Pemetrexed Accord: detailed information

Package leaflet: Information for the user

Pemetrexed Accord 25 mg/ml concentrate for solution for infusion

pemetrexed
Please 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 questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it may be harmful.
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

What Pemetrexed Accord is and what it is used for
What you need to know before taking Pemetrexed Accord
How to take Pemetrexed Accord
Possible side effects
How to store Pemetrexed Accord
Contents of the pack and other information

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

Pemetrexed Accord is a medicine used in the treatment of cancers.
Pemetrexed Accord is given in combination with cisplatin, another anticancer medicine, as
treatment for malignant pleural mesothelioma, a type of cancer affecting the lining of the
lungs, in patients who have not received prior chemotherapy.
Furthermore, Pemetrexed Accord, in combination with cisplatin, is administered as first-line therapy
in patients with advanced-stage lung cancer.
Pemetrexed Accord may be prescribed for advanced-stage lung cancer if the disease has responded to
treatment or remains largely unchanged after initial chemotherapy.
Additionally, Pemetrexed Accord is a treatment for patients with advanced-stage lung cancer
whose disease has progressed after a prior initial chemotherapy treatment.

2. What you need to know before taking Pemetrexed Accord

Do not take Pemetrexed Accord:

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

Children and adolescents
This medicine must not be given to children and adolescents, as there is no experience with use in
children and adolescents under 18 years of age.

Other medicines and Pemetrexed Accord
Inform your doctor if you are taking any medicine for pain or inflammation (swelling), such as medicines
called "non-steroidal anti-inflammatory drugs" (NSAIDs), including medicines purchased without a
prescription (such as ibuprofen). There are many types of NSAIDs with different durations of action.
Depending on the scheduled date for your Pemetrexed Accord infusion and/or your kidney function,
your doctor will advise you which medicines you can take and when you can take them. If you are
unsure, ask your doctor or pharmacist whether any of your medicines are NSAIDs.
Inform your doctor if you are taking medicines called proton pump inhibitors (omeprazole, esomeprazole,
lansoprazolo, pantoprazole, and rabeprazole) used to treat heartburn and acid reflux.
Inform your doctor or hospital pharmacist if you are taking or have recently taken any other medicines,
including those without a prescription.

Pregnancy
If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your
doctor or pharmacist before taking this medicine. The use of Pemetrexed Accord during pregnancy
should be avoided. Your doctor will discuss with you the potential risks of taking Pemetrexed Accord
during pregnancy. Women must use an effective method of contraception during treatment with
Pemetrexed Accord and for 6 months after receiving the last dose.

Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be stopped during treatment with Pemetrexed Accord.

Fertility
Men are advised not to father a child during treatment with Pemetrexed Accord and for up to 3 months
after treatment ends, and should therefore use an effective contraceptive method during treatment
with Pemetrexed Accord and for up to 3 months afterwards. If you wish to father a child during treatment
or within 3 months afterwards, consult your doctor or pharmacist. Pemetrexed Accord may affect your
ability to have children. Talk to your doctor for advice on sperm preservation before starting therapy.

Driving and using machines
Pemetrexed Accord may cause tiredness. Be careful when driving a vehicle or operating machinery.

Pemetrexed Accord contains sodium
The recommended maximum daily dose of this medicine contains 304 mg of sodium (present in table
salt). This corresponds to 15.2% of the maximum daily dietary intake recommended for an adult.
Talk to your pharmacist or doctor if you need Pemetrexed Accord on a daily basis for a prolonged period,
especially if you have been advised to follow a low-sodium diet.

