Pemetrexed ever pharma

Package leaflet: Information for the user

Pemetrexed EVER Pharma, 25 mg/ml, concentrate for solution for infusion
pemetrexed
Please read all of this leaflet carefully before this medicine is administered because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Pemetrexed EVER Pharma is and what it is used for

Pemetrexed EVER Pharma is a medicine used in cancer treatment. It contains the active substance
pemetrexed. Pemetrexed belongs to a group of medicines called folic acid analogues. It interferes with
processes essential for cell proliferation.
Pemetrexed EVER Pharma, in combination with another anticancer medicine, cisplatin, is used to treat
malignant pleural mesothelioma, a type of cancer affecting the membrane covering the lungs, in patients
who have not previously received chemotherapy.
Pemetrexed EVER Pharma in combination with cisplatin is also used as first-line treatment in patients
with advanced-stage lung cancer.
Pemetrexed EVER Pharma may be used in patients with advanced-stage lung cancer who have responded
to initial chemotherapy or whose disease has remained largely stable following initial chemotherapy.
Pemetrexed EVER Pharma is also used to treat patients with advanced-stage lung cancer in whom the
disease has progressed after initial treatment with other chemotherapeutic agents.

2. Important information before using Pemetrexed EVER Pharma

When not to use Pemetrexed EVER Pharma:

• if the patient is allergic to pemetrexed or any of the other ingredients of this medicine (listed in section 6).
• if the patient is breastfeeding, breastfeeding must be discontinued during treatment with Pemetrexed EVER Pharma.
• in patients who have recently been vaccinated or are scheduled to be vaccinated against yellow fever.

Warnings and precautions
Before starting treatment with Pemetrexed EVER Pharma, discuss this with your doctor or
hospital pharmacist.
Patients who have or have previously had impaired kidney function should inform their doctor or
hospital pharmacist, as this may mean that Pemetrexed EVER Pharma cannot be used.
Before each infusion, medical staff will take blood samples from the patient to assess liver and
kidney function and to check whether blood cell counts are sufficient to allow administration of
Pemetrexed EVER Pharma. Depending on the patient's general condition and in case of excessive
reduction in blood cell counts, the doctor may adjust the dose or delay administration of the medicine.
If the patient is being treated concurrently with cisplatin, the doctor will assess hydration status and
recommend appropriate treatment to prevent vomiting.
Patients who have undergone or are scheduled to undergo radiotherapy should inform their doctor,
as early or delayed radiation reactions may occur after administration of Pemetrexed EVER Pharma.
Patients who have recently been vaccinated should inform their doctor, as this may cause adverse
reactions in combination with Pemetrexed EVER Pharma.
Patients who have or have had heart disease should inform their doctor.
If fluid has accumulated around the patient's lung, the doctor may decide to perform a procedure to
drain the fluid before administering Pemetrexed EVER Pharma.

Children and adolescents
Pemetrexed EVER Pharma is not indicated for use in children and adolescents.

Pemetrexed EVER Pharma and other medicines
Tell your doctor or hospital pharmacist about all medicines the patient is currently taking or has
recently taken, as well as any medicines the patient plans to take, including painkillers and anti-inflammatory medicines (e.g. those that reduce swelling), such as non-steroidal anti-inflammatory drugs (NSAIDs), including those available without a prescription (e.g. ibuprofen). There are many types of non-steroidal anti-inflammatory drugs (NSAIDs) with different durations of action.
Depending on the planned date of Pemetrexed EVER Pharma infusion and (or) the patient's kidney function, the doctor will advise which medicines can be taken and when. If in doubt whether a medicine belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs), ask the doctor or pharmacist.
Inform the doctor if the patient is taking medicines known as proton pump inhibitors (omeprazole, esomeprazole, lanzoprazole, pantoprazole and rabeprazole) used to treat heartburn and acid reflux.
As with other chemotherapeutic agents, co-administration of Pemetrexed EVER Pharma with live attenuated vaccines is not recommended. Inactivated vaccines should be used whenever possible.

Pregnancy
If the patient is pregnant, suspects she may be pregnant, or is planning to have a child, she should
consult her doctor before using Pemetrexed EVER Pharma. Use of Pemetrexed EVER Pharma during pregnancy should be avoided. The doctor will inform the patient about the potential risks associated with using Pemetrexed EVER Pharma during pregnancy. Women must use an effective method of contraception during treatment with Pemetrexed EVER Pharma and for 6 months after receiving the last dose.

