Armisarte

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Armisarte 25 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of concentrate contains 25 mg pemetrexed (as pemetrexed diacid). 
 
Each vial of 4 ml concentrate contains 100 mg pemetrexed (as pemetrexed diacid). 
Each vial of 20 ml concentrate contains 500 mg pemetrexed (as pemetrexed diacid). 
Each vial of 34 ml concentrate contains 850 mg pemetrexed (as pemetrexed diacid). 
Each vial of 40 ml concentrate contains 1000 mg pemetrexed (as pemetrexed diacid). 
 
For the full list of excipients see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
The concentrate is clear, colourless to slightly yellowish or yellow-greenish solution. 
 
The pH is between 7.0 and 8.0. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Malignant pleural mesothelioma 
Pemetrexed in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients 
with unresectable malignant pleural mesothelioma. 
 
Non-small cell lung cancer 
Pemetrexed in combination with cisplatin is indicated for the first line treatment of patients with 
locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell 
histology (see section 5.1). 
 
Pemetrexed is indicated as monotherapy for the maintenance treatment of locally advanced or 
metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients 
whose disease has not progressed immediately following platinum-based chemotherapy (see 
section 5.1). 
 
Pemetrexed is indicated as monotherapy for the second line treatment of patients with locally 
advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology 
(see section 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
Pemetrexed must only be administered under the supervision of a physician qualified in the use of 
anti-cancer chemotherapy. 
 



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Pemetrexed in combination with cisplatin 
The recommended dose of pemetrexed is 500 mg/m2 of body surface area (BSA) administered as an 
intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of 
cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion of the 
pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic 
treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin 
Summary of Product Characteristics for specific dosing advice). 
 
Pemetrexed as single agent 
In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of 
pemetrexed is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first 
day of each 21-day cycle. 
 
Pre-medication regimen 
To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior 
to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent 
to 4 mg of dexamethasone administered orally twice a day (see section 4.4). 
 
To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation 
(see section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 
1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven 
days preceding the first dose of pemetrexed, and dosing must continue during the full course of 
therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular 
injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of pemetrexed and 
once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as 
pemetrexed. 
 
Monitoring 
Patients receiving pemetrexed should be monitored before each dose with a complete blood count, 
including a differential white cell count (WCC) and platelet count. Prior to each chemotherapy 
administration blood chemistry tests should be collected to evaluate renal and hepatic function. Before 
the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil 
count (ANC) should be ≥ 1500 cells/mm3 and platelets should be ≥ 100,000 cells/mm3. 
Creatinine clearance should be ≥ 45 ml/min. 
The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate 
aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times 
upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper limit of normal is 
acceptable if liver has tumour involvement. 
 
Dose adjustments 
Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or 
maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment may be delayed 
to allow sufficient time for recovery. Upon recovery patients should be retreated using the guidelines 
in Tables 1, 2 and 3, which are applicable for pemetrexed used as a single agent or in combination 
with cisplatin. 
  



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Table 1 - Dose modification table for pemetrexed (as single agent or in combination) and 
cisplatin – Haematologic toxicities 

Nadir ANC < 500/mm3 and nadir platelets 
≥ 50,000 /mm3 

75% of previous dose (both pemetrexed and 
cisplatin) 

Nadir platelets  <50,000 /mm 3 regardless of 
nadir ANC 
 
 

75% of previous dose (both pemetrexed and 
cisplatin) 

Nadir platelets <50,000/mm 3 with bleedinga, 
regardless of nadir ANC 

50% of previous dose (both pemetrexed and 
cisplatin) 

a These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) 
definition of ≥CTC Grade 2 bleeding. 
 

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), pemetrexed 
should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment 
should be resumed according to the guidelines in Table 2. 
 
Table 2 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin– Non-haematologic toxicitiesa,b 
 

  Dose of pemetrexed 
(mg/m2) 

Dose for cisplatin 
(mg/m2) 

Any Grade 3 or 4 toxicities except 
mucositis 

75% of previous dose 75% of previous dose 

Any diarrhoea requiring 
hospitalisation (irrespective of 
grade) or grade 3 or 4 diarrhoea. 

75% of previous dose 75% of previous dose 

Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose 

a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) 
b Excluding neurotoxicity 

 
In the event of neurotoxicity, the recommended dose adjustment for pemetrexed and cisplatin is 
documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed. 
 
Table 3 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin – Neurotoxicity 
CTCa Grade Dose of pemetrexed (mg/m2) Dose for cisplatin (mg/m2) 

0 – 1 100% of previous dose 100% of previous dose 

2 100% of previous dose 50% of previous dose 

a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) 
 
Treatment with pemetrexed should be discontinued if a patient experiences any haematologic or non-
haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 
neurotoxicity is observed. 
 
