PEMETREXED EBEWE 25 mg/mL concentrate for infusion solution

2. What you need to know before you are given Pemetrexed Ebewe

Do not usePemetrexed Ebewe:

• if you are allergic to pemetrexed or any of the other ingredients of this medicine (listed in section 6),
• if you are breastfeeding, you must stop breastfeeding during treatment with pemetrexed,
• if you have recently received or are going to receive the yellow fever vaccine.

Warnings and precautions

Talk to your doctor or hospital pharmacist before you are given Pemetrexed Ebewe.

If you have had or have kidney problems, talk to your doctor or hospital pharmacist, as you may not be able to receive pemetrexed.

Before each infusion, you will have to give blood samples to check if your kidney and liver function are sufficient and to check if you have enough blood cells to receive pemetrexed. Your doctor may decide to change your dose or delay treatment depending on your general condition and if your blood cell count is too low. If you are also receiving cisplatin, your doctor will make sure you are properly hydrated and receive appropriate treatment before and after receiving cisplatin to prevent vomiting.

If you have received or are going to receive radiotherapy, please consult your doctor, as there may be an early or late reaction between radiation and pemetrexed.

If you have been vaccinated recently, please consult your doctor, as this may cause some negative effect with pemetrexed.

If you have heart disease or a history of heart disease, please consult your doctor.

If you have fluid accumulated around the lung, your doctor may decide to remove the fluid before administering pemetrexed.

Children and adolescents

This medicine must not be used in children or adolescents, as there is no experience with this medicine in children and adolescents under 18 years.

Other medicines and Pemetrexed Ebewe

Tell your doctor if you are using pain or inflammation medicines (swelling), such as medicines called "non-steroidal anti-inflammatory drugs" (NSAIDs), including those purchased without a prescription (such as ibuprofen). There are many classes of NSAIDs with different durations of action. Based on the date of your pemetrexed infusion and/or the status of your kidney function, your doctor will advise you which medicines you can use and when you can take them. If you are unsure, consult your doctor or pharmacist to see if any medicine you are taking is an NSAID.

Tell your doctor if you are taking medicines called proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) used to treat stomach acid and acid reflux.

Tell your doctor or hospital pharmacist if you are using, have recently used, or may need to use any other medicine, including those purchased without a prescription.

Pregnancy, breastfeeding, and fertility

Pregnancy

If you are pregnant, think you may be pregnant, or plan to become pregnant, tellyour doctor. Pemetrexed should be avoided during pregnancy. Your doctor will inform you of the possible risks of using pemetrexed during pregnancy. Women must use effective contraceptive methods during treatment with pemetrexed and for 6 months after receiving the last dose.

Breastfeeding

If you are breastfeeding, tell your doctor.

Breastfeeding should be stopped during treatment with pemetrexed.

Fertility

Male patients are advised not to father a child during and up to 3 months after treatment with pemetrexed and to use effective contraceptive methods during and up to 3 months after treatment with pemetrexed. If you wish to have a child during treatment or in the 3 months following treatment, ask your doctor or pharmacist for advice. Pemetrexed may affect your ability to have children. Consult your doctor about sperm preservation before starting your treatment.

Driving and using machines

Pemetrexed may make you feel tired. Be careful when driving a vehicle or using machines.

Pemetrexed Ebewe contains sodium and propylene glycol

Pemetrexed Ebewe 100 mg (vial with 4 ml)

This medicine contains less than 1 mmol of sodium (23 mg) per vial; this is essentially "sodium-free".

This medicine contains 200 mg of propylene glycol in each vial.

Pemetrexed Ebewe 500 mg (vial with 20 ml)

This medicine contains 55.6 mg of sodium (main component of table/cooking salt) in each vial. This is equivalent to 3% of the maximum recommended daily sodium intake for an adult.

This medicine contains 1,000 mg of propylene glycol in each vial.

Pemetrexed Ebewe 1,000 mg (vial with 40 ml)

This medicine contains 111.2 mg of sodium (main component of table/cooking salt) in each vial. This is equivalent to 6% of the maximum recommended daily sodium intake for an adult.

This medicine contains 2,000 mg of propylene glycol in each vial.

3. How to use Pemetrexed Ebewe

Pemetrexed should only be administered under the supervision of a qualified doctor experienced in the use of anticancer chemotherapy.

The dose of pemetrexed is 500 milligrams per square meter of your body surface area. Your height and weight will be measured to calculate your body surface area. Your doctor will use this surface area to calculate the correct dose for you. This dose may be adjusted or treatment delayed depending on your blood cell count and general condition. The hospital pharmacist, nurse, or doctor will have mixed the pemetrexed solution with a solution for infusion of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) before it is given to you.

You will always receive pemetrexed through an infusion in one of your veins. The infusion will take about 10 minutes.

When using Pemetrexed Ebewe in combination with cisplatin

Your doctor or hospital pharmacist will calculate the dose you need based on your height and weight. Cisplatin is also given through an infusion in one of your veins and is given about 30 minutes after the pemetrexed infusion has finished. The cisplatin infusion will take about 2 hours.