3. How to take Pemetrexed Accord

Take this medicine exactly as your doctor or pharmacist has told you. If you have any doubts, consult your doctor or pharmacist.
The recommended dose of Pemetrexed Accord is 500 mg per square metre of body surface area.
Your height and weight will be measured to calculate your body surface area. Your doctor will use this body surface area to determine the correct dose for you. This dose may be adjusted or the treatment may be delayed depending on blood test results and your general condition.
You will always receive Pemetrexed Accord as an intravenous infusion. The infusion will last approximately 10 minutes.
When Pemetrexed Accord is used in combination with cisplatin:
Your hospital doctor or pharmacist will calculate the dose you need based on your height and weight. Cisplatin is also administered as an intravenous infusion, approximately 30 minutes after completion of the Pemetrexed Accord infusion. The cisplatin infusion will last about 2 hours.
You will usually receive the infusion once every 3 weeks.
Additional medicines:
Corticosteroids: Your doctor will prescribe steroid tablets (equivalent to 4 milligrams of dexamethasone twice daily) to be taken the day before, on the day of, and the day after treatment with Pemetrexed Accord. This medicine is given to reduce the frequency and severity of skin reactions that may occur during anticancer treatment.
Vitamin supplement: Your doctor will prescribe folic acid (vitamin) or a multivitamin product containing folic acid (350–1000 micrograms) to be taken orally once daily throughout your treatment with Pemetrexed Accord. You must take at least 5 doses during the 7 days before your first dose of Pemetrexed Accord. You should continue taking folic acid for 21 days after your last dose of Pemetrexed Accord. You will also receive an injection of vitamin B({12}) (1000 micrograms) during the week before administration of Pemetrexed Accord, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed Accord). Vitamin B({12}) and folic acid are administered to reduce the potential toxic effects of anticancer treatment.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
You must contact your doctor immediately if you notice any of the following side effects:

Fever or infection (common or very common, respectively): if you have a body temperature of 38°C or higher, sweating, or other signs of infection (because you may have fewer white blood cells than normal, which is very common). Infection (sepsis) can be severe and may lead to death.
If you start experiencing chest pain (common) or an increased heart rate (uncommon).
If you have pain, redness, swelling, or sores in your mouth (very common).
Allergic reaction: if you develop a rash (very common), burning or tingling sensation (common), or fever (common). Rarely, skin reactions can be severe and may lead to death. Contact your doctor if you develop a severe rash, itching, or blisters (Stevens-Johnson syndrome or toxic epidermal necrolysis).
If you feel tired, faint, short of breath, or look pale (because you may have lower haemoglobin levels than normal, which is very common).
If you have bleeding from gums, nose, or mouth, or any bleeding that does not stop easily, reddish or slightly pink urine, or unexpected bruising (because you may have fewer platelets than normal, which is common).
If you experience sudden shortness of breath, severe chest pain, or cough up blood (uncommon) (this may indicate a blood clot in the blood vessels of the lungs).

Other side effects with Pemetrexed Accord may include:

Very common (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 haemoglobin levels
Pain, redness, swelling, or ulcers in the mouth
Loss of appetite
Vomiting
Diarrhoea
Nausea
Skin redness
Skin peeling
Abnormal blood tests showing reduced kidney function
Fatigue (tiredness)

Common (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 reactions
Loss of body fluids
Altered taste
Nerve damage that could cause stiffness and muscle atrophy, leading to muscle weakness and primary atrophy in arms and legs
Sensory nerve damage that may cause loss of sensation, burning sensations, and unsteady gait
Dizziness
Inflammation or swelling of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye)
Dry eyes
Excessive tearing
Dryness of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye) and cornea (the transparent layer in front of the iris and pupil)
Swollen eyelids
Eye disorders with dryness, tearing, irritation, and/or pain
Heart failure (a condition affecting the heart muscle’s pumping ability)
Irregular heartbeat
Indigestion
Constipation
Abdominal pain
Liver: increased blood levels of chemicals produced by the liver
Increased skin pigmentation
Skin itching
Widespread red spots
Hair loss
Hives
Kidney failure
Reduced kidney function
Fever
Pain
Excess fluid in body tissues causing swelling
Chest pain
Inflammation and ulceration of mucous membranes lining the digestive tract

Uncommon (may affect up to 1 in 100 people)
Reduction in the number of white and red blood cells and platelets
Stroke
Type of stroke when a neck artery is blocked
Bleeding in the skull
Angina (chest pain caused by reduced blood flow to the heart)
Heart attack
Narrowing or blockage of the coronary arteries
Increased heart rate
Inadequate blood supply to the limbs
Blockage in the lungs, of one of the pulmonary arteries
Inflammation and scarring of the lung lining causing breathing problems
Bright red bleeding from the anus
Gastrointestinal tract bleeding
Intestinal rupture
Inflammation of the oesophageal lining
Inflammation of the lining of the large intestine, which may be accompanied by intestinal or rectal bleeding (seen only in combination with cisplatin)
Inflammation, swelling, redness, and erosion of the oesophageal mucosal surface caused by radiation therapy
Lung inflammation caused by radiation therapy

