Leaflet: Information for the user

Pemetrexed Accord 25 mg/ml concentrate for solution for infusion

pemetrexed

Read this leaflet carefully before you start taking 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, pharmacist or nurse.
• This medicine has been prescribed for you only and must not be given to others, even if they have the same symptoms, as it may harm them.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

Pemetrexed Accord is a medication used for the treatment of cancer.

Pemetrexed Accord can be administered along with cisplatino, another anticancer medication, as treatment for malignant pleural mesothelioma, a form of cancer that affects the lung lining, in patients who have not received prior chemotherapy.

Pemetrexed Accord can also be administered, along with cisplatino, for the initial treatment of patients in advanced stages of lung cancer.

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

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

No use Pemetrexed Accord:

• If you are allergic (hypersensitive) to pemetrexed or to any of the other components of Pemetrexed Accord (listed in section 6).
• If you are breastfeeding, you must stop breastfeeding during treatment with Pemetrexed Accord.
• If you have recently received or are to receive the yellow fever vaccine.

Warnings and precautions

Consult your doctor, pharmacist, or hospital nurse before they administerPemetrexed Accord.

If you have or have had kidney problems, tell your doctor or hospital pharmacist as it may be possible that you cannot receive Pemetrexed Accord.

Before each infusion, you will need to give blood samples to evaluate if your renal and hepatic function is sufficient and to evaluate if you have enough blood cells to receive Pemetrexed Accord. 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 ensure that you are properly hydrated and receive the appropriate treatment before and after receiving cisplatin to prevent vomiting.

If you have received or are to receive radiation therapy, please consult with your doctor, as there may be an early or late reaction between the radiation and Pemetrexed Accord.

If you have recently been vaccinated, please consult with your doctor, as it may cause a negative effect with Pemetrexed Accord.

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

If you have fluid accumulated around your lung, your doctor may decide to drain the fluid before administering Pemetrexed Accord.

Children and adolescents

This medication should not be administered to children and adolescents, as there is no experience with this medication in children and adolescents under 18 years old.

Use of Pemetrexed Accord with other medications

Inform your doctor if you are using pain or anti-inflammatory medications (such as non-steroidal anti-inflammatory drugs, or NSAIDs), including those obtained without a prescription (such as ibuprofen). There are many types of NSAIDs with different durations of action. Based on the date of your Pemetrexed Accord infusion and/or your renal function, your doctor will advise you which medications you can use and when. If you are unsure, consult your doctor or pharmacist to see if any medication you are taking is an NSAID.

Inform your doctor or hospital pharmacist if you are using or have recently used other medications, including those obtained without a prescription.

Pregnancy

If you are pregnant, think you may be pregnant, or are planning to become pregnant, ask your doctor or pharmacist before taking this medication. During pregnancy, the use of Pemetrexed Accord should be avoided. Your doctor will inform you of the possible risks of taking Pemetrexed Accord during pregnancy. Women should use effective contraceptive methods during treatment with Pemetrexed Accord and for 6 months after receiving the last dose.

Breastfeeding

If you are breastfeeding, inform your doctor.

During treatment with Pemetrexed Accord, breastfeeding should be interrupted.

Fertility

Men are advised not to father a child during and for 3 months after treatment with Pemetrexed Accord, and therefore should use effective contraceptive methods during and for 3 months after treatment with Pemetrexed Accord. If you wish to have a child during treatment or in the 3 months following treatment, please consult your doctor or pharmacist. Pemetrexed Accord may affect your ability to have children. Talk to your doctor about sperm conservation before starting your treatment.

Driving and operating machinery

Pemetrexed Accord may cause fatigue. Be careful when driving a vehicle or operating machinery.

Pemetrexed Accord contains sodium

The maximum daily dose of this medication contains 304 mg of sodium (component of table salt). This is equivalent to 15.2% of the recommended daily maximum sodium intake for an adult.

Consult your pharmacist or doctor if you need to take Pemetrexed Accord for a prolonged period, especially if you have been advised to follow a low-sodium diet.

Always use this medicine exactly as your doctor or pharmacist has told you. Consult your doctor or pharmacist if you are unsure.

