Alimta

Package leaflet: Information for the user

ALIMTA 100 mg powder for concentrate for solution for infusion, 500 mg powder for concentrate for solution for infusion

pemetrexed
Read all of 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 further questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. See section 4.

What is in this leaflet

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

1. What ALIMTA is and what it is used for

ALIMTA is a medicine used in the treatment of cancers.
ALIMTA 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, ALIMTA, in combination with cisplatin, is administered as first-line therapy in patients with advanced-stage lung cancer.
ALIMTA may be prescribed for advanced-stage lung cancer if the disease has responded to treatment or remains mostly unchanged after initial chemotherapy.
Furthermore, ALIMTA is a treatment for patients with advanced-stage lung cancer whose disease has progressed after prior initial chemotherapy treatment.

2. What you should know before taking ALIMTA

Do not take ALIMTA

• if you are allergic (hypersensitive) 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 ALIMTA.
• 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 receiving ALIMTA.
If you have or have had kidney problems, inform your doctor or hospital pharmacist, as you may not be able to receive ALIMTA.
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 ALIMTA. 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.
If you have undergone or will undergo radiation therapy, inform your doctor, as with ALIMTA, an early or delayed reaction due to radiation therapy may occur.
If you have recently been vaccinated, inform your doctor, as with ALIMTA this could cause harmful effects.
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 ALIMTA.

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

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

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

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

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

Driving and using machines
ALIMTA may cause fatigue. Be cautious when driving a vehicle or operating machinery.

ALIMTA contains sodium
ALIMTA 100 mg concentrate powder for solution for infusion
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. it is essentially "sodium-free".
ALIMTA 500 mg concentrate powder for solution for infusion
This medicine contains 54 mg of sodium (the main component of table salt) per vial. This is equivalent to 2.7% of the maximum daily recommended dietary sodium intake for an adult.

3. How to take ALIMTA

The dose of ALIMTA 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 the ALIMTA powder with a sodium chloride solution 9 mg/ml (0.9%) for injectable preparations before administering it to you.
You will always receive ALIMTA by intravenous infusion. The infusion will last approximately 10 minutes.
When ALIMTA 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 ALIMTA infusion has been completed. The cisplatin infusion will last approximately 2 hours.
You will usually receive the infusion once every 3 weeks.
Additional medicines:
Corticosteroids: Your doctor will prescribe steroid tablets (equivalent to 4 milligrams of dexamethasone twice daily) to be taken the day before, on the day of, and the day after ALIMTA treatment. 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 ALIMTA. You must take at least 5 doses during the 7 days before your first dose of ALIMTA. You should continue taking folic acid for 21 days after your last dose of ALIMTA. You will also receive an injection of vitamin B({12}) (1000 micrograms) during the week before administration of ALIMTA, and then approximately every 9 weeks (corresponding to 3 treatment cycles of ALIMTA). Vitamin B({12}) and folic acid are administered to reduce the potential toxic effects of anticancer treatment.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone 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 experience chest pain (common) or have 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 the gums, nose, or mouth, or any bleeding that does not stop easily, reddish or slightly pink urine, or unexpected bruising (because you may have fewer platelets than normal, which is common).
• If you suddenly 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).

Side effects with ALIMTA 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 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 the blood of chemicals produced by the liver
Increased skin pigmentation
Skin itching
Widespread red spots
Hair loss
Hives
Kidney failure
Reduced kidney function
Fever
Pain
Excess fluid in body tissues causing swelling
Chest pain
Inflammation and ulceration of 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
Stroke
Type of stroke when a neck artery is blocked
Bleeding in the skull
Angina (chest pain caused by reduced blood flow to the heart)
Heart attack
Narrowing or blockage of the coronary arteries
Increased heart rate
Inadequate blood supply to the limbs
Blockage in the lungs of one of the pulmonary arteries
Inflammation and scarring of the lung lining causing breathing problems
Bright red bleeding from the anus
Gastrointestinal tract bleeding
Intestinal perforation
Inflammation of the oesophageal lining
Inflammation of the large intestine lining, 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 liver condition
Skin redness
Sudden skin redness developing in a previously irradiated area

Very rare (may affect up to 1 in 10,000 people)
Skin and soft tissue infection
Stevens-Johnson syndrome (a type of severe skin and mucous membrane reaction that may be life-threatening)
Toxic epidermal necrolysis (a type of severe 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 subcutaneous fat (pseudocellulitis)
Skin inflammation (dermatitis)
Skin becoming inflamed, itchy, red, cracked, and rough
Intensely itchy spots

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

You may experience one or more of these symptoms and/or conditions. You must inform your doctor as soon as possible if you start experiencing 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 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 ALIMTA

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and the carton.
This medicine does not require any special storage conditions.
Reconstituted and infusion solutions: the product should be used immediately. If prepared as directed, the chemical and physical in-use stability of reconstituted pemetrexed infusion solutions has been demonstrated for 24 hours under refrigerated conditions.
This medicine is for single use only; any unused solution must be disposed of in accordance with local legal requirements.