Breastfeeding
If the patient is breastfeeding, she should inform her doctor.
Breastfeeding must be discontinued during treatment with Pemetrexed EVER Pharma.

Effect on fertility
Men are advised not to attempt to father a child during treatment and for 3 months after completion of Pemetrexed EVER Pharma therapy, and to use effective contraception during this time. If a man wishes to father a child during treatment or within 3 months after completion of treatment, he should consult his doctor or pharmacist. Pemetrexed EVER Pharma may affect the ability to have children. Before starting treatment, patients may consult their doctor for advice regarding sperm storage.

Driving and operating machinery
Pemetrexed EVER Pharma may cause fatigue. Caution should be exercised when driving and operating machinery.

Pemetrexed EVER Pharma contains sodium
This medicine contains 96.6 mg of sodium (the main component of table salt) per 500 mg dose of pemetrexed per square metre of body surface area. This corresponds to 4.8% of the maximum recommended daily dietary intake of sodium for adults.

3. How to use Pemetrexed EVER Pharma

Pemetrexed EVER Pharma will always be administered by qualified medical personnel.
The recommended dose of Pemetrexed EVER Pharma is 500 milligrams per square meter of the patient's body surface area. Body surface area is calculated based on the patient's height and weight measurements. The physician will determine the dose of the medication according to the calculated body surface area.
Dose adjustments or treatment delays may be necessary depending on blood count test results and the patient's overall condition. Prior to administration of Pemetrexed EVER Pharma, the hospital pharmacist, nurse, or physician will mix the concentrate with 9 mg/ml (0.9%) sodium chloride injection solution or 5% glucose solution.
Pemetrexed EVER Pharma is always administered as an intravenous infusion. The infusion lasts approximately 10 minutes.

Administration of Pemetrexed EVER Pharma in combination with cisplatin:
The physician or hospital pharmacist will calculate the dose based on the patient's height and weight. Cisplatin is also administered as an intravenous infusion. The cisplatin infusion begins approximately 30 minutes after completion of the Pemetrexed EVER Pharma infusion and lasts about two hours.
Infusions are usually given every 3 weeks.

Additional medications:

Corticosteroids: Your doctor will prescribe oral corticosteroids (in a dose equivalent to 4 milligrams of dexamethasone twice daily) to be taken the day before, on the day of, and the day after Pemetrexed EVER Pharma infusion. These medications are used to reduce the frequency and severity of skin reactions (skin changes) that may occur during anticancer treatment.

Vitamins: 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 EVER Pharma. At least five doses of folic acid must be taken during the seven days preceding the first dose of Pemetrexed EVER Pharma. Folic acid should be continued for 21 days after receiving the last dose of Pemetrexed EVER Pharma.

During the week preceding the first administration of Pemetrexed EVER Pharma, and then every approximately 9 weeks (corresponding to three cycles of chemotherapy with Pemetrexed EVER Pharma), patients will also receive vitamin B₁₂ (1000 micrograms) by injection. Administration of vitamin B₁₂ and folic acid is intended to reduce potential adverse effects of anticancer drugs.

The patient's condition will be closely monitored during treatment with Pemetrexed EVER Pharma. This monitoring routinely includes blood tests as well as liver and kidney function tests. The dose of the medication may be adjusted or treatment delayed depending on the results of these tests.

If you have any further questions about the use of this medication, please consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
If any of the following symptoms occur, contact your doctor immediately:

• Fever or infection (common): if you have a fever of 38°C or higher, excessive sweating, or other signs of infection (due to the possibility of a severe decrease in white blood cells, which is a very common effect). Infection (sepsis) may be severe and may lead to death.
• Chest pain (common) or rapid heartbeat (uncommon).
• Pain, redness, swelling or sores in the mouth (very common).
• Allergic reaction: skin rash (very common), burning or tingling sensation (common), or fever (common). In rare cases, skin reactions may be severe and lead to death. If you develop a severe rash, itching or blisters (symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis), contact your doctor.
• Feeling tired, weak, sudden shortness of breath or pale skin (due to the possibility of a severe decrease in hemoglobin levels, which is a very common effect).
• Bleeding from gums, nose or mouth, or other bleeding that cannot be stopped, red or pink urine, unexpected bruising on the skin (due to the possibility of a severe decrease in platelet count, which is a very common effect).
• Sudden shortness of breath, severe chest pain or cough with blood-stained sputum (uncommon) (may indicate blood clots in the lung vessels).

