Cyramza

Package leaflet: Information for the user

Cyramza 10 mg/ml concentrate for solution for infusion

ramucirumab
Please read this leaflet carefully before you are given this medicine because it contains important information for you.

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

Contents of this leaflet

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

1. What Cyramza is and what it is used for

Cyramza is an anticancer medicine that contains the active substance ramucirumab, which is a monoclonal antibody. This is a specialised protein able to recognise and bind to another protein found on blood vessels called 'VEGF receptor 2'. This receptor is required for the development of new blood vessels. Cancer needs new blood vessels in order to grow. By binding to 'VEGF receptor 2' and blocking it, the medicine interrupts the blood supply to cancer cells.

Cyramza is given in combination with paclitaxel, another anticancer medicine, for the treatment of advanced gastric carcinoma (or carcinoma of the gastro-oesophageal junction) in adults whose disease has worsened after treatment with other anticancer medicines.

Cyramza is used to treat advanced gastric carcinoma (or carcinoma of the gastro-oesophageal junction) in adults whose disease has worsened after treatment with other anticancer medicines and for whom treatment with Cyramza in combination with paclitaxel is not suitable.

Cyramza is used to treat advanced colorectal carcinoma (cancer of the colon or rectum, parts of the large intestine) in adults. It is given together with other medicines known as 'FOLFIRI chemotherapy', which includes '5-fluorouracil', 'folinic acid', and 'irinotecan'.

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

Cyramza is given in combination with docetaxel, another anticancer medicine, for the treatment of advanced lung cancer in adult patients whose disease has progressed after treatment with other anticancer medicines.

Cyramza is used to treat advanced liver cancer or cancer that cannot be surgically removed in adults who have previously been treated with another anticancer drug (sorafenib) and who have high levels of a particular protein in the blood (alpha-fetoprotein).

2. What you need to know before taking Cyramza

Do not take Cyramza

• if you are allergic to ramucirumab or to any of the other ingredients of this medicine (listed in section 6).
• if there is X-ray evidence that the lung carcinoma has a cavity or excavation within it, or if the lung carcinoma is located near major blood vessels.

Warnings and precautions
Talk to your doctor or nurse before taking Cyramza if you:

• have any condition that increases the risk of bleeding. Also, inform your doctor if you are taking other medicines that may increase the risk of bleeding or interfere with blood clotting. In such cases, your doctor will perform regular blood tests to monitor your risk of bleeding.
• have liver cancer and have previously had bleeding due to enlarged veins in the food pipe (esophagus), or have high blood pressure in the portal vein that carries blood from the intestine and spleen to the liver.
• have lung cancer and have recently had bleeding in the lung (coughing up bright red blood), or are regularly taking non-steroidal anti-inflammatory drugs (NSAIDs), or medicines that interfere with blood clotting.
• have high blood pressure. Cyramza can increase the incidence of high blood pressure. Before starting treatment with Cyramza, your doctor will ensure that, if you already have high blood pressure, it is under control before starting treatment. Your doctor will monitor your blood pressure and, if necessary, adjust your blood pressure medication during treatment with Cyramza. Treatment with Cyramza may need to be temporarily suspended until blood pressure is controlled with medication, or permanently discontinued if blood pressure cannot be adequately controlled.
• have or have had an aneurysm (a bulging and weakening of the wall of a blood vessel) or a tear in the wall of a blood vessel.
• are scheduled to have surgery, have recently had surgery, or have had poor wound healing after surgery. Cyramza may increase the risk of wound healing problems. You must not receive Cyramza for at least four weeks before undergoing planned surgery, and your doctor will decide when to restart treatment. If you have a wound that is healing very slowly during treatment, the dose of Cyramza will be suspended until the wound is fully healed.
• have severe liver disease (“cirrhosis”) and associated conditions, such as excessive fluid accumulation in the abdomen (“ascites”). Your doctor will discuss whether the potential benefits of treatment outweigh the potential risks. If you have liver cancer, your doctor will monitor you for signs and symptoms of confusion and/or disorientation related to chronic liver problems and will stop treatment with Cyramza if you develop these signs and symptoms.
• have severe kidney problems. Limited data are available on the use of Cyramza in patients with severe impairment of kidney function.