You should normally have your infusion once every 3 weeks.

Additional medication

Corticosteroids: your doctor will prescribe steroid tablets (equivalent to 4 milligrams of dexamethasone twice a day) that you must take the day before, the day of, and the day after treatment with pemetrexed. This medicine is given to reduce the frequency and severity of skin reactions that you may experience during your cancer treatment.

Vitamin supplement: your doctor will prescribe oral folic acid (vitamin) or a multivitamin complex containing folic acid (350 to 1,000 micrograms) that you must take once a day while you are taking pemetrexed. You must take at least five doses during the 7 days before the first dose of pemetrexed. You must continue taking folic acid during 21 days after the last dose of pemetrexed. You will also receive a vitamin B12 injection (1,000 micrograms) in the week before administration of pemetrexed and then approximately every 9 weeks (corresponding to 3 cycles of treatment with pemetrexed). Vitamin B12 and folic acid are given to reduce the possible toxic effects of cancer treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

You must tell your doctor immediately if you notice any of the following symptoms:

• fever or infection(frequent or very frequent, respectively): if you have a temperature of 38°C or higher, sweating, or other signs of infection (as you may have fewer white blood cells than normal, which is very frequent). Infections (sepsis) can be serious and life-threatening.
• if you start to feel chest pain(frequent) or your heart rate is faster (uncommon),
• if you have pain, redness, swelling, or soresinthemouth(very frequent),
• allergic reaction: if you develop rash(very frequent), burningsensationorprickling(frequent), or fever(frequent). In rare cases, skin reactions can be serious and life-threatening.

Contact your doctor if you experience severe rash, itching, or blisters(Stevens-Johnson syndrome or toxic epidermal necrolysis).

• If you feel tiredor dizzy, if you lack breathor are pale (due to having fewer red blood cells than normal, which is very frequent),
• if you experience bleedingfromthegums, nose, ormouthor any bleeding that does not stop, red or pink urine, or unexpected bruising (due to having fewer platelets than normal, which is very frequent),
• if you experience sudden difficulty breathing, chest pain(intense) or coughing up blood in your sputum (uncommon) (may indicate that there is a blood clot in the lungs).

The side effects with pemetrexed may include:

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

• infection,
• pharyngitis (sore throat),
• low neutrophil count (a type of white blood cell),
• low white blood cell count,
• low hemoglobin levels,
• pain, redness, swelling, or sores in the mouth,
• loss of appetite,
• vomiting,
• diarrhea,
• nausea,
• skin rash,
• scaly skin,
• abnormal blood tests showing reduced kidney function,
• fatigue (tiredness).

Common(may affect up to 1 in 10 people)

• blood infection,
• fever with low neutrophil count (a type of white blood cell),
• low platelet count,
• allergic reaction,
• loss of body fluids,
• altered sense of taste,
• nerve damage that can cause muscle weakness and wasting (mainly in arms and legs),
• nerve damage that can cause loss of sensation, burning (pain), and unsteady gait,
• dizziness,
• inflammation or swelling of the conjunctiva (membrane covering the eyelids and the white part of the eye),
• dry eyes,
• tearful eyes,
• dryness of the conjunctiva (membrane inside the eyelids and covering the white part of the eye) and the cornea (transparent layer in front of the iris and pupil),
• swelling of the eyelids,
• eye disorder with dryness, tearing, irritation, and/or pain,
• heart failure (a condition that affects the heart's pumping ability),
• irregular heart rhythm,
• indigestion,
• constipation,
• abdominal pain,
• liver: increased levels of chemicals in the blood produced by the liver,
• increased skin pigmentation,
• itching of the skin,
• skin rash that develops in a previously irradiated area,
• hair loss,
• hives,
• kidney failure,
• reduced kidney function,
• fever,
• pain,
• excess fluid in the body tissue that causes swelling,
• chest pain,
• inflammation and ulceration of the mucous membranes lining the digestive tract.

Uncommon(may affect up to 1 in 100 people)

• reduction in the number of red blood cells, white blood cells, and platelets,
• ischemia or lack of blood flow,
• ischemia due to blockage of a cerebral artery,
• intracranial bleeding,
• angina (chest pain caused by reduced blood flow to the heart),
• heart attack,
• narrowing or blockage of the coronary arteries,
• increased heart rate,
• poor distribution of blood to the limbs,
• blockage in one of the pulmonary arteries in the lungs,
• inflammation and scarring of the lung mucosa with respiratory problems,
• loss of bright red blood through the anus,
• bleeding in the gastrointestinal tract,
• perforation of the intestine,
• inflammation of the esophagus mucosa,
• inflammation of the colon mucosa, which may be accompanied by intestinal or rectal bleeding (seen only in combination with cisplatin),
• inflammation, edema, erythema, and erosion of the mucous membrane surface of the esophagus caused by radiotherapy,
• inflammation of the lung caused by radiotherapy.

