartbeat
• Heart attack
• Kidney problems, including kidney failure
• Blood clots in veins (deep vein thrombosis)
• Feeling of excessive warmth
• Blood clots in the lungs
• Fluid in the lungs
• Wheezing
• Severe infection, including blood infection (sepsis)
• Lung infection
• Liver problems, including increased liver enzymes in blood
• Flu-like symptoms (influenza)
• Reactivation of varicella virus which may cause a skin rash and pain (herpes zoster)
• Urinary tract infection (infection of the tubes that carry urine)
• Cough which may include chest tightness or pain, nasal congestion (bronchitis)
• Sore throat
• Inflammation of nose and throat
• Runny nose, nasal congestion or sneezing
• Viral infection
• Stomach and intestinal infection (gastroenteritis)
• Bleeding in the stomach and intestines
• Changes in blood test results (decreased levels of sodium, magnesium, protein, calcium or phosphate in blood, increased levels of calcium, uric acid, potassium, bilirubin, C-reactive protein or blood sugar)
• Dehydration
• Anxiety
• Feeling confused
• Blurred vision
• Cataract
• Low blood pressure (hypotension)
• Nosebleeds
• Voice changes or hoarseness
• Digestive difficulties
• Toothache
• Rash
• Bone, muscle or chest pain
• Muscle weakness
• Sore muscles
• Itchy skin
• Redness of the skin
• Increased sweating
• Pain
• Pain, swelling, irritation or discomfort at the site where the injection was given into the vein
• Ringing in the ears (tinnitus)
• A general feeling of illness or malaise

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

• Bleeding in the lungs
• Inflammation of the colon caused by a bacterium called Clostridium difficile
• Allergic reaction to Kyprolis
• Reduced blood flow to the heart
• Bleeding in the brain
• Stroke
• Difficulty breathing, rapid breathing and/or bluish tint of fingers and lips (acute respiratory distress syndrome)
• Swelling of the membrane surrounding the heart (pericarditis), symptoms include chest pain behind the breastbone, sometimes spreading to the neck and shoulders, sometimes with fever
• Accumulation of fluid in the membrane lining the heart (pericardial effusion), symptoms include chest pain or pressure and shortness of breath
• Blockage in the flow of bile from the liver (cholestasis), which may cause itching, yellowing of the skin, very dark urine and very pale stools
• Bleeding in the stomach and intestines
• Cytomegalovirus infection
• Reactivation of hepatitis B virus infection (viral inflammation of the liver)
• Inflammation of the pancreas

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor, pharmacist or nurse.
You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Kyprolis

Kyprolis will be stored in the pharmacy.
Keep this medicine out of the sight and reach of children.
Do not use Kyprolis after the expiry date stated on the vial and carton. The expiry date refers to the last day of that month.
Store in the refrigerator (2°C - 8°C).
Do not freeze.
Keep in the original packaging to protect from light.
The reconstituted product should be clear, colourless to slightly yellowish, and must not be administered if any change in colour or presence of particles is observed.
Kyprolis is for single use only. Any unused medicine and waste material must be disposed of in accordance with local regulations.

6. Package contents and other information

What Kyprolis contains

• The active substance 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 betadex sulfobutyl ether sodium, anhydrous citric acid (E330) and sodium hydroxide (see section 2 “Kyprolis contains sodium”).

Description of the appearance of Kyprolis and contents of the pack
Kyprolis is supplied in a glass vial as a white to off-white powder for solution for infusion, to be reconstituted (dissolved) before use. The reconstituted solution is a clear, colourless or slightly yellowish solution.
Each pack contains 1 vial.

Marketing Authorisation Holder and Manufacturer
Amgen Europe B.V.
Minervum 7061,
4817 ZK Breda,
The Netherlands

Marketing Authorisation Holder
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands

Manufacturer
Amgen Technology (Ireland) Unlimited Company
Pottery Road
Dun Laoghaire
Dublin
Ireland

Manufacturer
Amgen NV
Telecomlaan 5-7
1831 Diegem
Belgium

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
s.a. Amgen n.v. Amgen Switzerland AG Vilniaus filialas
Tel/Tél: +32 (0)2 7752711 Tel: +370 5 219 7474

България Luxembourg/Luxemburg
Амджен България ЕООД s.a. Amgen
Тел.: +359 (0)2 424 7440 Belgique/Belgien
Tel/Tél: +32 (0)2 7752711