Talk to your doctor or nurse immediately if any of the following situations apply to you (or you are unsure) during treatment with Cyramza or at any time afterwards:

• Blockage of arteries caused by a blood clot ('arterial thromboembolic events'): Cyramza can cause blood clots to form in the arteries. Arterial blood clots can lead to serious conditions, including heart attack or stroke. Symptoms of a heart attack may include chest pain and a feeling of heaviness. Symptoms of a stroke may include sudden numbness or weakness in the arm, leg, or face, confusion, difficulty speaking or understanding others, sudden difficulty walking, loss of balance or coordination, or sudden dizziness. Cyramza will be permanently discontinued if an arterial blood clot develops.
• A hole in the intestinal wall ('gastrointestinal perforation'): Cyramza may increase the risk of developing a hole in the intestinal wall. Symptoms include severe abdominal pain, malaise (vomiting), fever, or chills. Cyramza will be permanently discontinued if a hole in the intestinal wall occurs.
• Severe bleeding: Cyramza may increase the risk of severe bleeding. Symptoms may include: extreme tiredness, weakness, dizziness, or changes in the color of your stool. Cyramza will be permanently discontinued if severe bleeding occurs.
• Infusion-related reactions: Infusion-related reactions may occur during treatment, as Cyramza is administered by intravenous infusion (see section 3). Your doctor or nurse will monitor you for side effects during the infusion. Symptoms may include: increased muscle tension, back pain, chest pain and/or chest tightness, chills, flushing, difficulty breathing, wheezing, and tingling or numbness in the hands or feet. In more severe cases, symptoms may include shortness of breath due to narrowing of the airways, rapid heartbeat, and feeling faint. Cyramza will be permanently discontinued if a severe infusion-related reaction occurs.
• A rare but serious brain condition called “reversible posterior encephalopathy syndrome” or “PRES”: Cyramza may increase the risk of developing this brain condition. Symptoms may include seizures, headache, nausea, vomiting, blindness, or reduced levels of consciousness, with or without high blood pressure. Cyramza will be stopped if you develop this brain condition.
• Heart failure: Cyramza, when given in combination with chemotherapy or erlotinib, may increase the risk of heart failure. Symptoms may include weakness and fatigue, swelling and fluid buildup in the lungs causing shortness of breath. Your symptoms will be evaluated and discontinuation of Cyramza treatment may be considered.
• Tube-like connections or abnormal passages in the body ('fistula'): Cyramza may increase the risk of developing tube-like connections or abnormal passages in the body between internal organs and the skin or other tissues. Cyramza will be permanently discontinued if a fistula develops.
• Abnormal urine test ('proteinuria'): Cyramza may increase the risk of developing or worsening abnormal levels of protein in the urine. Treatment with Cyramza may need to be temporarily suspended until protein levels in the urine decrease, after which treatment may be resumed at a lower dose, or permanently discontinued if protein levels do not sufficiently decrease.
• Mouth inflammation ('stomatitis'): Cyramza, when given in combination with chemotherapy, may increase the risk of developing mouth inflammation. Symptoms may include a burning sensation in the mouth, ulceration, blisters, or swelling. Your doctor may prescribe treatment to help manage these symptoms.
• Fever or infection: During treatment, you may develop a temperature of 38°C or higher (due to lower than normal white blood cell counts, which is very common). Symptoms may include sweating or other signs of infection, such as headache, limb pain, or loss of appetite. Infection (sepsis) can be severe and may lead to death.
• Elderly patients with lung cancer: Your doctor will carefully evaluate the most appropriate treatment for you.

Children and adolescents
Cyramza must not be given to patients under 18 years of age, as there is no information on its use in this age group.

Other medicines and Cyramza
Tell your doctor if you are taking, have recently taken, or might take any other medicines.
This includes medicines obtained without a prescription and herbal remedies.

Pregnancy, breastfeeding and fertility
Before starting treatment, you must inform your doctor if you are pregnant, breastfeeding, suspect you may be pregnant, or are planning a pregnancy. You must avoid becoming pregnant while taking this medicine and for at least 3 months after the last dose of Cyramza. Talk to your doctor about the most appropriate contraceptive measures for you.
Since Cyramza inhibits the development of new blood vessels, it may reduce the likelihood of becoming or remaining pregnant. It may also cause harm to the unborn child. You must not use this medicine during pregnancy. If you become pregnant during treatment with Cyramza, your doctor will discuss whether the benefit of treatment outweighs any possible risk to you or the unborn child.
It is not known whether the medicine passes into breast milk and it could harm a breastfed infant. Therefore, breastfeeding is not recommended during treatment with Cyramza and for at least 3 months after the last dose.

