Cyramza 10 mg/ml concentrado para solucion para perfusion

Patient Information Leaflet: Information for the Patient

Cyramza 10 mg/ml Concentrate for Solution for Infusion

ramucirumab

Read this 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, consult your doctor.
• If you experience any side effects, consult your doctor, even if they are not listed in this leaflet. See section 4.

Table of Contents

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

Cyramza is a cancer medication that contains ramucirumab as its active ingredient, which is a monoclonal antibody. It is a specialized protein that can recognize and bind to another protein found in blood vessels called the "VEGF type 2 receptor". This receptor is necessary for the development of new blood vessels. For growth, cancer needs to develop new blood vessels. By binding and blocking the "VEGF type 2 receptor", the medication interrupts blood supply to cancer cells.

Cyramza is also used in combination with paclitaxel, another anticancer medication, for the treatment of advanced stomach cancer (or cancer of the junction between the esophagus and stomach) in adults whose disease has worsened after treatment with cancer medications.

Cyramza is used for the treatment of advanced stomach cancer (or cancer of the junction between the esophagus and stomach) in adults whose disease has worsened after treatment with cancer medications and for whom Cyramza treatment in combination with paclitaxel is not suitable.

Cyramza is used for the treatment of colon or rectal cancer (parts of the large intestine) in adults. It is administered with another medication called "FOLFIRI", which includes "5-fluorouracil", "folic acid", and "irinotecan".

Cyramza is administered in combination with erlotinib, another anticancer medication, as first-line therapy for the treatment of adult patients with advanced non-small cell lung cancer when tumor cells have specific changes (mutations) in the epidermal growth factor receptor gene.

Cyramza is administered in combination with docetaxel, another anticancer medication, for the treatment of adult patients with advanced lung cancer whose disease has worsened after treatment with cancer medications.

Cyramza is used to treat advanced liver cancer that is advanced or cannot be removed by surgery, in adults who have been previously treated with another cancer medication (sorafenib) and who have a high level of a specific protein in the blood (alpha fetoprotein).

No use Cyramza:

• if you are allergic to ramucirumab or any of the other ingredients in this medicine (listed in section 6).
• if X-rays show signs that the lung cancer has a cavity or hole or if the lung cancer is attached to major blood vessels.

Warnings and precautions

Consult your doctor or nursebeforestarting to use Cyramza if:

• you have a disease that increases the risk of bleeding. Also, consult your doctor if you are taking other medicines that increase the risk of bleeding or affect blood clotting. In these cases, your doctor will perform regular blood tests to control the risk of bleeding.

• you have liver cancer and have had previous bleeding from varices in your digestive tract (esophagus) or have portal hypertension, which carries blood from the intestine and spleen to the liver.

• you have lung cancer and have had recent bleeding in the lungs (coughing up bright red blood) or are taking continuous nonsteroidal anti-inflammatory drugs or medicines that affect blood clotting.

• you have high blood pressure. Cyramza may increase the appearance of high blood pressure. Your doctor will ensure that if you already have high blood pressure, it must be under control before starting treatment with Cyramza. During treatment with Cyramza, your doctor will monitor your blood pressure and adjust antihypertensive medication if necessary. Treatment with Cyramza may be temporarily interrupted until high blood pressure is controlled with medication or permanently interrupted if it cannot be controlled adequately.

• you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in the wall of a blood vessel.

• you are to be operated on, if you have been recently operated on or if after the operation your wound is not healing well. Cyramza may increase the risk of problems with wound healing. Do not receive Cyramza for at least 4 weeks before the scheduled operation and your doctor will decide when to resume treatment. If during treatment you have a wound that is not healing well, the dose of Cyramza will be interrupted until the wound is fully healed.