Rare (may affect up to 1 in 1,000 people)
Destruction of red blood cells
Anaphylactic shock (severe allergic reaction)
Inflammatory liver condition
Skin redness
Sudden skin redness developing in a previously irradiated area

Very rare (may affect up to 1 in 10,000 people)
Skin and soft tissue infection
Stevens-Johnson syndrome (a type of severe skin and mucous membrane reaction that could be life-threatening)
Toxic epidermal necrolysis (a type of severe skin reaction that could be life-threatening)
Autoimmune disorders resulting in sudden skin redness and blisters on legs, arms, and abdomen
Skin inflammation characterized by fluid-filled blisters
Skin fragility, blistering, erosion, and scarring
Redness, pain, and swelling, mainly in the lower limbs
Inflammation of the skin and underlying fat (pseudocellulitis)
Skin inflammation (dermatitis)
Skin becoming inflamed, itchy, red, cracked, and rough
Intensely itchy spots

Not known (frequency cannot be estimated from available data)
A form of diabetes primarily due to kidney disease
Kidney disorders leading to death of tubular epithelial cells forming the kidney tubules

You may experience some of these symptoms and/or conditions. You must inform your doctor as soon as possible if you start having any of these side effects.
If you have any doubts about any side effect, discuss them with your doctor.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. 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 Pemetrexed Accord

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 on the outer
packaging after “EXP” or “Scad.”.
Store below 25 °C.
Infusion solution: the product should be used immediately. If prepared as directed, the chemical and physical stability of pemetrexed infusion solutions during use has been demonstrated for 72 hours at room temperature.
Do not use this medicine if you notice any visible signs of deterioration.
This medicine is for single use only. Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Pemetrexed Accord contains
The active substance is pemetrexed. One ml of concentrate contains pemetrexed disodium hemipentahydrate
equivalent to 25 mg of pemetrexed.
A 4 ml vial of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 100
mg of pemetrexed.
A 20 ml vial of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 500
mg of pemetrexed.
A 34 ml vial of concentrate contains pemetrexed disodium hemipentahydrate equivalent to 850
mg of pemetrexed.
A 40 ml vial 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 injections (see section 2 “Pemetrexed Accord contains sodium”).

Description of the appearance of Pemetrexed Accord and contents of the pack
Pemetrexed Accord is a concentrate for solution for infusion in a glass vial. It is a transparent solution ranging from colourless to pale yellow.
Each pack of Pemetrexed Accord contains one vial of 4 ml, 20 ml, 34 ml or 40 ml of concentrate.

Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center, Moll de Barcelona, s/n,
Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer
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
Accord Healthcare Single Member S.A.
64th Km National Road Athens, Lamia, 32009, Greece

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

AT / BE / BG / CY / CZ / DE / DK / EE / FI / FR / HR / HU / IE / IS / IT / LT / LV / LU / MT / NL / NO / PT / PL / RO / SE / SI / SK / ES
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64

EL
Win Medica Pharmaceutical S.A.
Tel: +30 210 7488 821

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

The following information is intended exclusively for physicians or healthcare professionals:

Instructions for use, handling, and disposal

Use aseptic techniques when diluting pemetrexed for intravenous infusion administration.
Calculate the required dose and number of Pemetrexed Accord vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of the labeled amount.
The appropriate volume of pemetrexed solution must be diluted to 100 ml with sodium chloride solution 9 mg/ml (0.9%) for injections, without preservatives, and administered as an intravenous infusion over 10 minutes.
Infusion solutions of pemetrexed prepared as described above are compatible with infusion bags and administration sets coated with polyvinyl chloride and polyolefins. Pemetrexed is incompatible with solvents containing calcium, including sodium lactate Ringer’s solution for injections and Ringer’s solution for injections.
Parenteral medicinal products should be visually inspected for particulate matter and discoloration prior to administration. Do not administer if particulate matter is observed.
Pemetrexed solutions are for single use only. Unused product and waste materials derived from this medicinal product must be disposed of in accordance with local legal requirements.

Storage
Chemical and physical in-use stability of pemetrexed infusion solutions has been demonstrated for
72 hours at temperatures between 20°C and 25°C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the
duration and conditions of storage prior to use are the responsibility of the user and should normally not
exceed 24 hours at a temperature between 2°C and 8°C, unless dilution occurs under controlled and
validated aseptic conditions.

