ARMISARTE 25 mg /Ml Concentrate For Infusion Solution

Зміст інструкції

1. Armisarte 25 mg/ml concentrate for solution for infusion
   1. What is Armisarte and what is it used for
   2. What you need to know before you take Armisarte
   3. How to take Armisarte
   4. Possible side effects
   5. How to store Armisarte
   6. Contents of the pack and other information

Armisarte 25 mg/ml concentrate for solution for infusion

pemetrexed

Read this leaflet carefully before you receive 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 any side effects occur, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

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

1. What is Armisarte and what is it used for

Armisarte is a medicine used in the treatment of tumors. It contains the active ingredient pemetrexed.
Pemetrexed belongs to a group of medicines called folic acid analogues and interrupts the
essential processes for cell division.
Armisarte is administered in association with cisplatin, another anticancer drug, as
treatment for malignant pleural mesothelioma, a form of tumor that affects the tissue
lining of the lungs, to patients who have not received previous chemotherapy.
Furthermore Armisarte, in association with cisplatin, is administered for first-line therapy in
patients affected by advanced stage lung cancer.
Armisarte may be prescribed in case of advanced stage lung cancer if the disease has
responded to treatment or if it remains largely unchanged after initial chemotherapy.
Furthermore Armisarte is a treatment for patients affected by advanced stage lung cancer whose
disease has progressed after a previous initial chemotherapeutic treatment.

2. What you need to know before you take Armisarte

Do not take Armisarte

• if you are allergic to pemetrexed or 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 had or are about to have the yellow fever vaccination.

Warnings and precautions
Talk to your doctor or hospital pharmacist before receiving Armisarte.
If you have or have had kidney problems, tell your doctor or hospital pharmacist because you may
not be able to receive Armisarte.
Before each infusion, blood tests will be performed to assess whether you have sufficient
liver and kidney function and to check that you have enough cells in your blood to receive
Armisarte. The doctor may decide to change the dose or delay treatment depending on your
general condition and if the blood test (white blood cells and platelets) results are inadequate
(too low). Also, if you are receiving cisplatin, the doctor must ensure that you are
adequately hydrated and that you receive appropriate treatment before and after receiving cisplatin
to prevent vomiting.
If you have had or will be undergoing radiation treatment, tell your doctor, as
with Armisarte, an early or delayed reaction due to radiation treatment may occur.
If you have been vaccinated recently, tell your doctor, as with Armisarte this could
cause adverse effects.
If you have heart disease or a history of heart disease, tell your doctor.
If you have fluid buildup around your lungs, the doctor may decide to remove the
fluid before administering Armisarte.

Children and adolescents
This medicine should not be used in children and adolescents as there is no experience in
children and adolescents under 18 years of age.

Other medicines and Armisarte
Tell your doctor or pharmacist if you are taking, have recently taken or might take
any other medicines, including medicines for pain or for an inflammatory process
(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 activity. Based on the planned infusion date of Armisarte and/or your
kidney function, the 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 if any of your medicines are an
NSAID.
Tell 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 when possible.

Pregnancy
If you are pregnant, if you suspect you are pregnant or are planning a pregnancy, tell your doctor. The use
of Armisarte during pregnancy should be avoided. The doctor will talk to you about the potential risk
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, tell your doctor.
Breastfeeding must be stopped during treatment with Armisarte.

Fertility
Men are advised not to father a child during treatment with Armisarte until 3 months
afterwards and therefore to use effective contraception during treatment with Armisarte and for
3 months afterwards. If you wish to father a child during treatment or within 3 months afterwards, ask
your doctor or pharmacist for advice. Armisarte may affect your ability to have children. Talk
to your doctor for advice on how to store sperm before starting
therapy.

Driving and operating machinery
Armisarte can cause fatigue. Be careful when driving a vehicle or operating machinery.