• you have severe liver disease (“cirrhosis”) and associated diseases such as excessive fluid accumulation in your abdomen (“ascites”). Your doctor will comment on whether the potential benefits of treatment justify the increased risk for you. If you have liver cancer, your doctor will monitor signs and symptoms of confusion and/or disorientation associated with chronic liver problems and suspend treatment with Cyramza if you develop those signs and symptoms.

• you have severe kidney problems. Available data on the use of Cyramza in patients with severe renal dysfunction are limited.

Consult your doctor or nurseimmediatelyif any of the following statements affect you (or you are unsure)during treatmentwith Cyramzaor at any other time:

• Blockage of arteries by a blood clot(“arterial thromboembolic disease”):

Cyramza may cause a blood clot in your arteries. Blood clots in arteries can cause serious diseases, including heart attack or stroke. Symptoms of heart attack may include chest pain or discomfort. Symptoms of stroke may include sudden numbness or weakness in the arm, leg, or face, confusion, difficulty speaking or understanding others, sudden difficulty walking or loss of balance or coordination, or sudden dizziness or loss of balance. If you develop a blood clot in your arteries, treatment with Cyramza will be permanently interrupted.

• Perforation of the intestinal wall(“gastrointestinal perforation”): Cyramza may increase therisk of developing perforations in the wall of your intestine. Symptoms may include severe abdominal pain, vomiting, fever, or chills. If you develop a perforation in the intestinal wall, treatment with Cyramza will be permanently interrupted.

• Severe bleeding:Cyramza may increase the risk of severe bleeding. Symptoms may

include: extreme fatigue, weakness, dizziness, or changes in the color of your stools. If you experience severe bleeding, treatment with Cyramza will be permanently interrupted.

• Reactions related to infusion:may occur reactions related to infusionduring treatment, due to the fact that Cyramza is administered through intravenous infusion by drip (see section 3). Your doctor or nurse will monitor the appearance of adverse effects during infusion. Symptoms may include: muscle tension, back pain, chest pain, or discomfort, chills, redness, difficulty breathing, wheezing, and a sensation of numbness or tingling in your hands or feet. In severe cases, symptoms may include difficulty breathing caused by narrowing of the airways, rapid pulse, and a sensation of fainting. If you experience a severe reaction related to infusion, treatment with Cyramza will be permanently interrupted.

• A rare but serious brain disease called “posterior reversible encephalopathy syndrome” or “PRES” (in English):Cyramza may increase the risk of developing this brain disease. Symptoms may include seizures (convulsions), headache, feeling sick (nausea), vomiting, blindness, or decreased level of consciousness, with or without high blood pressure. Interrupt treatment with Cyramza if you experience this brain disease.

• Heart failure:Cyramza, when administered in combination with chemotherapy or erlotinib, may increase the risk of heart failure. Symptoms may include weakness and fatigue, swelling and fluid accumulation in the lungs, which may cause difficulty breathing. Your symptoms will be evaluated, and treatment with Cyramza may be considered for suspension.

• Abnormal channels in the body(“fistula”): Cyramza may increase the risk ofdevelopment of abnormal channels in the body between internal organs and the skin or other tissues. If you develop a fistula, treatment with Cyramza will be permanently interrupted.

• Abnormal urine test(“proteinuria”): Cyramza may increase the risk of developing orworsening abnormal levels of protein in urine. Treatment with Cyramza may need to be interrupted temporarily until protein levels in urine decrease and then resumed at lower doses, or permanently interrupted if protein levels in urine do not decrease sufficiently.

• Mouth inflammation(“stomatitis”): Cyramza, when administered in combination withchemotherapy may increase the risk of developing mouth inflammation. Symptoms may include a burning sensation in the mouth, ulcers, blisters, or inflammation. Your doctor may prescribe treatment to help you with symptoms.

• Fever or infection:During treatment, you may have a temperature of 38°C or higher (sinceyou may have a lower-than-normal number of white blood cells, which is very common). Symptoms may include sweating or other signs of infection, such as headache, pain in the limbs, or decreased appetite. Sepsis could be severe and life-threatening.

