Pemetrexed Sun

Patient Information Leaflet

Pemetrexed SUN 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
Generic medicine (only for the 100 mg and 500 mg strengths)
Please read this leaflet carefully before this medicine is administered to you 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.
• If you get any side effects, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

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

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

Pemetrexed SUN contains the active substance pemetrexed, which belongs to a group of medicines used in the treatment of cancers. It is used:

• in combination with cisplatin, another anticancer medicine, as treatment for malignant pleural mesothelioma, a form of cancer affecting the lining of the lungs, in patients who have not received prior chemotherapy
• in combination with cisplatin, it is given as first-line therapy in patients with advanced-stage lung cancer
• as treatment in patients with advanced-stage lung cancer, if the disease has responded to treatment or remains mostly unchanged after initial chemotherapy
• as treatment for patients with advanced-stage lung cancer whose disease has progressed after prior initial chemotherapy treatment.

2. What you should know before being given Pemetrexed SUN

Pemetrexed SUN must NOT be administered

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

Warnings and precautions
Inform your doctor before being given Pemetrexed SUN

• if you have or have had kidney problems. Inform your doctor or hospital pharmacist, as you may not be able to receive Pemetrexed SUN.

Before each infusion, blood tests will be performed to assess whether your liver and kidney function are sufficient and to check that you have enough blood cells to receive Pemetrexed SUN. 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 (white blood cells and platelets too low). Additionally, if you are receiving cisplatin, your doctor must ensure that you are adequately hydrated and that you receive appropriate antiemetic treatment before and after receiving cisplatin to prevent vomiting.

• if you have undergone or are scheduled to undergo radiation therapy, inform your doctor, as Pemetrexed SUN may cause an early or delayed reaction related to radiation treatment
• if you have recently been vaccinated, as this may cause harmful effects when taking Pemetrexed SUN
• if you have heart disease or a history of heart disease
• if you have fluid accumulation around the lungs, your doctor may decide to drain the fluid before administering Pemetrexed SUN.

Children and adolescents
This medicine must not be used in children and adolescents, as there is no experience with Pemetrexed SUN in individuals under 18 years of age.
Other medicines and Pemetrexed SUN
Inform your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription.
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 those 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 SUN 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.

Pregnancy, breastfeeding and fertility
Pregnancy
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before receiving this medicine. The use of Pemetrexed SUN during pregnancy should be avoided. Your doctor will discuss with you the potential risks of taking Pemetrexed SUN during pregnancy. Women must use an effective method of contraception during treatment with Pemetrexed SUN.
Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be stopped during treatment with Pemetrexed SUN.
Fertility
Men are advised not to father a child during treatment with Pemetrexed SUN and for up to 6 months after treatment ends, and should use an effective contraceptive method during treatment with Pemetrexed SUN or for up to 6 months afterwards. If you wish to father a child during treatment or within 6 months after treatment, consult your doctor or pharmacist. You are advised to seek information about sperm preservation before starting therapy.
Driving and using machines
Pemetrexed SUN may cause fatigue. Exercise caution when driving a vehicle or operating machinery.
Pemetrexed SUN contains sodium
Pemetrexed SUN 100 mg contains 11 mg of sodium (≤ 1 mmol) per vial, which is essentially "sodium-free"
Pemetrexed SUN 500 mg contains approximately 54 mg (2.35 mmol) of sodium per vial. This should be taken into account by patients on a sodium-controlled diet.
Pemetrexed SUN 1000 mg contains approximately 108 mg (4.70 mmol) of sodium per vial. This should be taken into account by patients on a sodium-controlled diet.

3. How to take Pemetrexed SUN

The recommended dose of Pemetrexed SUN is 500 milligrams 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 pharmacist, nurse or doctor will have reconstituted the Pemetrexed SUN powder with a sodium chloride solution 9 mg/ml (0.9%) for injectable preparations before administering it to you.
You will always receive Pemetrexed SUN as an intravenous infusion. The infusion will last approximately 10 minutes.
When Pemetrexed SUN is used in combination with cisplatin:

• your doctor or pharmacist will calculate the dose you require based on your height and weight. Cisplatin is also administered as an intravenous infusion, approximately 30 minutes after completion of the Pemetrexed SUN 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, the day of, and the day after treatment with Pemetrexed SUN. 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 SUN. You must take at least 5 doses during the 7 days before your first dose of Pemetrexed SUN. You must continue taking folic acid for 21 days after your last dose of Pemetrexed SUN. You will also receive an injection of vitamin B12 (1000 micrograms) during the week before administration of Pemetrexed SUN, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed SUN). 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, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects
You must contact your doctor immediately if you notice any of the following serious side effects:

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

• pain, redness, swelling, or sores in the mouth
• allergic reaction: skin rash. Rarely, skin reactions can be severe and may lead to death
• low haemoglobin levels (anaemia). You may feel tired, faint, short of breath, or look pale
• low platelet count. You may experience bleeding from gums, nose, or mouth, or any bleeding that does not stop easily, red or slightly pink urine, or unexpected bruising.