3. How to take Armisarte

Armisarte 25 mg/ml concentrate for solution for infusion will always be administered to you by a
healthcare professional. The dose of Armisarte is 500 mg for each square meter of body surface area. Your
height and weight will be measured to calculate your body surface area. The doctor will use
this body surface area to calculate the right dose for you. This dosage may be adjusted or
treatment may be delayed depending on blood tests and your general condition. A
hospital pharmacist, nurse or doctor will have mixed the Armisarte concentrate with a
5% glucose solution for injectable preparations or with a 0.9% sodium chloride
solution for injectable preparations before administering it to you.
You will always receive Armisarte via infusion into a vein. The infusion will last approximately 10 minutes.
When Armisarte is used in combination with cisplatin:
The doctor or hospital pharmacist will calculate the dose you need based on your height and
your weight. Cisplatin is also administered by infusion into a vein, approximately 30 minutes after
the Armisarte infusion has been completed. The cisplatin infusion will last approximately 2 hours.
Usually you should receive the infusion once every 3 weeks.
Additional medicines:
Corticosteroids: the doctor will prescribe steroid tablets (equivalent to 4 milligrams of
dexamethasone twice a day) that you must take the day before, the day of and the day after
treatment with Armisarte. This medicine is given to you to reduce the frequency and severity of
skin reactions that may occur during cancer treatment.
Vitamin supplement: the doctor will prescribe folic acid (vitamin) or a multivitamin product
containing folic acid (350-1000 micrograms) orally that you must take once a day
while being treated with Armisarte. You must take at least 5 doses during the seven days before
the first dose of Armisarte. You should continue to take folic acid for 21 days after the last
dose of Armisarte. You will also receive an injection of vitamin B (1000 micrograms) in the week
before the administration of Armisarte and then approximately every 9 weeks (corresponding to 3 treatment cycles with Armisarte). Vitamin B and folic acid are administered to you to reduce
possible toxic effects of cancer treatment.
During treatment your condition will be carefully monitored. This routine consists of
blood tests, including checks of liver and kidney function. Based on the results of these tests,
your dose may be changed or treatment delayed.
If you have any questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
You should immediately contact your doctor if you notice any of the following side effects:

• Fever or infection (common or very common respectively): 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 serious and may lead to death.
• If you start to feel chest pain (common) or have an increased heartbeat (uncommon)
• If you have pain, redness, swelling or sores in your mouth (very common)
• Allergic reaction: if you develop a skin 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, or itching, or blisters appear (Stevens-Johnson syndrome or toxic epidermal necrolysis)
• If you feel tired, feel faint, feel short of breath easily or are pale (as you may have less haemoglobin than normal, which is very common)
• If you have bleeding from the gums, nose or mouth or any bleeding that doesn't tend to stop, reddish or slightly pink urine, unexplained bruising (as you may have fewer platelets than normal, which is common)
• If you experience sudden shortness of breath, severe chest pain or have blood in your sputum when coughing (uncommon) (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 number of neutrophils (a type of white blood cells)
• Few white blood cells in the blood
• Low level of haemoglobin
• Pain, redness, swelling or ulcers in the mouth
• Loss of appetite
• Vomiting
• Diarrhoea
• Nausea
• Redness of the skin
• Peeling of the skin
• Abnormal blood tests showing reduced kidney function
• Fatigue (tiredness)

Common (may affect up to 1 in 10 people)

• Bloodstream infection
• Fever with low number of neutrophils (a type of white cells)
• Low platelet count
• Allergic reactions
• Loss of body fluids
• Alteration of taste
• Damage to motor nerves that may cause stiffness and muscle atrophy which can cause muscle weakness and primary atrophy (wasting) in the arms and legs
• Damage to sensory nerves that can cause loss of sensation, burning and unstable gait
• Dizziness
• Inflammation or swelling of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye)
• Dry eye
• Excessive tearing
• Dryness of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye) and the cornea (the transparent layer in front of the iris and pupil).
• Swelling of the eyelids
• Eye disorders with dryness, tearing, irritation and/or pain
• Heart failure (a condition that affects the heart's ability to pump)
• Irregular heartbeat
• Indigestion
• Constipation
• Abdominal pain
• Liver: increased in the blood of chemicals produced by the liver
• Increased skin pigmentation
• Itching of the skin
• Widespread red spots
• Hair loss
• Urticaria (hives)
• Kidneys stopping 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
• 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
• Increased heart rate
• Poor distribution of blood to the limbs
• Blockage in the lungs, of one of the pulmonary arteries
• Inflammation and scarring of the lining of the lungs with breathing problems
• Bright red blood from the anus
• Bleeding from the gastrointestinal tract
• Rupture of the intestine
• Inflammation of the lining of the esophagus
• Inflammation of the lining of the large intestine which may be accompanied by intestinal or rectal bleeding (seen only in combination with cisplatin)
• Inflammation, edema, erythema and erosion of the surface of the mucosa of the esophagus caused by radiation therapy
• Inflammation of the lung 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
• Redness of the skin
• Sudden redness of the skin that develops in an area previously irradiated