• Patients of advanced age with lung cancer:Your doctor will carefully consider the most appropriate treatment for you.

Children and adolescents

Cyramza should not be administered to patients under 18 years of age due to the lack of information on how it works in this age group.

Use of Cyramza with other medicines

Inform your doctor if you are using, have used recently, or may need to use any other medicine. This includes medicines obtained without a prescription and herbal remedies.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medicine. You should avoid becoming pregnant while receiving this medicine and for at least 3 months after receiving the last dose of Cyramza. Consult your doctor about the best contraceptive method for you.

Cyramza prevents the development of new blood vessels, which may decrease the likelihood of becoming pregnant or maintaining a pregnancy. It may also harm the fetus. Do not use this medicine during pregnancy. If you become pregnant during treatment with Cyramza, your doctor will discuss with you whether the benefits of treatment outweigh any possible risk to you or your baby.

It is not known whether the medicine passes into breast milk and may affect the baby. Therefore, do not breastfeed your baby during treatment with Cyramza and for at least 3 months after receiving the last dose.

Driving and operating machines

Cyramza has no or negligible influence on the ability to drive and operate machines. If you experience any symptoms that affect your ability to concentrate and react, do not drive or operate machines until the symptoms disappear.

Cyramza contains sodium

This medicine contains less than 1mmol of sodium (23mg) in each 10ml vial; this is, essentially “sodium-free”.

This medicine contains approximately 85mg of sodium (main component of table salt/for cooking) in each 50ml vial. This is approximately 4% of the maximum daily sodium intake recommended for an adult.

This cancer treatment will be administered by your doctor or nurse.

Dose and administration frequency

The appropriate amount of Cyramza needed to treat your condition will be calculated by your doctor or hospital pharmacist based on your body weight.

The recommended dose of Cyramza for the treatment of stomach cancer, advanced colon or rectal cancer, and liver cancer is 8 mg per kilogram of body weight every 2 weeks.

The recommended dose of Cyramza for the treatment of lung cancer is 10 mg per kilogram of body weight every 2 weeks when administered in combination with erlotinib or every 3 weeks when administered in combination with docetaxel.

The number of infusions you will receive will depend on how you are responding to treatment. Your doctor will discuss this with you.

Previous medication

You may receive another medication to reduce the risk of infusion-related reactions before receiving Cyramza. If you experience an infusion-related reaction during treatment with Cyramza, you will receive previous medication for all subsequent infusions.

Dose adjustment

During each infusion, your doctor or nurse will check for any adverse effects.

If you experience an infusion-related reaction during treatment, the final duration of the infusion will be increased for the remainder of that infusion and for subsequent infusions.

Your urine protein levels will be checked regularly during treatment. Cyramza may be temporarily interrupted based on the measurement of protein levels in your urine. Once your urine protein levels have decreased to certain levels, treatment may be resumed at a lower dose.

Route and form of administration

Cyramza is a concentrate for solution for infusion (also known as "sterile concentrate"). A hospital pharmacist, nurse, or doctor will dilute the contents of the vial in a sodium chloride 9 mg/ml (0.9%) solution before use. This medication is administered via infusion over approximately 60 minutes.

Treatment with Cyramza will be temporarily interrupted if:

• You have high blood pressure, until it is controlled with antihypertensives.

• You have difficulty healing wounds, until the wound heals.
• You are scheduled for surgery, 4 weeks before the procedure.

Treatment with Cyramza will be permanently discontinued if:

• You experience a thrombus in your arteries.
• You experience a perforation in the wall of your intestine.
• You experience severe bleeding.

• You experience a severe infusion-related reaction.
• You have high blood pressure that cannot be controlled with medication.

• You are excreting an excessive amount of protein in your urine or have a severe kidney disease (nephrotic syndrome).
• You have an abnormal fistula in your body between internal organs and the skin or other tissues.
• You develop confusion and/or disorientation associated with chronic liver disease.