Česká republika Magyarország
Amgen s.r.o. Amgen Kft.
Tel: +420 221 773 500 Tel.: +36 1 35 44 700

Danmark Malta
Amgen, filial af Amgen AB, Sverige Amgen B.V.
Tlf: +45 39617500 The Netherlands
Tel: +31 (0)76 5732500

Deutschland Nederland
AMGEN GmbH Amgen B.V.
Tel.: +49 89 1490960 Tel: +31 (0)76 5732500

Eesti Norge
Amgen Switzerland AG Vilniaus filialas Amgen AB
Tel: +372 586 09553 Tel: +47 23308000

Ελλάδα Österreich
Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. Amgen GmbH
Τηλ.: +30 210 3447000 Tel: +43 (0)1 50 217

España Polska
Amgen S.A. Amgen Biotechnologia Sp. z o.o.
Tel: +34 93 600 18 60 Tel.: +48 22 581 3000

France Portugal
Amgen S.A.S. Amgen Biofarmacêutica, Lda.
Tél: +33 (0)9 69 363 363 Tel: +351 21 4220606

Hrvatska România
Amgen d.o.o. Amgen România SRL
Tel: +385 (0)1 562 57 20 Tel: +4021 527 3000

Ireland Slovenija
Amgen Ireland Limited AMGEN zdravila d.o.o.
Tel: +353 1 8527400 Tel: +386 (0)1 585 1767

Ísland Slovenská republika
Vistor hf. Amgen Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 2 321 114 49

Italia Suomi/Finland
Amgen S.r.l. Amgen AB, sivuliike Suomessa/Amgen AB, filial
Tel: +39 02 6241121 i Finland
Puh/Tel: +358 (0)9 54900500

Kύπρος Sverige
C.A. Papaellinas Ltd Amgen AB
Τηλ.: +357 22741 741 Tel: +46 (0)8 6951100

Latvija United Kingdom (Northern Ireland)
Amgen Switzerland AG Rīgas filiāle Amgen Limited
Tel: +371 257 25888 Tel: +44 (0)1223 420305

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency:
http://www.agenziafarmaco.gov.it/
This leaflet is available in all languages of the European Union/European Economic Area on the website of the European Medicines Agency.

The following information is intended exclusively for healthcare professionals:

Instructions for reconstitution and preparation of Kyprolis powder for solution for infusion
for intravenous administration
Carfilzomib is a cytotoxic agent. Therefore, caution must be exercised during handling and
preparation of Kyprolis. The use of gloves and other protective devices is recommended.
Kyprolis vials contain no antimicrobial preservatives and are for single use only. An appropriate aseptic technique must be used.
The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the detailed preparation instructions before reconstitution:

1. Calculate the dose (mg/m²) and the number of Kyprolis vials required using the patient’s baseline body surface area (BSA). Patients with a BSA greater than 2.2 m² should receive a dose calculated on a BSA of 2.2 m². Dose adjustments are not required for weight variations ≤ 20%.
2. Remove the vial from the refrigerator immediately before use.
3. Use only a 21 gauge or larger gauge needle (needle with an outer diameter of 0.8 mm or smaller) to reconstitute each vial using an aseptic technique, 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 injections through the stopper, directing the stream of solution toward the INNER WALL OF THE VIAL to minimize foaming.
4. Gently rotate and/or slowly invert the vial for approximately 1 minute or until complete dissolution. DO NOT SHAKE. If foam forms, allow the solution in the vial to stand until the foam dissipates (approximately 5 minutes) and the solution becomes clear.
5. Visually inspect for the absence of particles and discoloration prior to administration. The reconstituted product should be clear, colourless to slightly yellowish, and should not be administered if discoloration or particulate matter is observed.
6. Discard any unused solution remaining in the vial.
7. Kyprolis may be administered directly via intravenous infusion or alternatively, may be administered using an intravenous infusion bag. Do not administer by rapid intravenous injection or bolus.
8. If administering via an intravenous infusion bag, use only a 21 gauge or larger gauge needle (needle with an outer diameter of 0.8 mm or smaller) to withdraw the calculated dose from the vial and dilute it in a 50 mL or 100 mL intravenous infusion bag containing 5% glucose for injection solution.

From a microbiological standpoint, the product should be used immediately. Otherwise, storage times and conditions during use are the responsibility of the user and must not exceed 24 hours at a temperature of 2°C – 8°C.
Any unused medicinal product and waste materials derived from such medicinal product must be disposed of in accordance with local regulations.