Special populations 
 
Elderly 
In clinical studies, there has been no indication that patients 65 years of age or older are at increased 
risk of adverse reactions compared to patients younger than 65 years old. No dose reductions other 
than those recommended for all patients are necessary. 
 



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Paediatric population 
There is no relevant use of pemetrexed in the paediatric population in malignant pleural mesothelioma 
and non-small cell lung cancer. 
 
Patients with renal impairment (standard cockcroft and gault formula or glomerular filtration rate 
measured Tc99m-DPTA serum clearance method) 
Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with 
creatinine clearance of ≥ 45 ml/min required no dose adjustments other than those recommended for 
all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance 
below 45 ml/min; therefore the use of pemetrexed is not recommended (see section 4.4). 
 
Patients with hepatic impairment 
No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed 
pharmacokinetics were identified. However patients with hepatic impairment such as bilirubin > 1.5 
times the upper limit of normal and/or aminotransferase > 3.0 times the upper limit of normal (hepatic 
metastases absent) or > 5.0 times the upper limit of normal (hepatic metastases present) have not been 
specifically studied. 
 
Method of administration 
 
Armisarte is for intravenous use. It should be administered as an intravenous infusion over 10 minutes 
on the first day of each 21-day cycle. 
 
For precautions to be taken before handling or administering pemetrexed andfor instructions on 
dilution of Armisarte before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Breast-feeding (see section 4.6). 
 
Concomitant yellow fever vaccine (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and 
anaemia (or pancytopenia) (see section 4.8). Myelosuppression is usually the dose-limiting toxicity. 
Patients should be monitored for myelosuppression during therapy and pemetrexed should not be 
given to patients until absolute neutrophil count (ANC) returns to ≥ 1500 cells/mm3 and platelet count 
returns to ≥ 100,000 cells/mm3. Dose reductions for subsequent cycles are based on nadir ANC, 
platelet count and maximum non-haematologic toxicity seen from the previous cycle (see section 4.2). 
 
Less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities such as 
neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia were reported when pre-
treatment with folic acid and vitamin B12 was administered. Therefore, all patients treated with 
pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce 
treatment-related toxicity (see section 4.2). 
 
Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment with 
dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see 
section 4.2). 
 
An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. 
Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 ml/min is not 
recommended (see section 4.2). 
 



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Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should 
avoid taking non-steroidal anti-inflammatory medicinal products (NSAIDs) such as ibuprofen, and 
acetylsalicylic acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed 
administration (see section 4.5). 
In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs with 
long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 
2 days following pemetrexed administration (see section 4.5). 
 
Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in 
association with other chemotherapeutic agents. Many of the patients in whom these occurred had 
underlying risk factors for the development of renal events including dehydration or pre-existing 
hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis were also reported 
in post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of these 
events resolved after pemetrexed withdrawal. Patients should be regularly monitored for acute tubular 
necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g. 
hypernatraemia). 
 
The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. 
A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated 
no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients 
without third space fluid collections. Thus, drainage of third space fluid collection prior to pemetrexed 
treatment should be considered, but may not be necessary. 
 
Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe 
dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment and 
appropriate hydration prior to and/or after receiving treatment. 
 
Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been 
uncommonly reported during clinical studies with pemetrexed, usually when given in combination 
with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-
existing cardiovascular risk factors (see section 4.8). 
 
Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated 
vaccines is not recommended (see section 4.3 and 4.5). 
 
Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a 
child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are 
recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men 
are advised to seek counselling on sperm storage before starting treatment. 
 
Women of childbearing potential must use effective contraception during treatment with pemetrexed 
(see section 4.6). 
 
Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, 
during or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients 
and caution exercised with use of other radiosensitising agents. 
 
Cases of radiation recall have been reported in patients who received radiotherapy weeks or years 
previously. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by 
glomerular filtration. Concomitant administration of nephrotoxic active substances (e.g. 
aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed 
clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine 
clearance should be closely monitored. 



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Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin) 
could potentially result in delayed clearance of pemetrexed. Caution should be made when these 
substances are combined with pemetrexed. If necessary, creatinine clearance should be closely 
monitored. 
 
In patients with normal renal function (creatinine clearance > 80 ml/min), high doses of non-steroidal 
anti-inflammatory medicinal products (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic 
acid at higher dose (> 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase 
the occurrence of pemetrexed adverse reactions. Therefore, caution should be made when 
administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with pemetrexed to 
patients with normal function (creatinine clearance > 80 ml/min). 
 
In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the 
concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or acetylsalicylic acid at 
higher dose should be avoided for 2 days before, on the day of, and 2 days following pemetrexed 
administration (see section 4.4). 
 
