Pemetrexed Fresenius Kabi: detailed information

Package leaflet: Information for the user

Pemetrexed Fresenius Kabi 100 mg powder for concentrate for solution for infusion, 500 mg powder for concentrate for solution for infusion

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

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Pemetrexed Fresenius Kabi is and what it is used for

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

Do not use Pemetrexed Fresenius Kabi

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 Fresenius Kabi.
if you have recently received or are scheduled to receive the yellow fever vaccine.

Warnings and precautions
Talk to your doctor or hospital pharmacist before taking Pemetrexed Fresenius Kabi.
If you have or have had kidney problems, inform your doctor or hospital pharmacist, as you may
not be able to receive Pemetrexed Fresenius Kabi.
Before each infusion, blood tests will be performed to assess whether your liver and kidney functions
are adequate and to check that you have enough blood cells to receive Pemetrexed Fresenius Kabi.
Your doctor may decide to adjust the dose or delay treatment depending on your general condition and
if blood test results (blood cell counts) 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 are scheduled to undergo radiation therapy, as with
Pemetrexed Fresenius Kabi, an early or delayed reaction related to radiation therapy may occur.
Inform your doctor if you have recently been vaccinated, as this could cause harmful effects when
taking Pemetrexed Fresenius Kabi.
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 Fresenius Kabi.

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

Other medicines and Pemetrexed Fresenius Kabi
Inform your doctor if you are taking, have recently taken, or might take any medicine for pain or
inflammation (swelling), such as medicines called “non-steroidal anti-inflammatory drugs” (NSAIDs),
including medicines available 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
Fresenius Kabi 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 medicine,
including those without a prescription.

Pregnancy
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, inform your doctor.
The use of Pemetrexed Fresenius Kabi during pregnancy should be avoided. Your doctor will discuss
with you the potential risks of taking Pemetrexed Fresenius Kabi during pregnancy. Women must use an
effective method of contraception during treatment with Pemetrexed Fresenius Kabi and for 6 months
after receiving the last dose.

Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be discontinued during treatment with Pemetrexed Fresenius Kabi.

Fertility
Men are advised not to father a child during treatment with Pemetrexed Fresenius Kabi and for up to
3 months after treatment. Therefore, an effective contraceptive method should be used during
treatment with Pemetrexed Fresenius Kabi or up to 3 months afterwards. If you wish to father a child
during treatment or within 3 months thereafter, consult your doctor or pharmacist. Pemetrexed
Fresenius Kabi may affect the ability to have children. Speak with your doctor for advice on sperm
preservation before starting therapy.

Driving and using machines
Pemetrexed Fresenius Kabi may cause fatigue. Be careful when driving a vehicle or operating
machinery.

3. How to use Pemetrexed Fresenius Kabi

The dose of Pemetrexed Fresenius Kabi 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 may be delayed depending on your blood test results and your general condition. A hospital pharmacist, nurse or doctor will have mixed Pemetrexed Fresenius Kabi with glucose 5% solution for intravenous infusion before administering it to you.
You will always receive Pemetrexed Fresenius Kabi by intravenous infusion. The infusion will last approximately 10 minutes.

When Pemetrexed Fresenius Kabi is used in combination with cisplatin:
Your doctor or hospital pharmacist will calculate the dose you require based on your height and weight. Cisplatin is also administered by intravenous infusion, approximately 30 minutes after completion of the Pemetrexed Fresenius Kabi infusion. The cisplatin infusion will last about 2 hours.
Generally, the infusion will be administered once every 3 weeks.

Additional medicines:
Corticosteroids: Your doctor will prescribe steroid tablets (equivalent to 4 milligrams of dexamethasone twice daily) that you must take the day before, on the day of, and the day after treatment with Pemetrexed Fresenius Kabi. 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 during treatment with Pemetrexed Fresenius Kabi. You must take at least 5 doses during the 7 days before your first dose of Pemetrexed Fresenius Kabi. You must continue taking folic acid for 21 days after your last dose of Pemetrexed Fresenius Kabi. You will also receive an injection of vitamin B12 (1000 micrograms) during the week before administration of Pemetrexed Fresenius Kabi, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed Fresenius Kabi). Vitamin B12 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 begin to feel chest pain (common) or have 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), a burning or tingling sensation (common), or fever (common). Rarely, skin reactions can be severe and may lead to death. Contact your doctor if a severe rash appears, or if you experience itching or blistering (Stevens-Johnson syndrome or toxic epidermal necrolysis).
If you feel tired, faint, short of breath, or look pale (because you may have lower than normal haemoglobin levels, which is very common).
If you experience 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 suddenly feel 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 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 (wasting) in the 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 levels in blood of chemicals produced by the liver
Increased skin pigmentation
Itchy skin
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 in the blood
Stroke
Type of stroke when an artery in the neck 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 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 (observed 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

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 severe type of skin and mucous membrane reaction that may be life-threatening)
Toxic epidermal necrolysis (a severe type of skin reaction that may be life-threatening)
Autoimmune disorders resulting in sudden skin redness and blisters on the 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 one or more of these symptoms and/or conditions. You should inform your doctor as soon as possible if you experience any of these side effects.
If you have any concerns 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 or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Pemetrexed Fresenius Kabi

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 label and on the carton after
EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Reconstituted solutions and infusion solutions: the product should be used immediately. If prepared
as indicated, the chemical and physical stability during use of reconstituted pemetrexed solutions has
been demonstrated for 24 hours under refrigerated conditions. For pemetrexed infusion solutions,
chemical and physical stability during use has been demonstrated for 21 days under refrigerated conditions and for 7 days at 25°C.
This medicine must not be used if any particles are present.
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 you no longer use. This will help protect the environment.

6. Package contents and other information

What Pemetrexed Fresenius Kabi contains
The active substance is pemetrexed.
Pemetrexed Fresenius Kabi 100 mg: each vial contains 100 milligrams of pemetrexed (as pemetrexed diacid).
Pemetrexed Fresenius Kabi 500 mg: each vial contains 500 milligrams of pemetrexed (as pemetrexed diacid).
After reconstitution, the solution contains 25 mg/ml of pemetrexed. Further dilution by healthcare personnel is required prior to administration.
The other ingredients are mannitol, hydrochloric acid and trometamol.

Description of the appearance of Pemetrexed Fresenius Kabi and contents of the pack
Pemetrexed Fresenius Kabi is a lyophilised powder or off-white to white solid for concentrate for solution for infusion in a glass vial.
It is available in packs of 1 vial.

Marketing Authorisation Holder
Fresenius Kabi Deutschland GmbH
Else-Kröner-Straße 1,
61352 Bad Homburg v.d. Höhe
Germany

Manufacturer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53
61169 Friedberg
Germany
Fresenius Kabi Polska Sp. z o.o.
ul. Sienkiewicza 25, Kutno, 99-300, Poland
Fresenius Kabi France - Louviers
6 rue du Rempart
Louviers, 27400
France

For further information about this medicinal product, please contact the Marketing Authorisation Holder.

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.

During reconstitution and further dilution of pemetrexed for intravenous infusion, aseptic techniques must be used.
Calculate the required dose and number of Pemetrexed Fresenius Kabi vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of the amount stated on the label.
Pemetrexed Fresenius Kabi 100 mg:
Reconstitute each 100 mg vial with 4.2 ml of 5% glucose solution for intravenous infusion to obtain a solution containing 25 mg/ml of pemetrexed.
Pemetrexed Fresenius Kabi 500 mg:
Reconstitute each 500 mg vial with 20 ml of 5% glucose solution for intravenous infusion 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 greenish-yellow; this 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 a final volume of 100 ml with 5% glucose solution for intravenous infusion 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 calcium-containing solvents, including Ringer's lactate for injectable preparations and Ringer's solution for injectable preparations.
Pemetrexed Fresenius Kabi contains trometamol as an excipient. Trometamol is incompatible with cisplatin, resulting in degradation of cisplatin. This medicinal product must not be mixed with other medicinal products. Intravenous administration lines must be flushed after administration of Pemetrexed Fresenius Kabi.
Prior to administration, parenteral medicinal products should be inspected visually for particulate matter and discoloration. Do not administer if particulate matter is observed.
Pemetrexed solutions are for single use only. Unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.

Precautions for preparation and administration: As with other potentially toxic antineoplastic agents, caution should be exercised when handling and preparing pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution comes into contact with the skin, wash immediately and thoroughly with water and soap. If pemetrexed solutions come into contact with mucous membranes, rinse thoroughly with water. Pregnant women should avoid contact with cytostatic drugs. Pemetrexed is not a vesicant. There is no specific antidote for pemetrexed extravasation. Cases of pemetrexed extravasation have been reported and were not considered severe by the investigator. Extravasation should be managed according to standard procedures for non-vesicant agents.

Package leaflet: Information for the user

Pemetrexed Fresenius Kabi 25 mg/ml concentrate for solution for infusion

pemetrexed
Please read this leaflet carefully before receiving 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 or pharmacist.
If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Pemetrexed Fresenius Kabi is and what it is used for

Pemetrexed Fresenius Kabi is a medicine used to treat cancers.
Pemetrexed Fresenius Kabi 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.
Additionally, Pemetrexed Fresenius Kabi, in combination with cisplatin, is used as first-line therapy in patients with advanced-stage lung cancer.
Pemetrexed Fresenius Kabi may be prescribed for advanced-stage lung cancer if the disease has responded to treatment or remains mostly unchanged after initial chemotherapy.
Furthermore, Pemetrexed Fresenius Kabi 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 using Pemetrexed Fresenius Kabi

Do not use Pemetrexed Fresenius Kabi

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

Warnings and precautions
Talk to your doctor or hospital pharmacist before receiving Pemetrexed Fresenius Kabi.
If you have or have had kidney problems, inform your doctor or hospital pharmacist, as you may not
be able to receive Pemetrexed Fresenius Kabi.
Before each infusion, blood tests will be performed to assess whether your liver and kidney functions are
adequate and to check that you have enough blood cells to receive Pemetrexed Fresenius Kabi. Your
doctor may decide to adjust the dose or delay treatment depending on your general condition and if
blood test results (blood cell counts) 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.
If you have undergone or will undergo radiation therapy, inform your doctor, as Pemetrexed Fresenius
Kabi may cause an early or delayed reaction related to radiation treatment.
If you have recently been vaccinated, inform your doctor, as this could lead to harmful effects with
Pemetrexed Fresenius Kabi.
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 drain the fluid before
administering Pemetrexed Fresenius Kabi.

Children and adolescents
This medicine should not be used in children and adolescents, as there is no experience with its use in
individuals under 18 years of age.

Other medicines and Pemetrexed Fresenius Kabi
Inform your doctor if you are taking any medicine for pain or inflammation (swelling), such as
medicines known as “non-steroidal anti-inflammatory drugs” (NSAIDs), including over-the-counter
medicines (such as ibuprofen). There are many types of NSAIDs with different durations of action.
Depending on the scheduled date for your Pemetrexed Fresenius Kabi infusion and/or your kidney
function, your doctor will advise you on which medicines you can take and when. 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 medicines,
including those without a prescription.

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

Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be discontinued during treatment with Pemetrexed Fresenius Kabi.

Fertility
Men are advised not to father a child during treatment with Pemetrexed Fresenius Kabi and for 3 months
after treatment. Therefore, an effective contraceptive method should be used during treatment with
Pemetrexed Fresenius Kabi or for 3 months thereafter. If you wish to father a child during treatment or
within 3 months after, consult your doctor or pharmacist. Pemetrexed Fresenius Kabi may affect the
ability to have children. Speak with your doctor for advice on sperm preservation before starting therapy.

Driving and use of machines
Pemetrexed Fresenius Kabi may cause fatigue. Be cautious when driving or operating machinery.

Pemetrexed Fresenius Kabi contains 964 mg of hydroxypropylbetadex per 100 mg of pemetrexed.
If you have kidney disease, consult your doctor before receiving this medicine.

3. How to use Pemetrexed Fresenius Kabi

The dose of Pemetrexed Fresenius Kabi 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 may be delayed depending on your blood test results and your general condition. A hospital pharmacist, nurse, or doctor will have reconstituted the Pemetrexed Fresenius Kabi powder with sodium chloride 9 mg/ml (0.9%) injection solution or with glucose 5% solution for intravenous infusion before administering it to you.
You will always receive Pemetrexed Fresenius Kabi as an intravenous infusion. The infusion will last approximately 10 minutes.

When Pemetrexed Fresenius Kabi is used in combination with cisplatin:
Your doctor or hospital pharmacist will calculate the dose you require based on your height and weight. Cisplatin is also administered by intravenous infusion, approximately 30 minutes after the Pemetrexed Fresenius Kabi infusion has been completed. The cisplatin infusion will last about 2 hours.
Generally, the infusion will be administered once every 3 weeks.

Additional medicines:

Corticosteroids: Your doctor will prescribe steroid tablets (equivalent to 4 mg of dexamethasone twice daily) to be taken the day before, the day of, and the day after treatment with Pemetrexed Fresenius Kabi. 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 during treatment with Pemetrexed Fresenius Kabi. You must take at least 5 doses during the 7 days before the first dose of Pemetrexed Fresenius Kabi. You should continue taking folic acid for 21 days after the last dose of Pemetrexed Fresenius Kabi. You will also receive an injection of vitamin B12 (1000 micrograms) during the week before administration of Pemetrexed Fresenius Kabi, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed Fresenius Kabi). Vitamin B12 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 lower than normal white blood cells, which is very common). Infection (sepsis) can be severe and may lead to death.
If you start experiencing chest pain (common) or have 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 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 than normal haemoglobin, 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 lower than normal platelets, 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 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 may cause stiffness and muscle atrophy, leading to muscle weakness and primary atrophy (wasting) 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 levels in blood of chemicals produced by the liver
Increased skin pigmentation
Itching of the skin
Widespread red spots
Hair loss
Hives
Kidneys stop working
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 in the blood
Stroke
Type of stroke when an artery in the neck is blocked
Bleeding in the skull
Angina (chest pain caused by reduced blood flow to the heart)
Heart attack
Narrowing or blockage of coronary arteries
Increased heart rate
Poor blood supply to limbs
Blockage in the lungs of one of the pulmonary arteries
Inflammation and scarring of the lung lining with breathing problems
Loss of bright red blood from the anus
Gastrointestinal tract bleeding
Intestinal perforation
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 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 condition of the liver
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 characterised by fluid-filled blisters
Skin fragility, blistering, erosion, and scarring of the skin
Redness, pain, and swelling, mainly in the lower limbs
Inflammation of the skin and fat beneath the skin (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)
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 start experiencing 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 experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Pemetrexed Fresenius Kabi

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 that month.
Store below 25 °C.
Keep the vial in its outer packaging to protect it from light.
Infusion solutions: the product should be used immediately. If prepared as recommended, the chemical and physical stability during use of diluted pemetrexed solutions has been demonstrated for 21 days under refrigerated conditions and for 7 days at 25°C.
This medicine must not be used if there is any trace of particles present.
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 Fresenius Kabi contains
The active substance is pemetrexed.
One ml of concentrate contains 25 mg of pemetrexed.
After dilution, a 4 ml vial of concentrate contains 100 mg of pemetrexed (as pemetrexed diacid).
A 20 ml vial of concentrate contains 500 mg of pemetrexed (as pemetrexed diacid).
A 40 ml vial of concentrate contains 1,000 mg of pemetrexed (as pemetrexed diacid).
The other components are hydroxypropylbetadex, hydrochloric acid, tromethamine, and water for injections.

Description of the appearance of Pemetrexed Fresenius Kabi and package contents
Pemetrexed Fresenius Kabi is a concentrate for solution for infusion (sterile concentrate) in a glass vial. It is a solution ranging from colourless to slightly yellowish or yellowish-green.
It is available in packages containing 1 vial.

Marketing Authorization Holder
Fresenius Kabi Deutschland GmbH
Else Kröner Straße 1,
61352 Bad Homburg v.d. Höhe
Germany

Manufacturer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53
61169 Friedberg
Germany
Fresenius Kabi Polska Sp. z o.o.
ul. Sienkiewicza 25, Kutno, 99-300, Poland

For further information about this medicinal product, please contact the Marketing Authorization Holder.

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

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The following information is intended exclusively for physicians or healthcare professionals:
Instructions for use, handling, and disposal.

During dilution of pemetrexed for intravenous infusion administration, aseptic techniques must be used.
Calculate the required dose and number of Pemetrexed Fresenius Kabi vials.
The appropriate volume of Pemetrexed Fresenius Kabi must be diluted to a final volume of 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for intravenous infusion and administered by 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 chloride and potassium chloride with calcium chloride and sodium lactate injection (Ringer lactate) and sodium chloride and potassium chloride with calcium chloride injection (Ringer's solution).
Pemetrexed Fresenius Kabi contains tromethamine as excipient. Tromethamine is incompatible with cisplatin, resulting in degradation of cisplatin. This medicinal product must not be mixed with other medicinal products. Intravenous lines must be flushed after administration of Pemetrexed Fresenius Kabi.
Prior to administration, parenteral medicinal products should be inspected visually for particulate matter and discoloration. Do not administer if particulate matter is observed.
Pemetrexed solutions are for single use only. Unused medicinal product and waste material arising from this medicinal product must be disposed of in accordance with local requirements.

Precautions for preparation and administration: As with other potentially toxic antineoplastic agents, caution should be exercised when handling and preparing pemetrexed infusion solutions. Wearing 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, rinse thoroughly with water. Pregnant women should avoid contact with cytostatic drugs. Pemetrexed is not a vesicant. There is no specific antidote for pemetrexed extravasation. Cases of pemetrexed extravasation have been reported and 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 OF THE TERMS OF THE MARKETING AUTHORISATION

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for pemetrexed, the following are the scientific conclusions of the PRAC:
In light of 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 of 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.