Armisarte: detailed information

Patient Information Leaflet: Information for the User

Armisarte 25 mg/ml concentrate for solution for infusion

pemetrexed
Please 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 questions, ask your doctor or pharmacist.
If you get any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

What Armisarte is and what it is used for
What you need to know before you are given Armisarte
How Armisarte is given
Possible side effects
How to store Armisarte
Contents of the pack and other information

1. What Armisarte is and what it is used for

Armisarte is a medicine used in the treatment of cancers. It contains the active substance pemetrexed.
Pemetrexed belongs to a group of medicines called folic acid analogues and interrupts essential processes involved in cell division.
Armisarte is administered 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, Armisarte, in combination with cisplatin, is given as first-line therapy in patients with advanced-stage lung cancer.
Armisarte may be prescribed for advanced-stage lung cancer if the disease has responded to treatment or remains largely unchanged after initial chemotherapy.
Furthermore, Armisarte is a treatment for patients with advanced-stage lung cancer whose disease has progressed after a previous initial chemotherapy treatment.

2. What you need to know before taking Armisarte

Do not take Armisarte

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 Armisarte.
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 Armisarte.
If you have or have had kidney problems, inform your doctor or hospital pharmacist, as you may not
be able to receive Armisarte.
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 Armisarte. Your doctor may
decide to adjust the dose or delay treatment depending on your general condition and if blood test
results (white blood cells and platelets) are inadequate (too low). Additionally, if you are receiving
cisplatin, your doctor must ensure that you are adequately hydrated and that you 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 Armisarte
may cause an early or delayed reaction related to radiation treatment.
Inform your doctor if you have recently been vaccinated, as Armisarte may cause harmful effects in
this case.
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 Armisarte.
Children and adolescents
This medicine must not be used in children and adolescents, as there is no experience with Armisarte in
individuals under 18 years of age.
Other medicines and Armisarte
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines, including painkillers or medicines for inflammation (swelling), such as medicines known
as “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 Armisarte 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.
Like other chemotherapeutic medicines, Armisarte is not recommended together with live attenuated
vaccines. Inactivated vaccines should be used whenever possible.
Pregnancy
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, inform your doctor.
The use of Armisarte during pregnancy should be avoided. Your doctor will discuss with you the
potential risks of taking Armisarte during pregnancy. Women must use an effective method of
contraception during treatment with Armisarte and for 6 months after receiving the last dose.
Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be discontinued during treatment with Armisarte.
Fertility
Men are advised not to father a child during treatment with Armisarte and for up to 3 months after
treatment ends, and should use an effective contraceptive method during treatment with Armisarte
and for 3 months afterwards. If you wish to father a child during treatment or within 3 months after,
seek advice from your doctor or pharmacist. Armisarte may affect your ability to have children. Talk
to your doctor for advice on sperm preservation before starting therapy.
Driving and using machines
Armisarte may cause fatigue. Be cautious when driving a vehicle or operating machinery.

3. How to take Armisarte

Armisarte 25 mg/ml concentrate for infusion solution will always be administered to you by a healthcare professional. The dose of Armisarte 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 delayed depending on blood test results and your general condition. A hospital pharmacist, nurse, or doctor will have mixed the Armisarte concentrate with either a 5% glucose solution for injection or a 0.9% sodium chloride solution for injection before administration.

You will receive Armisarte always as an intravenous infusion. The infusion will last approximately 10 minutes.

When Armisarte 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 Armisarte infusion. 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 milligrams of dexamethasone twice daily), which you must take the day before, the day of, and the day after treatment with Armisarte. 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 Armisarte. You must take at least five doses during the seven days prior to the first dose of Armisarte. You must continue taking folic acid for 21 days after the last dose of Armisarte. You will also receive an injection of vitamin B({12}) (1000 micrograms) in the week before administration of Armisarte, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Armisarte). Vitamin B({12}) and folic acid are administered to reduce possible toxic effects of anticancer treatment.

During treatment, your condition will be closely monitored. This routine monitoring includes blood tests, including checks of liver and kidney function. Based on the results of these tests, your dose may be adjusted or treatment delayed.