Precautions for preparation and administration
As with other potentially toxic antineoplastic agents, caution should be exercised in handling and preparing pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution comes into contact with the skin, immediately and thoroughly wash with soap and water. If pemetrexed solutions contact mucous membranes, thoroughly rinse with 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 severe by the investigator. Extravasation should be managed according to standard procedures, as for other non-vesicant agents.

Package leaflet: Information for the user

Pemetrexed Accord 100 mg powder for concentrate for solution for infusion, 500 mg powder for concentrate for solution for infusion, 1000 mg powder for concentrate for solution for infusion

pemetrexed
Please read this leaflet carefully before using 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, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

What Pemetrexed Accord is and what it is used for
What you need to know before using Pemetrexed Accord
How to use Pemetrexed Accord
Possible side effects
How to store Pemetrexed Accord
Contents of the pack and other information

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

Pemetrexed Accord is a medicine used in the treatment of cancers.
Pemetrexed Accord is given in combination with cisplatin, another anticancer medicine, as
treatment for malignant pleural mesothelioma, a type of cancer affecting the lining of the
lungs, in patients who have not received previous chemotherapy.
Furthermore, Pemetrexed Accord, in combination with cisplatin, is administered as first-line therapy in patients with advanced-stage lung cancer.
Pemetrexed Accord may be prescribed for advanced-stage lung cancer if the disease has responded to treatment or remains mostly unchanged after initial chemotherapy.
Additionally, Pemetrexed Accord is a treatment for patients with advanced-stage lung cancer whose disease has progressed after a previous initial chemotherapy treatment.

2. What you need to know before taking Pemetrexed Accord

Do not take Pemetrexed Accord:

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

Warnings and precautions
Talk to your doctor, hospital pharmacist, or nurse before receiving Pemetrexed Accord.
If you have or have had kidney problems, inform your doctor or hospital pharmacist, as you may not
be able to receive Pemetrexed Accord.
Before each infusion, blood tests will be performed to assess whether you have adequate liver and kidney
function and to check that you have enough blood cells to receive Pemetrexed Accord. Your doctor may
decide to adjust the dose or delay treatment depending on your general condition and if blood test results
(white blood cells and platelets) are inadequate (too low). Additionally, if you are receiving cisplatin, your
doctor must ensure that you are adequately hydrated and receive appropriate treatment before and after
receiving cisplatin to prevent vomiting.
Inform your doctor if you have undergone or will undergo radiation therapy, as with Pemetrexed Accord
you may experience an early or delayed reaction due to radiation treatment.
Inform your doctor if you have recently been vaccinated, as this may cause harmful effects when taking
Pemetrexed Accord.
If you have heart disease or a history of heart disease, inform your doctor.
If you have fluid accumulation around the lungs, your doctor may decide to remove the fluid before
administering Pemetrexed Accord.
Children and adolescents
This medicine must not be given to children and adolescents, as there is no experience with use in
children and adolescents under 18 years of age.
Other medicines and Pemetrexed Accord
Inform your doctor if you are taking any medicine for pain or inflammation (swelling), such as medicines
called "non-steroidal anti-inflammatory drugs" (NSAIDs), including medicines purchased without a
prescription (such as ibuprofen). There are many types of NSAIDs with different durations of action.
Depending on the scheduled date for your Pemetrexed Accord infusion and/or your kidney function, your
doctor will advise you which medicines you can take and when you can take them. If you are unsure, ask
your doctor or pharmacist whether any of your medicines are NSAIDs.
Inform your doctor if you are taking medicines called proton pump inhibitors (omeprazole, esomeprazole,
lansoprazole, pantoprazole, and rabeprazole) used to treat heartburn and acid reflux.
Inform your doctor or hospital pharmacist if you are taking or have recently taken any other medicine,
including those without a prescription.
Pregnancy
If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor
or pharmacist before taking this medicine. The use of Pemetrexed Accord during pregnancy should be
avoided. Your doctor will discuss with you the potential risks of taking Pemetrexed Accord during
pregnancy. Women must use an effective method of contraception during treatment with Pemetrexed
Accord and for 6 months after receiving the last dose.
Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be stopped during treatment with Pemetrexed Accord.
Fertility
Men are advised not to father a child during treatment with Pemetrexed Accord and for up to 3 months
after treatment. Therefore, use an effective contraceptive method during treatment with Pemetrexed
Accord and for up to 3 months afterwards. If you wish to father a child during treatment or within 3 months
after, consult your doctor or pharmacist. Pemetrexed Accord may affect your ability to have children.
Talk to your doctor for advice on sperm preservation before starting therapy.
Driving and using machines
Pemetrexed Accord may cause fatigue. Be cautious when driving a vehicle or operating machinery.
Pemetrexed Accord contains sodium
Pemetrexed Accord 100 mg contains less than 1 mmol of sodium (23 mg) per vial, i.e. essentially
'sodium-free'.
Pemetrexed Accord 500 mg contains 54 mg of sodium (a principal component of table salt) in each vial.
This corresponds to 2.7% of the maximum daily dietary intake recommended for an adult.
Pemetrexed Accord 1000 mg contains 108 mg of sodium (a principal component of table salt) in each vial.
This corresponds to 5.4% of the maximum daily dietary intake recommended for an adult.