Driving and using machines
Cyramza has no or negligible influence on the ability to drive and use machines. However, if symptoms affecting concentration or reaction time occur, do not drive or operate machinery until the effect has passed.

Cyramza contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 10 mL vial, i.e., essentially 'sodium-free'.
This medicine contains approximately 85 mg of sodium (the main component of table salt) per 50 mL vial. This is equivalent to approximately 4% of the maximum daily dietary intake recommended for an adult.

Cyramza contains polysorbate
This medicine contains approximately 1 mg of polysorbate 80 per 10 mL vial and 5 mg of polysorbate 80 per 50 mL vial. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How to use Cyramza

This cancer treatment will be administered by a doctor or nurse.
Dosage and frequency of administration
The correct amount of Cyramza needed to treat the disease will be calculated by your doctor or hospital pharmacist and depends on body weight.
The recommended dose of Cyramza for the treatment of gastric carcinoma, advanced-stage colorectal carcinoma, and hepatocellular carcinoma is 8 mg per kilogram of body weight, administered once every 2 weeks.
The recommended dose of Cyramza for the treatment of lung carcinoma is 10 mg per kilogram of body weight once every 2 weeks when administered in combination with erlotinib, or once every 3 weeks when administered in combination with docetaxel.
The number of infusions you will receive depends on how you respond to treatment. Your doctor will discuss this with you.
Premedication
Before receiving Cyramza, you may be prescribed other medicines to reduce the risk of an infusion-related reaction. If an infusion-related reaction occurs during Cyramza therapy, premedication will be given prior to all subsequent infusions.
Dose adjustments
During each infusion, your doctor or nurse will monitor for adverse effects.
If an infusion-related reaction occurs during treatment, the infusion time will be prolonged for the remainder of that infusion and for all subsequent infusions.
The level of protein in your urine will be monitored regularly during treatment. Depending on the measured protein level, Cyramza may be temporarily withheld. Once the level of protein in the urine has decreased to a certain level, treatment may be resumed at a lower dose.
Method and route of administration
Cyramza is a concentrate for solution for infusion (also called "sterile concentrate"). Before use, a hospital pharmacist, nurse, or doctor will dilute the contents of the vial with sodium chloride 9 mg/mL (0.9%). This medicine is administered by intravenous infusion over approximately 60 minutes.
Cyramza treatment will be temporarily suspended if:

• high blood pressure occurs, until it is controlled with antihypertensive medication;
• wound healing problems occur, until the wound has healed;
• you are scheduled for a planned surgical procedure, four weeks before surgery.

Cyramza treatment will be permanently discontinued if:

• an arterial blood clot occurs;
• a perforation in the intestinal wall occurs;
• a severe bleeding episode occurs;
• a severe infusion-related reaction occurs;
• high blood pressure occurs that cannot be controlled with medication;
• protein levels in the urine increase significantly or if severe kidney disease (nephrotic syndrome) develops;
• abnormal tubular-like connections or passages develop in the body between internal organs and the skin or other tissues (fistulas);
• confusion and/or disorientation occur associated with chronic liver problems;
• worsening of kidney function occurs (in the context of liver dysfunction).

If you receive Cyramza in combination with paclitaxel or docetaxel
Paclitaxel and docetaxel are also administered by intravenous infusion over approximately 60 minutes. If you are receiving Cyramza in combination with paclitaxel or docetaxel on the same day, Cyramza will be administered first.
The amount of paclitaxel or docetaxel required depends on body surface area. Your doctor or hospital pharmacist will calculate body surface area by measuring height and weight and will determine the correct dose.
The recommended dose of paclitaxel is 80 mg per square meter (m²) of body surface area, administered once weekly for 3 weeks, followed by 1 week without treatment.
The recommended dose of docetaxel is 75 mg per m² of body surface area, administered once every 3 weeks. If you are of East Asian origin, you may receive a reduced initial dose of docetaxel of 60 mg per m² of body surface area, administered once every 3 weeks.
Before each paclitaxel infusion, blood tests must be performed to ensure that blood cell counts are sufficiently high and that liver function is adequate.
Please read the package leaflet of paclitaxel or docetaxel for further information.
When receiving Cyramza in combination with FOLFIRI
The FOLFIRI chemotherapy regimen is administered by intravenous infusion after completion of the Cyramza infusion. Please read the package leaflets of the other medicines included in the treatment regimen to determine whether they are suitable for you. If you are unsure, ask your doctor, pharmacist, or nurse whether there is any reason why you should not use these medicines.
When receiving Cyramza in combination with erlotinib
Please read the package leaflet of erlotinib for information about erlotinib and to determine whether it is suitable for you.
If you are uncertain, ask your doctor, pharmacist, or nurse whether there are any other reasons why you cannot use erlotinib.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor immediately if you experience any of the following serious side effects which have been observed during treatment with Cyramza (see also What you must know before taking Cyramza):