The recommended dose of Pemetrexed Accord is 500 milligrams per square meter of your body surface. They will measure your height and weight 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 overall condition.

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

When using Pemetrexed Accord in combination with cisplatin:

Your doctor or hospital pharmacist will calculate the dose you need based on your height and weight. Cisplatin is also administered through an infusion into one of your veins and is given approximately 30 minutes after you have finished the Pemetrexed Accord infusion. The cisplatin infusion lasts approximately two hours.

You should normally receive your infusion once every three weeks.

Additional medication:

Corticosteroids: Your doctor will prescribe you some steroid tablets (equivalent to 4 milligrams of dexamethasone twice a day) that you will have to take the day before, on the day of, and the day after treatment with Pemetrexed Accord. 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 you oral folic acid (vitamin) or a multivitamin complex containing folic acid (350 to 1,000 micrograms) that you must take once a day while taking Pemetrexed Accord. You must take at least five doses during the seven days before your first dose of Pemetrexed Accord. You must continue taking folic acid for 21 days after your last dose of Pemetrexed Accord. You will also receive an injection of vitamin B12 (1,000 micrograms) the week before administration of Pemetrexed Accord and approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed Accord). Vitamin B12 and folic acid are given to reduce possible toxic effects of cancer treatment.

If you have any other questions about the use of this product, ask your doctor or pharmacist.

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

You should inform 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 (since you may have fewer white blood cells than normal, which is very frequent). Infections (sepsis) can be severe and cause death.
• If you start to feel chest pain (frequent) or your heart rate is faster (rare).
• If you have mouth pain, redness, swelling, or sores (very frequent).
• Allergic reaction: if you develop hives (very frequent), burning sensation, or itching (frequent), or fever (frequent). In rare cases, skin reactions can be severe and cause death. Contact your doctor if you present severe rash, itching, or blistering (Stevens-Johnson syndrome or toxic epidermal necrolysis).
• If you feel tired or dizzy, if you lack breath or are pale (since you have fewer hemoglobin than normal, which is very frequent).
• If you experience bleeding gums, nose, or mouth, or any bleeding that does not stop, pink or red urine, or unexpected bruises (since you have fewer platelets than normal, which is frequent).
• If you experience sudden difficulty breathing, intense chest pain, or coughing up blood (rare) (which may indicate that there is a blood clot in the pulmonary veins).

Other side effects with Pemetrexed Accord may include:

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

Infection

Pharyngitis (sore throat)

Low neutrophil granulocyte count (a type of white blood cell)

Low white blood cell count

Low hemoglobin levels

Mouth pain, redness, swelling, or sores

Loss of appetite

Vomiting

Diarrhea

Nausea

Skin rash

Dry skin

Abnormal blood test results showing reduced kidney function

Weakness (fatigue)

Frequent (may affect up to 1 in 10 people)

Blood infection

Fever with low neutrophil granulocyte count (a type of white blood cell)

Low platelet count

Allergic reaction

Fluid loss

Alteration in taste

Muscle weakness and atrophy (wasting, mainly in arms and legs) due to nerve damage

Sensory nerve damage that may cause numbness, burning sensation, and unstable gait

Dizziness

Conjunctivitis (inflammation or swelling of the conjunctiva)

Dry eyes

Watery eyes

Dryness and inflammation of the conjunctiva and cornea

Swelling of the eyelids

Ocular disorder with dryness, tearing, irritation, and/or pain

Heart failure (condition affecting the heart's pumping ability)

Irregular heart rhythm

Indigestion

Constipation

Abdominal pain

Liver: increased levels of substances produced by the liver in the blood

Pigmentation of the skin

Itching skin

Rash on the body where each lesion resembles a target

Hair loss

Urticaria

Renal failure

Reduced kidney function

Fever

Pain

Excess fluid in the body tissue causing swelling

Chest pain

Inflammation and ulceration of the mucous membranes lining the digestive tract

Rare (may affect up to 1 in 100 people)

Reduction in the number of red blood cells, white blood cells, and platelets

Ischemia or reduced blood flow

Ischemia due to blockage of a cerebral artery

Intracranial hemorrhage

Angina (chest pain caused by reduced blood flow to the heart)