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 (as you may have lower than normal white blood cell counts, 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 you develop a severe rash, itching, or blisters (Stevens-Johnson syndrome or toxic epidermal necrolysis).
If you feel tired, faint, short of breath, or look pale (as 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 (as you may have lower than normal platelet counts, which is common)
If you suddenly experience shortness of breath, severe chest pain, or cough up blood (uncommon) (this may indicate a blood clot in the pulmonary blood vessels)

Other side effects with Armisarte 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
Damage to motor nerves that may cause muscle stiffness and atrophy, leading to muscle weakness and primary atrophy (wasting) in arms and legs
Damage to sensory nerves 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 blood levels of chemicals produced by the liver
Increased skin pigmentation
Skin itching
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)

Decreased number of white and red blood cells and platelets in the blood
Stroke
Type of stroke caused by blockage of a brain artery
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
Inadequate blood supply to limbs
Blockage in the lungs, affecting one of the pulmonary arteries
Inflammation and scarring of the lung lining 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, possibly accompanied by intestinal or rectal bleeding (observed 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 severe reaction affecting the skin and mucous membranes, potentially life-threatening)
Toxic epidermal necrolysis (a severe skin reaction, potentially life-threatening)
Autoimmune disorders resulting in sudden skin redness and blisters on 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 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 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.
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or nurse. 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 Armisarte

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.

Closed vial
Store and transport refrigerated (2 °C–8 °C).
Do not freeze.
Keep vials in the outer container to protect from light.

After first opening of the vial
4 ml vial (100 mg/4 ml)
Chemical and physical in-use stability has been demonstrated for 7 days at 2 °C–8 °C.
20 ml vials (500 mg/20 ml), 34 ml vials (850 mg/34 ml) and 40 ml vials (1.000 mg/40 ml)
Chemical and physical in-use stability has been demonstrated for 14 days at 2 °C–8 °C.

Infusion solution
Chemical and physical in-use stability of pemetrexed infusion solutions has been demonstrated for 24 hours at room temperature and for 7 days under refrigerated conditions.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2 °C–8 °C, unless reconstitution/dilution has been carried out under controlled and validated aseptic conditions.

Armisarte must not be used if particulate matter is observed.
Any unused concentrate remaining in the vial that has exceeded its in-use shelf-life must be disposed of in accordance with local legal requirements.

6. Package contents and other information

What Armisarte contains
The active substance is pemetrexed. Each ml of concentrate contains 25 mg of pemetrexed (as
pemetrexed diacid).
Each 4 ml vial contains 100 mg of pemetrexed (as pemetrexed diacid).
Each 20 ml vial contains 500 mg of pemetrexed (as pemetrexed diacid).
Each 34 ml vial contains 850 mg of pemetrexed (as pemetrexed diacid).
Each 40 ml vial contains 1000 mg of pemetrexed (as pemetrexed diacid).
The other components are tromethamine (for pH adjustment), citric acid, methionine and water
for injection.

Description of the appearance of Armisarte and contents of the pack
Armisarte concentrate for infusion solution (sterile concentrate) is a clear, colourless to slightly yellow or yellow-green solution.
Armisarte is supplied in a clear glass vial with a rubber stopper and an aluminium cap with a polypropylene disc. The vials may or may not be placed in a protective overwrap.
Each Armisarte pack contains one vial.

Pack sizes
1 vial x 4 ml (100 mg/4 ml)
1 vial x 20 ml (500 mg/20 ml)
1 vial x 34 ml (850 mg/34 ml)
1 vial x 40 ml (1000 mg/40 ml)
Not all pack sizes may be marketed.