6. Package contents and other information

What ALIMTA contains
The active substance is pemetrexed.
ALIMTA 100 mg: Each vial contains 100 milligrams of pemetrexed (as pemetrexed disodium).
ALIMTA 500 mg: Each vial contains 500 milligrams of pemetrexed (as pemetrexed disodium).
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 sodium hydroxide.

Description of the appearance of ALIMTA and contents of the pack
ALIMTA is a powder for concentrate for solution for infusion in a vial. It is a lyophilized powder with a colour ranging from white to pale yellow or yellowish-green.
It is available in packs of 1 vial.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Eli Lilly Nederland B.V.
Papendorpseweg 83, 3528 BJ Utrecht
The Netherlands

Manufacturer
Lilly France S.A.S.
rue du Colonel Lilly
F-67640, Fegersheim
France

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

Belgique/België/Belgien
Eli Lilly Benelux S.A./N.V.
Tél/Tel: + 32-(0)2 548 84 84

България
ТП "Ели Лили Недерланд" Б.В. - България
тел. + 359 2 491 41 40

Česká republika
ELI LILLY ČR, s.r.o.
Tel: + 420 234 664 111

Danmark
Eli Lilly Danmark A/S
Tlf: +45 45 26 6000

Deutschland
Lilly Deutschland GmbH
Tel. + 49-(0) 6172 273 2222

Eesti
Eli Lilly Nederland B.V.
Tel: + 372 6817 280

Ελλάδα
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε.
Τηλ: +30 210 629 4600

España
Lilly S.A.
Tel: + 34 91-663 50 00

France
Lilly France
Tél: +33-(0) 1 55 49 34 34

Hrvatska
Eli Lilly Hrvatska d.o.o.
Tel: +385 1 2350 999

Ireland
Eli Lilly and Company (Ireland) Limited
Tel: + 353-(0) 1 661 4377

Ísland
Icepharma hf.
Sími + 354 540 8000

Italia
Eli Lilly Italia S.p.A.
Tel: + 39- 055 42571

Κύπρος
Phadisco Ltd
Τηλ: +357 22 715000

Latvija
Eli Lilly (Suisse) S.A. Pārstāvniecība Latvijā
Tel: + 371 6 7364000

Lietuva
Eli Lilly Lietuva
Tel. +370 (5) 2649600

Luxembourg/Luxemburg
Eli Lilly Benelux S.A./N.V.
Tél/Tel: + 32-(0)2 548 84 84

Magyarország
Lilly Hungária Kft.
Tel: + 36 1 328 5100

Malta
Charles de Giorgio Ltd.
Tel: + 356 25600 500

Nederland
Eli Lilly Nederland B.V.
Tel: + 31-(0) 30 60 25 800

Norge
Eli Lilly Norge A.S.
Tlf: + 47 22 88 18 00

Österreich
Eli Lilly Ges. m.b.H.
Tel: + 43-(0) 1 711 780

Polska
Eli Lilly Polska Sp. z o.o.
Tel.: +48 22 440 33 00

Portugal
Lilly Portugal - Produtos Farmacêuticos, Lda
Tel: + 351-21-4126600

România
Eli Lilly România S.R.L.
Tel: + 40 21 4023000

Slovenija
Eli Lilly farmacevtska družba, d.o.o.
Tel: +386 (0)1 580 00 10

Slovenská republika
Eli Lilly Slovakia s.r.o.
Tel: + 421 220 663 111

Suomi/Finland
Oy Eli Lilly Finland Ab
Puh/Tel: + 358-(0) 9 85 45 250

Sverige
Eli Lilly Sweden AB
Tel: + 46-(0) 8 7378800

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

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, use aseptic techniques.
2. Calculate the required dose and number of ALIMTA vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of the labeled amount.
3. ALIMTA 100 mg: Reconstitute each 100 mg vial with 4.2 mL of sodium chloride solution 9 mg/mL (0.9%) for injection, without preservatives, to obtain a solution containing 25 mg/mL of pemetrexed. ALIMTA 500 mg: Reconstitute each 500 mg vial with 20 mL of sodium chloride solution 9 mg/mL (0.9%) for injection, without preservatives, to obtain a solution containing 25 mg/mL of pemetrexed. 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 product quality. 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 injection, without preservatives, and administered by intravenous infusion over 10 minutes.
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 solvents containing calcium, including sodium chloride and potassium chloride for injection (Ringer lactate) and sodium chloride, potassium chloride, and calcium chloride for injection (Ringer's solution).
6. Prior to administration, parenteral medicinal products 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. Use of gloves is recommended. If a pemetrexed solution comes into contact with the skin, wash immediately and thoroughly with soap and water. If pemetrexed solutions come into contact with mucous membranes, 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.

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

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for pemetrexed, the scientific conclusions of the PRAC are as follows:
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 rationale of the recommendation.

Reasons for the variation of the terms of the marketing authorisation
Based on the scientific conclusions regarding 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 the variation of the terms of the marketing authorisation.