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

• hole in the intestinal wall: this is a perforation that develops in the wall of the stomach, small intestine or large intestine. Symptoms include severe abdominal pain, feeling unwell (vomiting), fever or chills.
• severe bleeding in the intestine: symptoms may include extreme tiredness, weakness, dizziness or changes in the colour of the stools.
• blood clots in the arteries: arterial blood clots may lead to heart attack or stroke. Symptoms of a heart attack may include chest pain and a feeling of pressure in the chest. Symptoms of a stroke may include sudden numbness or weakness in the arm, leg or face, confusion, difficulty speaking or understanding others, sudden difficulty walking, loss of balance or coordination, or sudden dizziness.

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

• a brain condition called reversible posterior encephalopathy syndrome: symptoms may include seizures, headache, feeling unwell (nausea), feeling unwell (vomiting), blindness or reduced level of consciousness, with or without high blood pressure.

Tell your doctor if you experience any of the following other side effects:
Very common side effects (may affect more than 1 in 10 patients):

• feeling tired or weak
• low white blood cell count (may increase the risk of infection)
• infections
• diarrhoea
• hair loss
• nosebleeds
• inflammation of the mucous membranes in the mouth
• high blood pressure
• reduction in red blood cells which may cause paleness of the skin
• swelling of the hands, feet and legs due to fluid retention
• low platelet count (blood cells involved in blood clotting)
• abdominal pain
• protein in the urine (abnormal urine test)
• headache
• inflammation of mucous membranes, such as those in the digestive and respiratory tract

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

• fever accompanied by low white blood cell count in the blood
• low levels of a specific protein called albumin
• infusion-related reactions
• skin rash
• redness, swelling, 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 levels of sodium in the blood (hyponatremia), which may cause tiredness and confusion or muscle spasms
• bleeding from the gums
• confusion and/or disorientation in patients with chronic liver problems
• intestinal blockage; symptoms may include constipation and abdominal pain
• underactive thyroid which may cause tiredness or weight gain (hypothyroidism)
• abnormal growth of blood vessels
• severe infection (sepsis)
• low levels of potassium in the blood (hypokalemia), which may cause muscle weakness, spasms or changes in heart rhythm

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

• a heart condition in which the heart muscle does not pump blood as it should, causing shortness of breath and swelling in the legs and feet

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

• abnormal blood clotting in small blood vessels

Not known (frequency cannot be estimated from the available data):
Dilation and weakening of the wall of a blood vessel or a tear in the wall of a blood vessel (aneurysms and arterial dissections).
Cyramza may cause changes in laboratory tests. As indicated by the side effects listed above, these include: low white blood cell count; low platelet count; low levels of albumin, potassium or sodium in the blood; presence of protein in the urine.
Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor. 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 Cyramza

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and label of the vial after Exp. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C–8 °C).
Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
Do not freeze or shake the infusion solution. Do not administer the solution if particulate matter is observed or if there are signs of colour change.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer used. This will help protect the environment.

6. Package contents and other information

What Cyramza contains

• The active substance is ramucirumab. One mL of concentrate for infusion solution contains 10 mg of ramucirumab.
• Each 10 mL vial contains 100 mg of ramucirumab.
• Each 50 mL vial contains 500 mg of ramucirumab.
• The other components are histidine, monochloride histidine, sodium chloride, glycine (E 640), polysorbate 80 (E 433), and water for injections (see section 2 “Cyramza contains sodium” and “Cyramza contains polysorbate”).