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

• Infection of the skin and soft tissues
• Stevens-Johnson syndrome (a type of severe skin and mucous membrane reaction that can be life-threatening)
• Toxic epidermal necrolysis (a type of severe skin reaction that can lead to life-threatening conditions)
• Autoimmune disorders resulting in sudden redness of the skin and blisters on the legs, arms and abdomen
• Inflammation of the skin characterized by the presence of blisters that fill with fluid
• Fragility of the skin, blisters and erosion and scarring of the skin
• Redness, pain and swelling mainly of the lower limbs
• Inflammation of the skin and fat under the skin (pseudocellulitis)
• Inflammation of the skin (dermatitis)
• Skin that becomes inflamed, itchy, red, cracked and rough
• Intensely itchy spots

Frequency not known: the frequency cannot be estimated on the basis of the available data

• Form of diabetes primarily due to kidney disease
• Kidney disorders involving the death of tubular epithelial cells that form the renal tubules

You may experience one of these symptoms and/or conditions. You should tell your doctor as soon as
possible when you start to have one of these side effects.

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your
doctor or nurse. You can also report side effects directly through the national
reporting system detailed 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 the packaging 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 the vials in the outer container to protect from light.
After the first opening of the vial

Vial of 4 ml (100 mg/4 ml)
Chemical and physical stability during use has been demonstrated for 7 days at 2 °C-8 °C.

Vials of 20 ml (500 mg/20 ml), 34 ml (850 mg/34 ml) and 40 ml (1,000 mg/40 ml)
Chemical and physical stability during use has been demonstrated for 14 days at 2 °C-8 °C.
Solution for infusion
The chemical and physical stability during use of pemetrexed infusion solutions has been
demonstrated for 24 hours at room temperature and for 7 days at refrigerated temperature.
From a microbiological point of view, the product must be used immediately. If not used
immediately, the storage times during use and the conditions prior to use are the
responsibility of the user and should normally not exceed 24 hours at 2 °C-8 °C, unless
the opening/dilution has been carried out under controlled and validated aseptic conditions.
Armisarte must not be used if there are signs of particles.
The remaining unused concentrate in the vial that has exceeded the validity period during
use must be disposed of in accordance with local legal requirements.

6. Contents of the pack and other information

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

Description of the appearance of Armisarte and contents of the pack
Armisarte concentrate for solution for infusion (sterile concentrate) is a clear solution, from
colourless to slightly yellow or yellowish-green.
Armisarte is supplied in a transparent glass vial with a rubber stopper and an aluminium cap
with a polypropylene disc. The vials may or may not be enclosed in a protective case.
Each pack of Armisarte 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 Authorisation 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 medicine, contact the local representative of the marketing
authorisation holder:

België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A./AG
Tél/Tel: +32 38207373

Lietuva
UAB Teva Baltics
Tel: +370 52660203

България
Тева Фарма ЕАД
Teл: +359 24899585

Luxembourg/Luxemburg
Teva Pharma Belgium N.V./S.A./AG
Belgique/Belgien
Tél/Tel: +32 38207373

Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251007111

Magyarország
Teva Gyógyszergyár Zrt.
Tel: +36 12886400

Danmark
Teva Denmark A/S
Tlf: +45 44985511

Malta
Teva Pharmaceuticals Ireland
L-Irlanda
Tel: +44 2075407117

Deutschland
ratiopharm GmbH
Tel: +49 73140202

Nederland
Teva Nederland B.V.
Tel: +31 8000228400

Eesti
UAB Teva Baltics Eesti filiaal
Tel: +372 6610801

Norge
Teva Norway AS
Tlf: +47 66775590

Ελλάδα
TEVA HELLAS A.E.
Τηλ: +30 2118805000

Österreich
ratiopharm Arzneimittel Vertriebs-GmbH
Tel: +43 1970070

España
Teva Pharma, S.L.U.
Tel: +34 913873280

Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel: +48 223459300

France
Teva Santé
Tél: +33 155917800

Portugal
Teva Pharma - Produtos Farmacêuticos, Lda.
Tel: +351 214767550

Hrvatska
Pliva Hrvatska d.o.o.
Tel: +385 13720000

România
Teva Pharmaceuticals S.R.L.
Tel: +40 212306524

Ireland
Teva Pharmaceuticals Ireland
Tel: +44 2075407117

Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 15890390

Ísland
Teva Pharma Iceland ehf.
Sími: +354 5503300

Slovenská republika
TEVA Pharmaceuticals Slovakia s.r.o.
Tel: +421 257267911

Italia
Teva Italia S.r.l.
Tel: +39 028917981

Suomi/Finland
Teva Finland Oy
Puh/Tel: +358 201805900

Κύπρος
TEVA HELLAS A.E.
Ελλάδα
Τηλ: +30 2118805000

Sverige
Teva Sweden AB
Tel: +46 42121100

Latvija
UAB Teva Baltics filiāle Latvijā
Tel: +371 67323666

Other sources of information
More detailed information on this medicine is available on the website of the European
Medicines Agency: https://www.ema.europa.eu/.
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The following information is intended exclusively for doctors or healthcare professionals:
Instructions for use, handling and disposal

• 1. When diluting pemetrexed for intravenous infusion, use aseptic techniques.
• 2. Calculate the dose and the number of Armisarte vials needed.
• 3. Armisarte must be diluted only in 5% glucose solution or 0.9% sodium chloride solution, without preservatives. The appropriate volume of pemetrexed concentrate must be diluted to 100 ml with 5% glucose solution or 0.9% sodium chloride solution and administered by intravenous infusion over 10 minutes.
• 4. Infusion solutions of pemetrexed prepared as above are compatible with polyvinyl chloride and polyolefin-coated infusion bags and administration sets. Pemetrexed is incompatible with solvents containing calcium, including injectable Ringer's lactate and injectable Ringer's solution.

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

• 5. Before administration, parenteral medicinal products must be visually inspected for particles and colour changes. Do not administer if particles are observed.
• 6. The rubber stopper can be pierced and the contents of a vial withdrawn a maximum of two times. Any unused medicinal product remaining in the vial that has exceeded the expiry date during use and waste 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, wash thoroughly with
water. Pemetrexed is not vesicant. There is no specific antidote for pemetrexed extravasation.
A few cases of pemetrexed extravasation have been reported that were not considered serious
by the investigator. Extravasation should be managed according to standard procedures as for other
non-vesicant agents.
Diluted solution
The chemical and physical stability during use of pemetrexed infusion solutions has been
demonstrated for 24 hours at room temperature and for 7 days at refrigerated temperature. From a
microbiological point of view, the product must be used immediately. If not used immediately, the
storage times during use and conditions before use are the responsibility
of the user and must not normally exceed 24 hours at 2 °C-8 °C, unless the dilution has
been carried out under controlled and validated aseptic conditions.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND JUSTIFICATION FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION
Scientific conclusions
Taking into account the assessment of 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 data on the pharmacokinetics of pemetrexed, considering that in vitro studies
have indicated that pemetrexed is actively secreted by the organic anion transporter OAT3
(organic anion transporter 3), 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 of medicines containing pemetrexed must be amended accordingly.
Having examined the PRAC recommendation, the Committee for Human Medicinal Products
(CHMP) agrees with the related overall conclusions and with the justification of the recommendation.

Justification for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on pemetrexed, the CHMP considers that the benefit/risk
ratio of medicines containing pemetrexed remains unchanged, subject to the proposed changes
to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation.