PEMETREXED COMBIX 500 mg POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Pemetrexed Combix 100 mg powder for concentrate for solution for infusion EFG

Pemetrexed Combix 500 mg powder for concentrate for solution for infusion EFG

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

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

1. What Pemetrexed Combix is and what it is used for

Pemetrexed Combix is a medicine used to treat cancer.

Pemetrexed can be given with cisplatin, another anticancer medicine, as a treatment for malignant pleural mesothelioma, a type of cancer that affects the lining of the lungs, in patients who have not received chemotherapy before.

Pemetrexed can also be given, along with cisplatin, for the initial treatment of patients with advanced stages of lung cancer.

Pemetrexed may be prescribed for you if you have advanced lung cancer, if your disease has responded to treatment or if it remains unchanged after initial chemotherapy.

Pemetrexed can also be given for the treatment of patients with advanced stages of lung cancer whose disease has progressed, who have already received other initial chemotherapy treatment.

2. What you need to know before you use Pemetrexed Combix

Do not use Pemetrexed Combix:

• 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 this medicine.
• if you have recently received or are going to receive the yellow fever vaccine.

Warnings and precautions

Talk to your doctor, pharmacist, or hospital nurse before you are given this medicine

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

Before each infusion, you will need to give blood samples to check if your kidney and liver function is 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 an early or late reaction between radiation and pemetrexed may occur.
• if you have been vaccinated recently, please consult your doctor, as this may cause a negative effect with pemetrexed.
• if you have a heart condition 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 Combix

Tell your doctor if you are using pain or inflammation medicines (swelling), such as non-steroidal anti-inflammatory medicines (NSAIDs), including those bought without a prescription (such as ibuprofen). There are many classes of NSAIDs with different durations of action. Based on the date of your Pemetrexed Combix 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 not sure, 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 taking, have recently taken, or might take any other medicines, including those bought without a prescription.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before using this medicine.

Pregnancy

Pemetrexed should be avoided during pregnancy. Your doctor will inform you of the possible risks of taking pemetrexed during pregnancy. Women must use effective contraceptive methods during treatment with pemetrexed.

Breastfeeding

If you are breastfeeding, tell your doctor.

Breastfeeding must be stopped during treatment with pemetrexed.

Fertility

Male patients are advised not to father a child during and up to 6 months after treatment with pemetrexed and must use effective contraceptive methods during and up to 6 months after treatment with pemetrexed. If you wish to father a child during treatment or in the 6 months following treatment, consult your doctor or pharmacist. You may want to ask for information on sperm conservation before starting your treatment.

Driving and using machines

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

Pemetrexed Combix contains sodium

Pemetrexed Combix 100 mg and Pemetrexed Combix 500 mg contain less than 23 mg of sodium (1 mmol) per vial, which is essentially "sodium-free".

3. How to use Pemetrexed Combix

The recommended 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 may be delayed depending on your blood cell count and your general condition. The hospital pharmacist, nurse, or doctor will have mixed the Pemetrexed Combix powder with a solution of sodium chloride for injection 9 mg/ml (0.9%) before it is given to you.

You will always receive Pemetrexed Combix through an infusion (drip) in one of your veins. The infusion will last at least 10 minutes.

When using pemetrexed 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 approximately 30 minutes after the pemetrexed infusion has finished. The cisplatin infusion lasts approximately 2 hours.

You should normally receive 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. Your doctor gives you this medicine to reduce the frequency and severity of skin reactions you may experience during your cancer treatment.

Vitamin supplement: your doctor will prescribe oral folic acid (vitamin) or a multivitamin that contains folic acid (350 to 1,000 micrograms) that you must take once a day while you are using pemetrexed. You must take at least 5 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 pemetrexed is given 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 product, 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 sores in the mouth (very frequent).
• Allergic reaction: if you develop a rash (very frequent), burning sensation, or itching (frequent), or fever (frequent). In rare cases, skin reactions can be serious and life-threatening. Contact your doctor if you have a severe rash, itching, or blistering (Stevens-Johnson syndrome or toxic epidermal necrolysis).
• If you feel tired or dizzy, if you are short of breath or are pale (because you have less hemoglobin than normal, which is very frequent).
• If you experience bleeding from the gums, nose, or mouth, or any bleeding that does not stop, red or pink urine, or unexpected bruising (because you have fewer platelets than normal, which is frequent).
• If you experience sudden difficulty breathing, severe chest pain, or coughing up blood in your sputum (uncommon) (may indicate that there is a blood clot in the lungs).

