Pemetrexed Medac

Package leaflet: Information for the user

Pemetrexed medac 100 mg powder for concentrate for solution for infusion, 500 mg powder for concentrate for solution for infusion, 1.000 mg powder for concentrate for solution for infusion

pemetrexed
Please read all of this leaflet carefully before you start using this medicine as 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 get any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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

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

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

2. What you need to know before using Pemetrexed medac

Do not use Pemetrexed medac

• 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 medac.
• if you have recently received or are about to receive the yellow fever vaccine.

Warnings and precautions
Talk to your doctor or pharmacist before receiving Pemetrexed medac if:

• you have or have had kidney problems, as you may not be able to receive Pemetrexed medac. 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 medac. Your doctor may decide to adjust the dose or delay treatment depending on your general condition and if blood tests (white blood cells and platelets) show inadequate levels (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.
• you have undergone or are about to undergo radiation therapy, as Pemetrexed medac may cause an early or delayed reaction related to radiation treatment.
• you have recently been vaccinated, as this could cause harmful effects when using Pemetrexed medac.
• you have heart disease or a history of heart disease.
• you have fluid accumulation around the lungs, as your doctor may decide to remove the fluid before administering Pemetrexed medac.

Children and adolescents
This medicine must 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 medac
Inform your doctor or hospital pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription.
In particular, inform your doctor if you are using medicines for pain or inflammation (swelling), such as medicines called "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 medac 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.
Pregnancy
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine. Your doctor will discuss with you the potential risks of taking Pemetrexed medac during pregnancy. Women must use an effective method of contraception during treatment with Pemetrexed medac and for 6 months after receiving the last dose.
Breastfeeding
You must not breastfeed during treatment with Pemetrexed medac. Discuss with your doctor when it is safe to resume breastfeeding after completing treatment.
Fertility
Men are advised not to father a child during treatment with Pemetrexed medac and for up to 3 months after treatment ends, and should use an effective contraceptive method during treatment with Pemetrexed medac and for 3 months afterwards. If you wish to father a child during treatment or within 3 months afterwards, consult your doctor or pharmacist. Pemetrexed medac may affect your ability to have children. Talk to your doctor for advice on sperm preservation before starting therapy.
Driving and using machines
Pemetrexed medac may cause fatigue. Be cautious when driving or operating machinery.
Pemetrexed medac contains sodium
Pemetrexed medac 100 mg
This medicine contains less than 1 mmol (23 mg) of sodium per 100 mg vial, i.e. essentially 'sodium-free'.
Pemetrexed medac 500 mg
This medicine contains 54 mg of sodium (main component of table salt) per 500 mg vial. This corresponds to 2.70% of the maximum daily recommended dietary intake for an adult.
Pemetrexed medac 1.000 mg
This medicine contains 108 mg of sodium (main component of table salt) per 1.000 mg vial. This corresponds to 5.40% of the maximum daily recommended dietary intake for an adult.

3. How to use Pemetrexed medac

The recommended dose of Pemetrexed medac 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
treatment may be delayed depending on your blood test results and your general condition. A
hospital pharmacist, nurse or doctor will have mixed the Pemetrexed medac powder with a sodium chloride solution 9 mg/ml (0.9%) for injectable preparations before administering it to you.
You will always receive Pemetrexed medac by intravenous infusion. The infusion will last about 10 minutes.
When Pemetrexed medac 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 medac infusion has been completed. The cisplatin infusion will last about 2 hours.
Typically, you should receive the infusion 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 medac. 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
(350–1,000 micrograms) to be taken orally once daily during treatment with Pemetrexed medac. You must take at least 5 doses during the 7 days before the first dose of
Pemetrexed medac. You must continue taking folic acid for 21 days after the last dose of
Pemetrexed medac. You will also receive an injection of vitamin B\textsubscript{12} (1,000 micrograms) during the week before administration of Pemetrexed medac and then approximately every 9 weeks (corresponding to
3 treatment cycles with Pemetrexed medac). Vitamin B\textsubscript{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 experience 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), 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 have itching or blisters form (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 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 suddenly feel short of breath, have severe chest pain, or have a cough with blood in the sputum (uncommon) (this may indicate a blood clot in the blood vessels of the lungs).