Description of the appearance of Cyramza and contents of the pack
The concentrate for infusion solution (called sterile concentrate) is a solution that appears from clear to slightly opalescent and from colourless to slightly yellow, in a glass vial with a rubber stopper.
Cyramza is available in packs containing:

• 1 vial of 10 mL
• 2 vials of 10 mL
• 1 vial of 50 mL

Not all pack sizes may be marketed.
Marketing Authorization Holder
Eli Lilly Nederland B.V.
Orteliuslaan 1000
3528 BD Utrecht
The Netherlands
Manufacturer:
Lilly, S.A.
Avda de la Industria, 30
Alcobendas
28108 Madrid
Spain
Lilly France Fegersheim
2 rue du Colonel Lilly
67640 Fegersheim
France
For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:
Belgique/België/Belgien Lietuva
Eli Lilly Benelux S.A./N.V. Eli Lilly Lietuva
Tél/Tel: + 32-(0)2 548 84 84 Tel. +370 (5) 2649600
България Luxembourg/Luxemburg
ТП "Ели Лили Недерланд" Б.В. - България Eli Lilly Benelux S.A./N.V.
тел. + 359 2 491 41 40 Tél/Tel: + 32-(0)2 548 84 84
Česká republika Magyarország
ELI LILLY ČR, s.r.o. Lilly Hungária Kft.
Tel: + 420 234 664 111 Tel: + 36 1 328 5100
Danmark Malta
Eli Lilly Danmark A/S Charles de Giorgio Ltd.
Tlf.: +45 45 26 60 00 Tel: + 356 25600 500
Deutschland Nederland
Lilly Deutschland GmbH Eli Lilly Nederland B.V.
Tel. + 49-(0) 6172 273 2222 Tel: + 31-(0) 30 60 25 800
Eesti Norge
Eli Lilly Nederland B.V. Eli Lilly Norge A.S.
Tel: +372 6 817 280 Tlf: + 47 22 88 18 00
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ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. Eli Lilly Ges.m.b.H.
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Lilly S.A. Eli Lilly Polska Sp. z o.o.
Tel: + 34-91 663 50 00 Tel: +48 22 440 33 00
France Portugal
Lilly France Lilly Portugal Produtos Farmacêuticos, Lda
Tél: +33-(0) 1 55 49 34 34 Tel: + 351-21-4126600
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Eli Lilly Hrvatska d.o.o. Eli Lilly România S.R.L.
Tel: +385 1 2350 999 Tel: + 40 21 4023000
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Sími + 354 540 8000 Tel: + 421 220 663 111
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Tel: + 39- 055 42571 Puh/Tel: + 358-(0) 9 85 45 250
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Latvija
Eli Lilly (Suisse) S.A Pārstāvniecība Latvijā
Tel: + 371 67364000
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu

The following information is intended exclusively for healthcare professionals:

Do not shake the vial.
Prepare the infusion solution using aseptic technique to ensure sterility of the prepared solution.
Each vial is for single use only. Before dilution, inspect the vial contents for particulate matter and discoloration (the concentrate for infusion solution should appear clear to slightly opalescent and colorless to slightly yellow, without visible particles). If particulate matter or discoloration is observed, discard the vial.
Calculate the required dose and volume of ramucirumab needed to prepare the infusion solution. The vials contain 100 mg or 500 mg as a ramucirumab solution at 10 mg/mL. Only use sodium chloride 9 mg/mL (0.9%) injection solution as diluent.

When using a pre-filled intravenous infusion container:
Based on the calculated volume of ramucirumab, remove the corresponding volume of sodium chloride 9 mg/mL (0.9%) injection solution from the 250 mL pre-filled intravenous infusion container. Aseptically transfer the calculated volume of ramucirumab into the infusion container. The final total volume in the container must be 250 mL. Gently invert the container to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-administer by infusion with other electrolytes or medicinal products.

When using an empty intravenous infusion container:
Aseptically transfer the calculated volume of ramucirumab into an empty intravenous infusion container. Add sufficient sodium chloride 9 mg/mL (0.9%) injection solution to achieve a total volume of 250 mL. Gently invert the container to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-administer by infusion with other electrolytes or medicinal products.

After dilution and preparation, the medicinal product should be used immediately. If not used immediately, the user is responsible for the storage times and conditions prior to and during use, which normally should not exceed 24 hours at 2°C to 8°C.
Parenteral medicinal products should be visually inspected for particulate matter prior to administration. If particulate matter is observed, discard the infusion solution.
Discard any unused portion of ramucirumab remaining in the vial, as the product contains no antimicrobial preservatives.
Administer using an infusion pump. A separate infusion line with a 0.22 micron “protein sparing” filter must be used, and the line should be flushed with sodium chloride 9 mg/mL (0.9%) injection solution at the end of the infusion.
Unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.