3. How to take Pemetrexed Accord

Take this medicine exactly as your doctor or pharmacist has told you. If you have any doubts, consult your doctor or pharmacist.

The recommended dose of Pemetrexed Accord is 500 mg per square metre of body surface area. Your height and weight will be measured to calculate your body surface area. Your doctor will use this body surface area to determine the correct dose for you. This dosage may be adjusted or the treatment delayed depending on your blood test results and general condition. A hospital pharmacist, nurse or doctor will have mixed the Pemetrexed Accord powder with a sodium chloride solution (9 mg/ml, 0.9%) for injection before administering it to you.

Pemetrexed Accord will always be given by intravenous infusion (into a vein). The infusion will last approximately 10 minutes.

When Pemetrexed Accord is used 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 by intravenous infusion, approximately 30 minutes after the Pemetrexed Accord infusion has been completed. The cisplatin infusion will last about 2 hours.

Usually, you will receive the infusion once every 3 weeks.

Additional medicines:

Corticosteroids: Your doctor will prescribe steroid tablets (equivalent to 4 milligrams of dexamethasone twice daily) to be taken the day before, the day of, and the day after treatment with Pemetrexed Accord. These medicines are given to reduce the frequency and severity of skin reactions that may occur during anticancer treatment.

Vitamin supplement: Your doctor will prescribe folic acid (vitamin) or a multivitamin product containing folic acid (350–1000 micrograms) to be taken orally once daily during treatment with Pemetrexed Accord. You must take at least five doses during the seven days before your first dose of Pemetrexed Accord. You should continue taking folic acid for 21 days after your last dose of Pemetrexed Accord. You will also receive an injection of vitamin B_(12) (1000 micrograms) during the week before administration of Pemetrexed Accord, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed Accord). Vitamin B_(12) and folic acid are administered to reduce the potential toxic effects of anticancer treatment.

If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
You must contact your doctor immediately if you notice any of the following side effects:

Fever or infection (respectively common or very common): if you have a body temperature of 38°C or higher, sweating, or other signs of infection (because you may have fewer white blood cells than normal, which is very common). Infection (sepsis) can be severe and may lead to death.
If you start experiencing chest pain (common) or an increased heart rate (uncommon).
If you have pain, redness, swelling, or sores in the mouth (very common).
Allergic reaction: if you develop a rash (very common)/a burning or tingling sensation (common) or fever (common). Rarely, skin reactions can be serious and may lead to death. Contact your doctor if a severe rash appears, or if you experience itching or blisters form (Stevens-Johnson syndrome or toxic epidermal necrolysis).
If you feel tired, faint, become short of breath easily, or look pale (because you may have lower haemoglobin levels than normal, which is very common).
If you have bleeding from the gums, nose, or mouth, or any bleeding that does not stop easily, reddish or slightly pink urine, or unexpected bruising (because you may have fewer platelets than normal, which is common).
If you suddenly become short of breath, have severe chest pain, or cough up blood (uncommon) (this may indicate a blood clot in the blood vessels of the lungs).