The following side effects may occur during treatment with pemetrexed:
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 (wasting) 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 heart rhythm
Indigestion
Constipation
Abdominal pain
Liver: increased blood levels of chemicals produced by the liver
Increased skin pigmentation
Itchy 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 the coronary arteries
Increased heart rate
Inadequate blood supply to limbs
Blockage in the lungs of one of the pulmonary arteries
Inflammation and scarring of the lining of the lungs causing breathing problems
Bright red bleeding from the anus
Gastrointestinal tract bleeding
Intestinal rupture
Inflammation of the lining of the oesophagus
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 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 characterized by the presence of 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)
A form of diabetes primarily due to kidney disease
Kidney disorders leading to death of tubular epithelial cells forming the kidney tubules

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 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 medac

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 the carton after
Exp.
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 in-use stability of reconstituted pemetrexed solutions for infusion has been demonstrated for 24 hours under refrigerated conditions (2°C–8°C).
This medicine is for single use only; any unused solution must be disposed of in accordance with local regulations.

6. Package contents and other information

What Pemetrexed medac contains
The active substance is pemetrexed.
Pemetrexed medac 100 mg: Each vial contains 100 mg of pemetrexed (as pemetrexed
disodium hemipentahydrate).
Pemetrexed medac 500 mg: Each vial contains 500 mg of pemetrexed (as pemetrexed
disodium hemipentahydrate).
Pemetrexed medac 1,000 mg: Each vial contains 1,000 mg of pemetrexed (as pemetrexed
disodium hemipentahydrate).
After reconstitution, the solution contains 25 mg/mL of pemetrexed.
The other components are mannitol, hydrochloric acid and sodium hydroxide. See section 2
"Pemetrexed medac contains sodium".

Description of the appearance of Pemetrexed medac and contents of the pack
Pemetrexed medac is a powder for concentrate for solution for infusion in a glass vial with a rubber stopper.
It is a powder ranging in colour from white to pale yellow.
Each pack contains one vial of 100, 500 or 1,000 mg of pemetrexed.

Marketing Authorisation Holder
medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Tel.: +49 4103 8006-0
Fax: +49 4103 8006-100

Manufacturer:
Synthon Hispania SL
C/Castelló n°1, Pol. Las Salinas
08830 Sant Boi de Llobregat
Barcelona
Spain
Tel.: +34 936401516
Fax: +34 936401146

Synthon, s.r.o.
Brnĕnská 32/cp. 597
67801 Blansko
Czech Republic
Tel.: +420 516 427 311
Fax: +420 516 417 350

medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Tel.: +49 4103 8006-0
Fax: +49 4103 8006-100

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 for healthcare professionals only:

Instructions for use, handling, and disposal

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

Pemetrexed medac 500 mg:
Reconstitute each 500 mg vial with 20 ml of sodium chloride solution 9 mg/ml (0.9%) for injectable preparations, without preservatives, to obtain a solution containing 25 mg/ml of pemetrexed.
Pemetrexed medac 1,000 mg:
Reconstitute each 1,000 mg vial with 40 ml of sodium chloride solution 9 mg/ml (0.9%) for injectable preparations, 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, 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.

4. The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml with sodium chloride solution 9 mg/ml (0.9%) for injectable preparations, without preservatives, and administered as an intravenous infusion over 10 minutes.
5. 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 sodium chloride and potassium chloride and calcium chloride for injectable preparations, Ringer lactate for injectable preparations, and Ringer for injectable preparations.
6. Prior to administration, parenteral medicines should be visually inspected for particulate matter and discoloration. Do not administer if particulate matter is observed.
7. 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.

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. 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.