Common (may affect up to 1 in 10 people)

• fever or infection: if you have a body temperature of 38°C or higher, sweating, or other signs of infection (as you may have fewer white blood cells than normal, which is very common). Infection (sepsis) can be severe and may lead to death
• chest pain
• allergic reaction: burning or tingling sensation and fever.

Uncommon (may affect up to 1 in 100 people)

• fast heart rate
• blood clots in the blood vessels of the lungs (pulmonary embolism). You may experience sudden shortness of breath, severe chest pain, or coughing up blood.

Rare (may affect up to 1 in 1,000 people)

• allergic reaction: severe skin rash, itching, or blistering (Stevens-Johnson syndrome or toxic epidermal necrolysis).

Other side effects
Tell your doctor as soon as possible if you experience any of the following side effects:

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
• damage to motor nerves, which may cause muscle weakness and primary atrophy (wasting) in 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)
• eyelid swelling
• 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
• red spots on the body
• hair loss
• hives
• kidneys stop working
• 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 an artery in the brain 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
• abnormal heart rhythm
• poor blood supply to limbs
• blockage 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
• bowel 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 mucosal surface of the oesophagus 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 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 diseases 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
• 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

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 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 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 SUN

Your doctor, pharmacist, or nurse knows how to properly store Pemetrexed SUN.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and outer packaging following "Exp". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
After opening the vial, the medicine should be used immediately to avoid microbial contamination. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at 2°C - 8°C, unless reconstitution/dilution has taken place under controlled and validated aseptic conditions. Allow the refrigerated solution to reach room temperature before administration.

6. Package Contents and Other Information

What Pemetrexed SUN contains

• The active substance is pemetrexed. Each vial contains 100, 500, or 1000 milligrams of pemetrexed (as pemetrexed disodium heptahydrate). After reconstitution, the solution contains 25 mg/ml of pemetrexed. Further dilution by healthcare personnel is required prior to administration.
• The other components are mannitol, hydrochloric acid and/or sodium hydroxide (for pH adjustment) (see section 2 for further information).

Description of the appearance of Pemetrexed SUN and contents of the pack
Pemetrexed SUN is a powder for concentrate for solution for infusion in a vial. It is a lyophilized powder with a color ranging from white to pale yellow or yellow-green.
Pemetrexed SUN is available in packs containing one vial.

Marketing Authorization Holder and Manufacturer
Sun Pharmaceutical Industries Europe B.V.
Polarisavenue 87
2132 JH Hoofddorp
The Netherlands

Representative in Italy:
Sun Pharma Italia Srl
Viale Giulio Richard, 1
20143 Milan

This medicinal product is authorized in the Member States of the European Economic Area under the following names:
France: Pemetrexed SUN 100 mg/500 mg/1000 mg powder for solution for infusion
Germany: Pemetrexed SUN 100 mg/500 mg/1000 mg powder for concentrate for solution for infusion
Italy: Pemetrexed SUN
Netherlands: Pemetrexed SUN 100 mg/500 mg/1000 mg powder for concentrate for solution for infusion
Poland: Pemetreksed SUN 100 mg/500 mg/1000 mg powder for concentrate for solution for infusion
United Kingdom: Pemetrexed SUN 100 mg/500 mg/1000 mg powder for concentrate for solution for infusion
Romania: Pemetrexed SUN 100 mg/500 mg/1000 mg powder for concentrate for perfusable solution
Spain: Pemetrexed SUN 100 mg powder for concentrate for solution for infusion EFG
Pemetrexed SUN 500 mg powder for concentrate for solution for infusion EFG
Pemetrexed SUN 1000 mg powder for concentrate for solution for infusion EFG

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

1. During reconstitution and further dilution of pemetrexed for intravenous infusion administration, aseptic techniques must be used.
2. Calculate the required dose and number of Pemetrexed SUN vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of the labeled amount.
3. Pemetrexed SUN 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 SUN 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 SUN 1000 mg:
Reconstitute each 1000 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 colorless to yellow or yellow-green, without negatively affecting the quality of the product. The pH of the reconstituted solution is between 6.6 and 7.8. The osmolality of the reconstituted solution is between 480 and 570 mOsm/kg. 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 a 10-minute intravenous infusion.
5. Pemetrexed infusion solutions, 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 injectable lactated Ringer's solution and injectable Ringer's solution.
6. Prior to administration, parenteral medicinal products must be visually inspected for the presence of particles and discoloration. Do not administer if particles are observed.
7. 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 for cytotoxic agents.

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 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 but were not considered severe by the investigator. Extravasation should be managed according to standard procedures for non-vesicant agents.