Other side effects with Pemetrexed Accord may include:
Very common (may affect more than 1 in 10 people)
Infection
Pharyngitis (sore throat)
Low neutrophil granulocyte count (a type of white blood cell in the blood)
Low white blood cell count
Low haemoglobin levels
Pain, redness, swelling, or ulcers in the mouth
Loss of appetite
Vomiting
Diarrhoea
Nausea
Skin redness
Skin peeling
Abnormal blood tests showing reduced kidney function
Fatigue (tiredness)

Common (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 reactions
Loss of body fluids
Altered taste
Damage to motor nerves which could cause stiffness and muscle atrophy, leading to muscle weakness and primary atrophy (wasting) in the arms and legs
Damage to sensory nerves which may cause loss of sensation, burning sensations, and unsteady gait
Dizziness
Inflammation or swelling of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye)
Dry eyes
Excessive tearing
Dryness of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye) and cornea (the transparent layer in front of the iris and pupil)
Swelling of the eyelids
Eye disorders with dryness, tearing, irritation and/or pain
Heart failure (a condition affecting the heart muscle's pumping ability)
Irregular heartbeat
Indigestion
Constipation
Abdominal pain
Liver: increased levels in the blood of chemicals produced by the liver
Increased skin pigmentation
Skin itching
Widespread red spots
Hair loss
Hives
Kidneys stop functioning
Reduced kidney function
Fever
Pain
Excess fluid in body tissues causing 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 white and red blood cells and platelets in the blood
Stroke
Type of stroke when a neck artery is blocked
Bleeding in the skull
Angina (chest pain caused by reduced blood flow to the heart)
Heart attack
Narrowing or blockage of the coronary arteries
Increased heart rate
Poor blood supply to the limbs
Blockage in the lungs of one of the pulmonary arteries
Inflammation and scarring of the lung lining causing breathing problems
Loss of bright red blood from the anus
Gastrointestinal tract bleeding
Intestinal rupture
Inflammation of the oesophageal lining
Inflammation of the lining of the large intestine, which may be accompanied by intestinal or rectal bleeding (seen only in combination with cisplatin)
Inflammation, oedema, erythema, and erosion of the oesophageal mucosa surface caused by radiation therapy
Lung inflammation caused by radiation therapy

Very rare (may affect up to 1 in 10,000 people)
Skin and soft tissue infection
Stevens-Johnson syndrome (a type of severe reaction affecting the skin and mucous membranes which could be life-threatening)
Toxic epidermal necrolysis (a type of severe skin reaction which could be life-threatening)
Autoimmune disorders resulting in sudden skin redness and blisters on the legs, arms, and abdomen
Skin inflammation characterized by the presence of blisters that fill with fluid
Skin fragility, blistering, erosion, and scarring of the skin
Redness, pain, and swelling, mainly in the lower limbs
Inflammation of the skin and underlying fat (pseudocellulitis)
Skin inflammation (dermatitis)
Skin becoming inflamed, itchy, red, cracked, and rough
Intensely itchy spots

Not known: frequency cannot be estimated from the available data
A form of diabetes primarily due to kidney disease
Kidney disorders leading to death of tubular epithelial cells forming the kidney tubules

You may experience one or more of these symptoms and/or conditions. You must inform your doctor as soon as possible if you begin to experience any of these side effects.
If you have any concerns about any side effect, discuss them with your doctor.
If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system indicated in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Pemetrexed Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and packaging following “Exp.”.
This medicine does not require any special storage conditions.
Reconstituted and infusion solutions: the product should be used immediately. If prepared as directed, the chemical and physical stability during use of reconstituted pemetrexed solutions for infusion has been demonstrated for 24 hours under refrigerated conditions.
Do not use this medicine if you notice any visible signs of deterioration.
This medicine is for single use only. Do not dispose of medicines 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 other information

What Pemetrexed Accord contains
The active substance is pemetrexed.
Pemetrexed Accord 100 mg: One vial of powder contains 100 milligrams of pemetrexed (as
pemetrexed disodium hemipentahydrate).
Pemetrexed Accord 500 mg: One vial of powder contains 500 milligrams of pemetrexed (as
pemetrexed disodium hemipentahydrate).
Pemetrexed Accord 1000 mg: One vial of powder contains 1000 milligrams of pemetrexed (as
pemetrexed disodium hemipentahydrate).
After reconstitution, the solution contains 25 mg/ml of pemetrexed. Further dilution by healthcare professionals is required before administration.
The other components are mannitol, hydrochloric acid, and sodium hydroxide (see section 2, “Pemetrexed Accord contains sodium”).