• You experience a decrease in renal function (in the context of liver insufficiency).

When receiving Cyramza in combination with paclitaxel or docetaxel

Paclitaxel and also docetaxel are administered via intravenous infusion over a period of approximately 60 minutes. If you receive Cyramza in combination with paclitaxel or docetaxel on the same day, Cyramza will be administered first.

The amount of paclitaxel or docetaxel needed will depend on your body surface area. Your doctor or hospital pharmacist will calculate your body surface area by measuring your height and weight and calculate the appropriate dose for you.

The recommended dose of paclitaxel is 80 mg per square meter (m²) of your body surface area once a week for 3 weeks followed by 1 week without treatment.

The recommended dose of docetaxel is 75 mg per square meter (m²) of your body surface area once every 3 weeks. If you are of Asian descent, you may receive a reduced starting dose of docetaxel of 60 mg per m² of your body surface area once every 3 weeks.

Before starting any infusion with paclitaxel, a blood test will be performed to check that your blood cell count is sufficient and that your liver is functioning correctly.

Please read the package insert for paclitaxel or docetaxel for more information.

When receiving Cyramza in combination with FOLFIRI

FOLFIRI chemotherapy is administered via intravenous infusion after the Cyramza infusion is complete. Please read the package insert for the other medications that are part of your treatment to check if they are suitable for you. If you are unsure, consult your doctor, pharmacist, or nurse if there is any reason why you cannot use these medications.

When receiving Cyramza in combination with erlotinib

Please read the package insert for erlotinib for more information about erlotinib and check if it is suitable for you. If you are unsure, ask your doctor, pharmacist, or nurse if there is any reason why you cannot take erlotinib.

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

Consult your doctorimmediatelyif you experience any of the following severe side effects that have been observed during treatment with Cyramza (see alsoWhat you need to know before starting to use Cyramza):

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

• Intestinal wall perforation:A perforation that develops in the stomach or intestine.The symptoms include severe abdominal pain, vomiting, fever, or chills.
• Severe intestinal bleeding:The symptoms may include extreme fatigue, weakness, dizziness, or changes in your stool.
• Arterial thrombosis:Thrombi in the arteries can cause a heart attack or cerebral embolism.The symptoms of a heart attack may include chest pain or pressure.The symptoms of a cerebral embolism may include sudden numbness or weakness of the arm, leg, or face, confusion, difficulty speaking or understanding others, sudden difficulty walking or loss of balance or coordination, or sudden dizziness.

Rare side effects(may affect up to 1 in 1,000 people):

• A brain disease called reversible posterior leukoencephalopathy syndrome:The symptoms may include seizures, headache, feeling sick (nausea), vomiting, blindness, or decreased level of consciousness, with or without high blood pressure.

Consult your doctor if you experience any of the following side effects:

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

• Extreme fatigue or weakness
• Low white blood cell count in the blood (may increase the risk of infection)

• Infections
• Diarrhea

• Hair loss
• Nosebleeds
• Inflammation of the inside of the mouth

• High blood pressure
• Reduced number of red blood cells that may cause pale skin

• Swelling of hands, feet, and legs due to fluid retention

• Low platelet count (blood cells that help blood to clot)

• Abdominal pain
• Protein in the urine (abnormal urine test)
• Headache

• Inflammation of mucous membranes, such as the digestive and respiratory tracts

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

• Fever accompanied by low white blood cell count
• Low levels of a protein called albumin in the blood

• Reactions related to the infusion site
• Rash
• Erythema, inflammation, numbness/tingling, or pain and/or peeling of the skin on the hands and/or feet (called hand-foot syndrome)
• Hoarseness

• Bleeding in the lungs
• Low sodium levels in the blood (hyponatremia) that may cause fatigue and confusion or muscle spasms
• Bleeding gums
• Confusion and/or disorientation in patients with chronic liver disease