Myocardial infarction

Coronary artery stenosis or blockage

Increased heart rate

Poor blood distribution to the extremities Obstruction of one of the pulmonary arteries in the lungs

Inflammation and scarring of the lung mucosa with respiratory problems

Bright red blood loss through the anus

Bleeding in the gastrointestinal tract

Intestinal perforation

Inflammation of the esophageal 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 radiation therapy

Inflammation of the lung caused by radiation therapy

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

Red blood cell destruction

Anaphylactic shock (severe allergic reaction)

Inflammatory liver disease

Skin redness

Rash on the skin that develops in a previously irradiated area

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

Skin and soft tissue infections

Stevens-Johnson syndrome (a severe skin and mucous membrane reaction that can be fatal)

Toxic epidermal necrolysis (a severe skin reaction that can be fatal)

Autoimmune disorder causing skin eruptions 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 skin scars

Swelling, pain, and redness mainly of the lower limbs

Inflammation of the skin and subcutaneous fat (pseudocelulitis)

Inflammation of the skin (dermatitis)

The skin becomes inflamed, itches, reddens, cracks, and becomes rough

Intensely itchy spots

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

A type of diabetes primarily caused by kidney disease

Kidney disorder involving the death of tubular epithelial cells that form the renal tubules

You may experience some of these side effects and/or conditions. Inform your doctor as soon as you start experiencing any of these side effects.

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

Reporting side effects

If you experience any side effect, consult your doctor, pharmacist, or nurse, even if it is a side effect that does not appear in this leaflet. You can also report them directly through the national notification system included in theAnexo V. By reporting side effects, you can contribute to providing more information on 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 label and on the packaging after CAD.

Store at a temperature below 25°C.

Infusion solution: the medication must be used immediately. When prepared as indicated, the chemical and physical stability of the infusion solution in use is 72 hours at room temperature.

Do not use this medication if you observe any visible sign of deterioration.

This medication is for single use only. Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. In this way, you will help protect the environment.

Composition of Pemetrexed Accord

The active ingredient is pemetrexed. One milliliter of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 25 mg of pemetrexed.

A vial of 4 ml of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 100 mg of pemetrexed.

A vial of 20 ml of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 500 mg of pemetrexed.

A vial of 34 ml of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 850 mg of pemetrexed.

A vial of 40 ml of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 1000 mg of pemetrexed.

The other components are citric acid, L-methionine, monothioglycerol, sodium hydroxide, concentrated hydrochloric acid, and water for injection (see section 2 “Pemetrexed Accord contains sodium”).

Appearance of Pemetrexed Accord and contents of the package

Pemetrexed Accord is a concentrate for solution for infusion in a glass vial. It is a transparent, colorless to pale yellow solution.

Each package of Pemetrexed Accord contains a vial of 4 ml, 20 ml, 34 ml, or 40 ml of concentrate.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6th floor,

08039 Barcelona,

Spain

Responsible for manufacturing:

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice, Poland

LABORATORI FUNDACIÓ DAU

C/ C, 12-14 Pol. Ind. Zona Franca, Barcelona, 08040, Spain

Last review date of this leaflet:

Other sources of information

Detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu/ yon the website of the Spanish Agency of Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

This information is intended solely for doctors or healthcare professionals:

Instructions for use and handling and disposal

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

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

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

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

1. Parenteral medications must be visually inspected before administration to discard 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 must be disposed of according to local requirements.

Storage

Chemical and physical stability in use of pemetrexed infusion solutions has been demonstrated for 72 hours at a temperature of 20°C to 25°C.

From a microbiological point of view, the product must be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should normally not be more than 24 hours between 2°C and 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.

Precautions in preparation and administration

As with any other potentially toxic antineoplastic agent, special care must 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 abundantly with water and soap. If pemetrexed solutions come into contact with mucous membranes, wash with abundant water. Pemetrexed is not a vesicant. There is no specific antidote for pemetrexed extravasation. Cases of pemetrexed extravasation have been reported, which were not considered serious by the investigator. Extravasation should be treated according to standard clinical practice with non-vesicant drugs.