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
• Lack of appetite
• Vomiting
• Diarrhea
• Nausea
• Rash
• Scaly skin
• Changes in blood tests that show 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
• Changes in 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 walking
• Dizziness
• Inflammation or swelling of the conjunctiva (membrane that covers the eyelids and the white part of the eye)
• Dry eyes
• Tearing
• 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 heartbeat
• Indigestion
• Constipation
• Abdominal pain
• Liver: increased levels of chemicals in the blood produced by the liver
• Increased skin pigmentation
• Itching of the skin
• Rash on the body that looks like a target
• 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 that line the digestive tract

Uncommon (may affect up to 1 in 100 people)

• Decrease 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 large intestine mucosa, which may be accompanied by intestinal or rectal bleeding (seen only in combination with cisplatin)
• Inflammation, edema, erythema, and erosion of the esophageal mucosa 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
• Rash on the skin that develops in a previously irradiated area

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

• Skin and soft tissue infections
• 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 that are filled with fluid
• Frailty of the skin, 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

Frequency 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 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, even if they are 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 Combix

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 vial label and carton after EXP. The expiry date is the last day of the month shown.

This medicine does not require any special storage conditions.

Reconstituted and infusion solution: the medicine should be used immediately. When prepared as indicated, the chemical and physical stability of the reconstituted and infusion solution is 24 hours in refrigeration.

Do not use this medicine if you notice any visible signs of deterioration.

This medicine is for single use only. The unused solution should be discarded in accordance with local requirements.

6. Container Content and Additional Information

Pemetrexed CompositionCombix

The active ingredient is pemetrexed.

Pemetrexed Combix 100 mg: Each vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate)

Pemetrexed Combix 500 mg: Each vial contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate)

After reconstitution, the solution contains 25 mg/ml of pemetrexed. Before administration, it is required that the healthcare professional perform another dilution.

The other components are mannitol, hydrochloric acid, and sodium hydroxide (see section 2 "Pemetrexed Combix contains sodium").

Product Appearanceand Container Content

Pemetrexed Combix is a lyophilized powder of white to pale yellow or yellowish-green color in a transparent glass vial with a rubber stopper and an aluminum seal.

Each package of Pemetrexed Combix contains 1 vial.

Marketing Authorization Holder

Laboratorios Combix, S.L.U.

C/ Badajoz 2, Edificio 2

28223 Pozuelo de Alarcón (Madrid)

Spain

Manufacturer:

Netpharmalab Consulting Services

Crta. De Fuencarral, 22

28108 Alcobendas (Madrid)

Spain

Date of Last Revision of this Prospectus: January 2025

Detailed information about this medication 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 doctors or healthcare professionals:

Instructions for Use and Handling and Disposal

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

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

1. Pemetrexed Combix 100 mg

Reconstitute each 100 mg vial with 4.2 ml of a 0.9% sodium chloride injection solution (9 mg/ml), without preservatives, to obtain a solution containing 25 mg/ml of pemetrexed.

Pemetrexed Combix 500 mg:

Reconstitute each 500 mg vial with 20 ml of a 0.9% sodium chloride injection solution (9 mg/ml), without preservatives, to obtain a solution containing 25 mg/ml of pemetrexed.

Shake the vial carefully until the powder is completely dissolved. The resulting solution is transparent with a color range that may vary from colorless to yellow or yellowish-green, which does not negatively affect the product quality. The pH of the reconstituted solution is between 6.6 and 7.8. A subsequent dilution is required.

1. The appropriate volume of the reconstituted pemetrexed solution should be diluted to 100 ml with a 0.9% sodium chloride injection solution (9 mg/ml) without preservatives and should be administered as an intravenous infusion over 10 minutes.

1. The pemetrexed infusion solution prepared according to the instructions described above is compatible with polyvinyl chloride and polyolefin infusion systems and bags. Pemetrexed is incompatible with diluents containing calcium, including lactated Ringer's injection and Ringer's injection.

1. Parenteral medications should be visually inspected before administration to rule out the appearance of particles or color alteration. If particles are observed, the medication should not be administered.

1. Pemetrexed solutions are for single use. The medication and unused material should be discarded according to local requirements.

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 for handling. If pemetrexed solutions come into contact with the skin, the skin should be washed immediately and thoroughly with water and soap. If pemetrexed solutions come into contact with mucous membranes, they should be rinsed 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 usual clinical practice with other non-vesicant drugs.