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

• Destruction of red blood cells
• Anaphylactic shock (severe allergic reaction)
• Inflammatory liver disease
• Redness of the skin
• Skin rash that develops in a previously irradiated area

Very rare(may affect up to 1 in 10,000 people)

• Infections of the skin and soft tissues
• Stevens-Johnson syndrome (a type of severe skin and mucous membrane reaction that can be life-threatening)
• Toxic epidermal necrolysis (a type of severe skin reaction that can be life-threatening)
• Autoimmune disorder that causes skin rashes and blisters on the legs, arms, and abdomen
• Inflammation of the skin characterized by the presence of blisters filled with fluid
• Skin fragility, blisters, and erosions and scarring of the skin
• Redness, pain, and swelling mainly of the lower limbs
• Inflammation of the skin and the fat under the skin (pseudocellulitis)
• Inflammation of the skin (dermatitis)
• The skin becomes inflamed, itchy, red, cracked, and rough
• Itchy patches

Not known: frequency cannot be estimated from the available data

• A type of diabetes derived mainly from kidney disease
• Kidney disorder that involves the death of the epithelial tubular cells that form the renal tubules.

You may experience some of these symptoms and/or situations. You should tell your doctor as soon as you start to experience any of these side effects.

If you are concerned about any side effect, talk to your doctor.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Pemetrexed Ebewe

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

Do not use this medicine after the expiry date which is stated on the carton and label after “EXP”. The expiry date refers to the last day of the month.

Unopened vial

Do not store above 25°C. Store in the original packaging to protect from light.

After first opening

The product should be used immediately. All unused portions should be discarded.

After dilution

Vial with 100 mg

The stability of the infusion solution has been demonstrated for 3 days at temperatures between 2°C and 8°C, protected from light.

Vial with 500 mg and vial with 1,000 mg

The stability of the infusion solution has been demonstrated for 7 days at room temperature, protected from light, and for 14 days in the refrigerator, between 2°C and 8°C, protected from light.

From a microbiological point of view, this medicine should be used immediately after opening. If not used immediately, the in-use storage times and conditions are the responsibility of the user and should not exceed 24 hours at temperatures between 2°C and 8°C, unless the dilution has been made in a controlled and validated aseptic environment.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Pemetrexed Ebewe

The active substance is pemetrexed (as pemetrexed disodium hemipentahydrate).

1 ml of concentrate for solution for infusion contains 25 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

A vial with 4 ml contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

A vial with 20 ml contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

A vial with 40 ml contains 1,000 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

The other ingredients are sodium thiosulfate pentahydrate (E 539), propylene glycol (E 1520), hydrochloric acid (for pH adjustment), sodium hydroxide (E 524) (for pH adjustment), and water for injections.

Appearance and Package Contents of the Product

Pemetrexed Ebewe is a concentrate for solution for infusion. It is a clear, colorless to yellow or greenish-yellow solution. Solution practically free of particles.

Pemetrexed Ebewe is packaged in Type I glass vials with a bromobutyl rubber stopper and an aluminum flip-off cap with a light blue plastic flip-off cap.

Each vial contains 4 ml, 20 ml, or 40 ml of concentrate for solution for infusion.

Each pack contains 1 vial (with or without packaging).

Only certain pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Sandoz Farmacéutica, S.A.

Centro Empresarial Parque Norte

Edificio Roble

C/ Serrano Galvache, 56

28033 Madrid

Spain

Manufacturer

Ebewe Pharma Ges.m.b.H. Nfg.KG

Mondseestrasse 11

4866 Unterach am Attersee

Austria

or

Fareva Unterach GmbH

Mondseestrasse 11

4866 Unterach am Attersee

Austria

Date of Last Revision of this Leaflet:February 2025.

Detailed information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended only for healthcare professionals:

Special precautions for disposal and other handling.

Pemetrexed solutions are for single use. Disposal of unused medicine and all materials that have come into contact with it should be done in accordance with local regulations for cytotoxic agents.

1. Use aseptic techniques during the dilution of pemetrexed for intravenous infusion administration.

1. Calculate the dose and number of pemetrexed vials needed. Each vial contains an excess of pemetrexed to facilitate administration of the required nominal amount.

1. Dilute the appropriate volume of pemetrexed to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for infusion (without preservatives) or with glucose 50 mg/ml (5%) solution for infusion (without preservatives) and administer as an intravenous infusion over 10 minutes.

1. The prepared pemetrexed infusion solution is compatible with polyolefin infusion systems and bags.

1. Parenteral medicines should be inspected visually prior to administration for particulate matter or color change. If particulate matter is observed, the medicine should not be administered.

Precautions in preparation and administration:As with any other potentially toxic antineoplastic agent, special care should be taken in the handling and preparation of pemetrexed infusion solutions. The use of gloves is recommended. If pemetrexed solutions come into contact with the skin, wash the skin immediately and thoroughly with water and soap. If pemetrexed solutions come into contact with mucous membranes, rinse with plenty of water. Pemetrexed is not a vesicant drug. There is no specific antidote for pemetrexed extravasation. Some cases of pemetrexed extravasation have been reported, which were not considered serious by the investigator. Extravasation should be treated according to standard clinical practice for non-vesicant drugs.

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