Description of the appearance of Pemetrexed Accord and package contents
Pemetrexed Accord is a lyophilised powder for concentrate for solution for infusion in a glass vial.
It is a lyophilised powder with a colour ranging from white to pale yellow or yellowish-green.
Each package of Pemetrexed Accord contains one vial of Pemetrexed Accord.

Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center, Moll de Barcelona, s/n,
Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer
Accord Healthcare Polska Sp.z o.o.,
ul. Lutomierska 50, 95-200 Pabianice, Poland
Accord Healthcare Single Member S.A.
64th Km National Road Athens, Lamia, 32009, Greece

For further information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
AT / BE / BG / CY / CZ / DE / DK / EE / FI / FR / HR / HU / IE / IS / IT / LT / LV / LU / MT / NL / NO / PT / PL / RO / SE / SI / SK / ES
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64
EL
Win Medica Pharmaceutical S.A.
Tel: +30 210 7488 821

Other sources of information
More detailed information on this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu

The following information is intended exclusively for physicians or healthcare professionals:

Instructions for use, handling, and disposal

During reconstitution and further dilution of pemetrexed for intravenous infusion administration, aseptic techniques must be used.
Calculate the required dose and number of vials of Pemetrexed Accord needed. Each vial contains an excess of pemetrexed to facilitate delivery of the amount stated on the label.
Pemetrexed Accord 100 mg: Reconstitute each 100 mg vial with 4.2 ml of sodium chloride solution 9 mg/ml (0.9%) for injection, without preservatives, to obtain a solution containing 25 mg/ml of pemetrexed.

Pemetrexed Accord 500 mg:
Reconstitute each 500 mg vial with 20 ml of sodium chloride solution 9 mg/ml (0.9%) for injection, without preservatives, to obtain a solution containing 25 mg/ml of pemetrexed.
Pemetrexed Accord 1000 mg:
Reconstitute each 1000 mg vial with 40 ml of sodium chloride solution 9 mg/ml (0.9%) for injection, without preservatives, to obtain a solution containing 25 mg/ml of pemetrexed.
Gently shake each vial until the powder is completely dissolved. The resulting solution is clear and may vary from colourless to yellow or yellow-green, which does not negatively affect the quality of the product. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.

The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml with sodium chloride solution 9 mg/ml (0.9%) for injection, without preservatives, and administered by intravenous infusion over 10 minutes.
Pemetrexed infusion solutions prepared as described above are compatible with infusion bags and administration sets lined with polyvinyl chloride and polyolefins. Pemetrexed is incompatible with solvents containing calcium, including Ringer lactate solution for injection and Ringer solution for injection.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration. Do not administer if particulate matter is observed.
Pemetrexed solutions are for single use only. Unused product and waste materials arising from this medicinal product must be disposed of in accordance with local legal requirements.

Storage
Chemical and physical in-use stability of reconstituted and diluted pemetrexed solutions has been demonstrated for 24 hours at 25°C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not normally exceed 24 hours at 2–8°C, unless reconstitution/dilution takes place under controlled and validated aseptic conditions.

Precautions for preparation and administration
As with other potentially toxic antineoplastic agents, caution should be exercised when handling and preparing pemetrexed infusion solutions. Use of gloves is recommended. If a pemetrexed solution comes into contact with the skin, wash immediately and thoroughly with soap and water. If pemetrexed solutions come into contact with mucous membranes, flush thoroughly with 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 severe by the investigator. Extravasation should be managed according to standard procedures for non-vesicant agents.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION TO THE TERMS OF THE
MARKETING AUTHORISATION

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for pemetrexed, the PRAC's scientific conclusions are as follows:
In light of the available pharmacokinetic data on pemetrexed, considering that in vitro studies have indicated that pemetrexed is actively secreted by the organic anion transporter 3 (OAT3), and considering the IC50 values for proton pump inhibitors, the PRAC considers that a drug-drug interaction between proton pump inhibitors and pemetrexed is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing pemetrexed should be amended accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.

Reasons for the variation to the terms of the marketing authorisation
Based on the scientific conclusions on pemetrexed, the CHMP considers that the benefit-risk balance of medicinal products containing pemetrexed remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.