• Intestinal obstruction; the symptoms may include constipation and abdominal pain
• Underactive thyroid gland that may cause fatigue or weight gain (hypothyroidism)
• Abnormal growth of blood vessels
• Severe infections (sepsis)

• Low potassium levels in the blood (hypokalemia) that may cause muscle weakness, spasms, or abnormal heart rhythm

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

• Cardiac condition in which the heart muscle does not pump blood as well as it should, causing difficulty breathing and swelling of the legs and feet

Rare side effects(may affect up to 1 in 1,000 people):

• Abnormal blood clotting in small blood vessels

Unknown frequency(the frequency cannot be estimated from the available data):

• Increased and weakened wall of a blood vessel or tearing of the wall of a blood vessel (aneurysms and arterial dissections)

Cyramza may cause changes in laboratory tests. These changes may be, among the side effects mentioned earlier: low white blood cell count, low platelet count, low albumin, potassium, or sodium levels in the blood, presence of protein in the urine.

Reporting of side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information about the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the carton and vial label after CAD. 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 vial in the outer packaging to protect it from light.

Do not freeze or shake the infusion solution. Do not administer the solution if you notice any particles or an unusual color.

Medicines should not be disposed of through drains or trash. Ask your pharmacist how to dispose of the containers and medications you no longer need. This will help protect the environment.

Composition of Cyramza

• The active ingredient is ramucirumab. One milliliter of the concentrate for solution for infusion contains 10 mg of ramucirumab.
• Each vial of 10 ml contains 100 mg of ramucirumab.
• Each vial of 50 ml contains 500 mg of ramucirumab.
• The other components are histidine, monohydrochloride of histidine, sodium chloride, glycine (E640), polysorbate 80 (E433) and water for injection (see section 2 “Cyramza contains sodium”).

Appearance of the product and contents of the pack

The concentrate for solution for infusion (or sterile concentrate) is a transparent to slightly opalescent solution with a colorless to slightly yellowish tint that is presented in a glass vial with a rubber stopper.

Cyramza is available in packs of:

• 1 vial of 10 ml

• 2 vials of 10 ml
• 1 vial of 50 ml

Only some pack sizes may be marketed.

Marketing Authorization Holder

Eli Lilly Nederland B.V.

Papendorpseweg 83

3528 BJ Utrecht

Netherlands

Responsible for manufacturing

Lilly, S.A.

Avda de la Industria, 30

Alcobendas

28108 Madrid

Spain

Lilly France Fegersheim

2 rue du Colonel Lilly

67640 Fegersheim

France

Further information on this medicinal product can be obtained by contacting the local representative of the marketing authorization holder:

Belgique/België/BelgienLietuva

Eli Lilly Benelux S.A./N.V.Eli Lilly Lietuva

Tél/Tel: + 32-(0)2 548 84 84Tel. +370 (5) 2649600

????????Luxembourg/Luxemburg

?? "??? ???? ?????????" ?.?. - ????????Eli Lilly Benelux S.A./N.V.

???. + 359 2 491 41 40Tél/Tel: + 32-(0)2 548 84 84

Ceská republikaMagyarország

ELI LILLY CR, s.r.o.Lilly Hungária Kft.

Tel: + 420 234 664 111Tel: + 361 328 5100

DanmarkMalta

Eli Lilly Danmark A/SCharles de Giorgio Ltd.

Tlf: +45 45 26 60 00Tel: + 356 25600 500

DeutschlandNederland

Lilly Deutschland GmbHEli Lilly Nederland B.V.

Tel. + 49-(0) 6172 273 2222Tel: + 31-(0) 30 60 25 800

EestiNorge

Eli Lilly Nederland B.V.Eli Lilly Norge A.S.

Tel: +372 6 817 280Tlf: + 47 22 88 18 00

Ελλ?δαÖsterreich

ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε.Eli Lilly Ges.m.b.H.