Possible adverse reactions after administration of pemetrexed:
Very common (may affect more than 1 in 10 people)

• Infection
• Sore throat (throat pain)
• Low neutrophil count (a type of white blood cell)
• Low white blood cell count
• Low hemoglobin levels
• Pain, redness or ulceration in the mouth
• Loss of appetite
• Vomiting
• Diarrhea
• Nausea
• Skin rash
• Skin peeling
• Abnormal blood test results indicating impaired kidney function
• Fatigue

Common (may affect up to 1 in 10 people)

• Blood infection (sepsis)
• Fever with low neutrophil count (a type of white blood cell)
• Low platelet count
• Hypersensitivity reactions
• Fluid loss (dehydration)
• Taste disturbances
• Damage to motor nerves, which may lead to muscle weakness and atrophy, especially in arms and legs
• Damage to sensory nerves, which may lead to loss of sensation, burning pain and unsteady gait
• Dizziness
• Inflammation or swelling of the conjunctiva (membranes lining the inner eyelids and covering the white of the eye)
• Dry eye syndrome
• Excessive tearing of the eyes
• Dryness of the conjunctiva (membranes lining the inner eyelids and covering the white of the eye) and cornea (transparent layer in front of the iris and pupil)
• Swelling of the eyelids
• Eye disorders with accompanying dryness, tearing, irritation and (or) pain
• Heart failure (a condition causing reduced pumping strength of the heart muscle)
• Irregular heartbeat
• Indigestion
• Constipation
• Abdominal pain
• Liver: increased blood levels of chemicals produced in the liver
• Increased skin pigmentation
• Itching of the skin
• Skin rash with ring-shaped lesions resembling a target
• Urticaria (hives)
• Kidney shutdown
• Worsening of kidney function
• Fever
• Pain
• Excessive fluid accumulation in tissues causing swelling
• Chest pain
• Inflammation and ulceration of the mucous membranes lining the gastrointestinal tract

Uncommon (may affect up to 1 in 100 people)

• Decreased number of red blood cells, white blood cells and platelets
• Stroke
• A type of stroke caused by blockage of an artery supplying blood to the brain
• Intracranial hemorrhage
• Angina (chest pain caused by myocardial ischemia)
• Heart attack
• Narrowing or blockage of the coronary arteries
• Heart rhythm disorders
• Inadequate blood supply to the limbs
• Blockage of one of the pulmonary arteries
• Inflammatory condition and scarring of the membrane lining the lungs, causing breathing difficulties
• Bright red blood from the rectum
• Gastrointestinal bleeding
• Perforation of the intestinal wall
• Inflammation of the esophageal lining
• Inflammation of the large intestine lining, which may be accompanied by intestinal or rectal bleeding (observed only when used in combination with cisplatin)
• Inflammation, swelling, redness and ulceration of the esophageal mucosa caused by radiotherapy
• Radiation-induced lung inflammation

Rare (may affect up to 1 in 1000 people)

• Hemolysis (breakdown of red blood cells)
• Anaphylactic shock (severe allergic reaction)
• Hepatitis (liver inflammation)
• Skin redness
• Skin rash appearing in previously irradiated areas

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

• Skin and subcutaneous tissue infections
• Stevens-Johnson syndrome (a type of severe skin and mucous membrane reaction which may be life-threatening)
• Toxic epidermal necrolysis (a type of severe skin reaction which may be life-threatening)
• Autoimmune disorders causing rash and blistering on the skin of legs, arms and abdomen
• Skin inflammation with formation of fluid-filled blisters
• Skin fragility, presence of blisters and erosions, and skin scarring
• Redness, pain and swelling, mainly in the lower limbs
• Inflammation of the skin and subcutaneous fat tissue (pseudocellulitis)
• Dermatitis (skin inflammation)
• Inflammatory condition, itching, redness, cracking and roughness of the skin
• Intensely itchy skin lesions

Unknown (frequency cannot be estimated from available data)

• A type of diabetes primarily caused by kidney abnormalities
• Kidney disorders leading to necrosis of tubular epithelial cells

Any of these symptoms and (or) conditions may occur. If the first signs of these adverse reactions appear, inform your doctor as quickly as possible.
Talk to your doctor if you are concerned about any of these adverse reactions.
Reporting of adverse reactions
If any adverse effects occur, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw,
Tel.: +48 22 49 21 301,
Fax: +48 22 49 21 309,
Website: https://smz.ezdrowie.gov.pl
Adverse reactions may also be reported to the marketing authorization holder.
By reporting adverse reactions, additional information on the safety of this medicine can be collected.

5. How to store Pemetrexed EVER Pharma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton following:
Expiry date (EXP). The expiry date refers to the last day of the stated month.
Do not freeze.
Infusion solution after dilution: Physical and chemical stability of prepared solutions and diluted infusion solutions of pemetrexed has been demonstrated for 28 days when stored refrigerated at (2°C to 8°C) and for 7 days at temperatures from 20°C to 30°C.
From a microbiological standpoint, the product should be used immediately after preparation. If the product is not used immediately, the responsibility for storage duration and conditions prior to use lies with the user: the solution should be stored at 2°C to 8°C for no longer than 24 hours, unless dilution was carried out under controlled and validated aseptic conditions.
Pemetrexed EVER Pharma should not be used if it contains particulate matter or other visible signs of deterioration.
This medicine is for single use only. Any unused solution should be disposed of in accordance with applicable regulations.

6. Contents of the pack and other information

What Pemetrexed EVER Pharma contains
The active substance is pemetrexed.
One millilitre of concentrate contains 25 mg of pemetrexed (as pemetrexed disodium).
One 4 ml vial contains 100 mg of pemetrexed (as pemetrexed disodium).
One 20 ml vial contains 500 mg of pemetrexed (as pemetrexed disodium).
One 40 ml vial contains 1000 mg of pemetrexed (as pemetrexed disodium).
The other ingredients are tromethamine, monothioglycerol, citric acid, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), and water for injections.
The medicine must be further diluted before administration. This procedure will be carried out by a healthcare professional.

What Pemetrexed EVER Pharma looks like and contents of the pack
Pemetrexed EVER Pharma, concentrate for solution for infusion, is a clear, aqueous solution, yellowish or greenish-yellow in colour.
Pemetrexed EVER Pharma is supplied in vials made of colourless glass, closed with a bromobutyl rubber stopper and an aluminium flip-off cap, with or without a protective cap, packed in a cardboard box.
Each pack contains one vial with Pemetrexed EVER Pharma.

Pack sizes:
1 x 4 ml vial (100 mg/4 ml)
1 x 20 ml vial (500 mg/20 ml)
1 x 40 ml vial (1000 mg/40 ml)
Not all pack sizes may be marketed.

Marketing Authorisation Holder
EVER Valinject GmbH
Oberburgau 3
4866 Unterach am Attersee
Austria

Manufacturer
EVER Pharma Jena GmbH
Otto Schott Street 15
07745 Jena
Germany
EVER Pharma Jena GmbH
Brüsseler Str. 18
07747 Jena
Germany

This medicinal product is authorised in the European Economic Area under the following names:

Information intended exclusively for healthcare professionals:
For complete information, see the Summary of Product Characteristics.
Pregnant women should not handle this medicine.
Instructions for use, preparation and disposal of the medicinal product

1. The preparation of pemetrexed solution and further dilution for intravenous infusion must be carried out under aseptic conditions.

2. Calculate the required dose and number of vials of the medicinal product Pemetrexed EVER Pharma needed.

3. Dilute the appropriate volume of the medicinal product Pemetrexed EVER Pharma to a final volume of 100 ml using either sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for injection, without preservatives. The medicinal product should be administered as an intravenous infusion over 10 minutes.

4. Solutions of the medicinal product Pemetrexed EVER Pharma prepared as described above are compatible with infusion bags and administration sets made of polyvinyl chloride and polyolefin. Pemetrexed EVER Pharma is physically incompatible with diluents containing calcium, including Ringer's injection solution with lactate and Ringer's injection solution. Pemetrexed EVER Pharma contains tromethamine as an excipient. Tromethamine is incompatible with cisplatin, causing degradation of cisplatin. This medicinal product must not be mixed with other medicinal products. Intravenous lines should be flushed after administration of Pemetrexed EVER Pharma.

5. Prior to parenteral administration, visually inspect the solution for particulate matter and discoloration. If particulate matter is present in the solution, the medicinal product should not be administered.

6. Pemetrexed solutions are for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local regulations.

Precautions during preparation and administration of the medicinal product
As with other potentially toxic cytotoxic agents, caution should be exercised when handling the medicinal product and preparing pemetrexed solutions for infusion. The use of gloves is recommended. In case of skin contact with pemetrexed solution, wash the skin immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse the affected area thoroughly with water. Pemetrexed does not cause blistering. There is no known specific antidote in the event of extravasation. There have been rare reports of extravasation of pemetrexed, which were not considered serious by investigators. In the event of extravasation, manage according to established guidelines, as with other non-vesicant substances.