Marketing Authorization Holder
Actavis Group PTC ehf.
Dalshraun 1
220 Hafnarfjörður
Iceland

Manufacturer
PLIVA CROATIA Ltd.
10000 Zagreb
Prilaz baruna Filipovića 25
Croatia
Actavis Italy S.p.A.
Via Pasteur 10
20014 Nerviano (Milan)
Italy
S.C. Sindan-Pharma S.R.L.
11 Ion Mihalache Blvd.
011171 Bucharest
Romania

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

België/Belgique/Belgien Lietuva
Teva Pharma Belgium N.V./S.A./AG UAB Teva Baltics
Tél/Tel: +32 38207373 Tel: +370 52660203

България Luxembourg/Luxemburg
Тева Фарма ЕАД Teva Pharma Belgium N.V./S.A./AG
Teл: +359 24899585 Belgique/Belgien
Tél/Tel: +32 38207373

Česká republika Magyarország
Teva Pharmaceuticals CR, s.r.o. Teva Gyógyszergyár Zrt.
Tel: +420 251007111 Tel: +36 12886400

Danmark Malta
Teva Denmark A/S Teva Pharmaceuticals Ireland
Tlf: +45 44985511 L-Irlanda
Tel: +44 2075407117

Deutschland Nederland
ratiopharm GmbH Teva Nederland B.V.
Tel: +49 73140202 Tel: +31 8000228400

Eesti Norge
UAB Teva Baltics Eesti filiaal Teva Norway AS
Tel: +372 6610801 Tlf: +47 66775590

Ελλάδα Österreich
TEVA HELLAS A.E. ratiopharm Arzneimittel Vertriebs-GmbH
Τηλ: +30 2118805000 Tel: +43 1970070

España Polska
Teva Pharma, S.L.U. Teva Pharmaceuticals Polska Sp. z o.o.
Tel: +34 913873280 Tel: +48 223459300

France Portugal
Teva Santé Teva Pharma - Produtos Farmacêuticos, Lda.
Tél: +33 155917800 Tel: +351 214767550

Hrvatska România
Pliva Hrvatska d.o.o. Teva Pharmaceuticals S.R.L.
Tel: +385 13720000 Tel: +40 212306524

Ireland Slovenija
Teva Pharmaceuticals Ireland Pliva Ljubljana d.o.o.
Tel: +44 2075407117 Tel: +386 15890390

Ísland Slovenská republika
Teva Pharma Iceland ehf. TEVA Pharmaceuticals Slovakia s.r.o.
Sími: +354 5503300 Tel: +421 257267911

Italia Suomi/Finland
Teva Italia S.r.l. Teva Finland Oy
Tel: +39 028917981 Puh/Tel: +358 201805900

Κύπρος Sverige
TEVA HELLAS A.E. Teva Sweden AB
Ελλάδα Tel: +46 42121100
Τηλ: +30 2118805000

Latvija
UAB Teva Baltics filiāle Latvijā
Tel: +371 67323666

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

The following information is intended exclusively for physicians or healthcare professionals:

Instructions for use, handling, and disposal

Use aseptic techniques when diluting pemetrexed for intravenous infusion administration.
Calculate the required dose and the number of Armisarte vials needed.
Armisarte must be diluted only in 5% glucose solution or 0.9% sodium chloride solution, without preservatives. The appropriate volume of pemetrexed concentrate should be diluted to 100 ml with either 5% glucose solution or 0.9% sodium chloride solution and administered as an intravenous infusion over 10 minutes.
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 Ringer's lactate for injectable preparations and Ringer's solution for injectable preparations.

Armisarte contains trometamol as an excipient. Trometamol is incompatible with cisplatin,
as it leads to degradation of cisplatin. This medicinal product must not be mixed
with other medicinal products. Intravenous administration lines must be flushed after
administration of Armisarte.

Parenteral medicinal products should be visually inspected for particulate matter and discoloration prior to administration. Do not administer if particulate matter is observed.
The rubber stopper may be punctured and the contents withdrawn from a vial up to two times. Unused medicinal product remaining in a vial that has exceeded its in-use shelf life, 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 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 and were not considered severe by the investigator. Extravasation
should be managed according to standard procedures for non-vesicant agents.

Diluted solution
Chemical and physical in-use stability of pemetrexed infusion solutions has been demonstrated for 24 hours at room temperature and for 7 days under refrigerated conditions (2 °C–8 °C). From a microbiological standpoint, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2 °C–8 °C, unless dilution was performed under controlled and validated aseptic conditions.

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 and 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 the 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 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 therefore 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.

Armisarte