Τηλ: +30 210 629 4600Tel: + 43-(0) 1 711 780

EspañaPolska

Lilly S.A.Eli Lilly Polska Sp. z o.o.

Tel: + 34-91 663 50 00Tel: +48 22 440 33 00

FrancePortugal

Lilly France SASLilly Portugal Produtos Farmacêuticos, Lda

Tél: +33-(0) 1 55 49 34 34Tel: + 351-21-4126600

HrvatskaRomânia

Eli Lilly Hrvatska d.o.o.Eli Lilly România S.R.L.

Tel: +385 1 2350 999Tel: + 40 21 4023000

IrelandSlovenija

Eli Lilly and Company (Ireland) LimitedEli Lilly farmacevtska družba, d.o.o.

Tel: + 353-(0) 1 661 4377Tel: +386 (0)1 580 00 10

ÍslandSlovenská republika

Icepharma hf.Eli Lilly Slovakia s.r.o.

Sími + 354 540 8000Tel: + 421 220 663 111

ItaliaSuomi/Finland

Eli Lilly Italia S.p.A.Oy Eli Lilly Finland Ab

Tel: + 39- 055 42571Puh/Tel: + 358-(0) 9 85 45 250

Κ?προςSverige

Phadisco LtdEli Lilly Sweden AB

Τηλ: +357 22 715000Tel: + 46-(0) 8 7378800

LatvijaUnited Kingdom

Eli Lilly (Suisse) S.A Parstavnieciba LatvijaEli Lilly and Company Limited

Tel:+371 67364000Tel: + 44-(0) 1256 315000

Revision date of this leaflet:

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.

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This information is intended solely for healthcare professionals:

Do not shake the vial.

Prepare the infusion solution using aseptic techniques to ensure the sterility of the prepared solution.

Each vial is for single use only. Before dilution, check the contents of the vials for the presence of particles or discoloration (the concentrate for infusion solution must be transparent to slightly opalescent and colorless to slightly yellowish without visible particles). If particles or color changes are identified, the vial must be discarded.

Calculate the dose and volume of ramucirumab required to prepare the infusion solution. The vials contain 100 mg or 500 mg in solution at 10 mg/ml of ramucirumab. Use only sodium chloride 9 mg/ml (0.9%) injection solution as a diluent.

In the case of use of a preloaded infusion set for intravenous infusion

According to the calculated volume of ramucirumab, remove the corresponding volume of sodium chloride 9 mg/ml (0.9%) injection solution from the preloaded infusion set for intravenous infusion.

The passage of the calculated volume of ramucirumab to the infusion set for intravenous infusion must be performed aseptically. The final total volume of the infusion set must be 250 ml. The infusion set must be inverted carefully to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-administer with other medications or electrolytes.

In the case of use of an empty infusion set for intravenous infusion

The passage of the calculated volume of ramucirumab to the empty infusion set for intravenous infusion must be performed aseptically. Add a sufficient amount of sodium chloride 9 mg/ml (0.9%) injection solution to the infusion set to achieve a total volume of 250 ml. The infusion set must be inverted carefully to ensure adequate mixing. DO NOT FREEZE OR SHAKE. DO NOT dilute with other solutions or co-administer with other medications or electrolytes.

After dilution and preparation, the medicinal product must be used immediately. If not used immediately, the time and storage conditions prior to use are the responsibility of the user and should not normally exceed 24 hours between 2°C and 8°C.

Parenteral medicines must be visually inspected before administration to discard the presence of particles. If particles are identified, the vial must be discarded.

Dispose of any remaining ramucirumab in the vial as the medicinal product does not contain antimicrobial preservatives.

Administer through a separate infusion pump. A separate infusion line with a low protein-binding filter of 0.22 microns must be used for infusion and the line must be flushed with sodium chloride 9 mg/ml (0.9%) injection solution after infusion is completed.

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