In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as 
piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to 
moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at 
least 2 days following pemetrexed administration (see section 4.4). If concomitant administration of 
NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression 
and gastrointestinal toxicity. 
 
Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver 
microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition 
of the metabolic clearance of active substances metabolised by CYP3A, CYP2D6, CYP2C9, and 
CYP1A2. 
 
Interactions common to all cytotoxics 
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is 
frequent. The high intra-individual variability of the coagulation status during diseases and the 
possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased 
frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with 
oral anticoagulants. 
Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale disease 
(see section 4.3). 
Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for which 
concomitant use is contraindicated): risk of systemic, possibly fatal, disease. The risk is increased in 
subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine 
where it exists (poliomyelitis) (see section 4.4). 
 
4.6 Fertility, pregnancy and lactation 

 
Women of childbearing potential/Contraception in males and females 
Women of childbearing potential must use effective contraception during treatment with pemetrexed. 
Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a 
child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are 
recommended. 
 
Pregnancy 
There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other anti-
metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal 
studies have shown reproductive toxicity (see section 5.3). Pemetrexed should not be used during 
pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the 
risk for the foetus (see section 4.4). 



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Breast-feeding 
It is unknown whether pemetrexed is excreted in human milk and adverse reactions on the breast-fed 
child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy (see 
section 4.3). 
 
Fertility 
Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to 
seek counselling on sperm storage before starting treatment. 
 
4.7 Effects on ability to drive and use machines 
 
Pemetrexed has no or negligible influence on the ability to drive and use machines. However, it has 
been reported that pemetrexed may cause fatigue. Therefore patients should be cautioned against 
driving or operating machines if this event occurs. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy 
or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leukopenia, 
thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, 
constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, 
increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. 
Rarely seen events include Stevens-Johnson syndrome and toxic epidermal necrolysis. 
 
Tabulated list of adverse reactions 
 
The table 4 lists the adverse drug events regardless of causality associated with pemetrexed used either 
as a monotherapy treatment or in combination with cisplatin from the pivotal registration studies 
(JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period. 
 
ADRs are listed by MedDRA body system organ class. The following convention has been used for 
classification of frequency: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 
to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000) and not known (cannot be estimated 
from the available data). 
 
 
Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotal 
registration studies: JMEI (pemetrexed vs docetaxel), JMDB (pemetrexed and cisplatin versus 
gemcitabine and cisplatin, JMCH (pemetrexed plus cisplatin versus cisplatin), JMEN and 
PARAMOUNT (pemetrexed plus best supportive care versus placebo plus best supportive care) 
and from post-marketing period. 
 
System 
Organ Class  
(MedDRA) 
 

Very common 
 

Common Uncommon Rare Very rare Not 
known 

Infections and 
infestations 

Infectiona 
Pharyngitis 

Sepsisb   Dermohypo
dermitis 

 

Blood and 
lymphatic 
system 
disorders 

Neutropenia 
Leukopenia 
Haemoglobin 
decreased 

Febrile 
neutropenia 
Platelet count 
decreased 

Pancytopenia Autoimmune 
haemolytic 
anaemia 

  

Immune 
System 
disorders 

 Hypersensitivi
ty 

 Anaphylactic 
shock 

  



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Metabolism 
and nutrition 
disorders 

 Dehydration     

Nervous 
system 
disorders 

 Taste disorder 
Peripheral 
motor 
neuropathy 
Peripheral 
sensory 
neuropathy 
Dizziness 

Cerebrovascul
ar accident 
Ischaemic 
stroke 
Haemorrhage 
intracranial  

   

Eye disorders  Conjunctivitis 
Dry eye 
Lacrimation 
increased 
Keratoconjunc
tivitis sicca 
Eyelid oedema 
Ocular surface 
disease 

    

Cardiac 
disorders  

 Cardiac failure 
Arrhythmia 

Angina 
Myocardial 
infarction 
Coronary 
artery disease 
Arrhythmia 
supraventricul
ar 

   

Vascular 
disorders 

  Peripheral 
ischaemiac 

   

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Pulmonary 
embolism 
Interstitial 
pneumonitisbd 

   

Gastrointes-
tinal disorders 

Stomatitis 
Anorexia 
Vomiting 
Diarrhoea 
Nausea 

Dyspepsia 
Constipation 
Abdominal 
pain 

Rectal 
haemorrhage 
Gastrointestina
l haemorrhage 
Intestinal 
perforation 
Oesophagitis 
Colitis e 

   

Hepatobiliary 
disorders 

 Aalanine 
aminotransfera
se increased 
Aspartate 
aminotransfera
se increased 

 Hepatitis   

Skin and 
subcutaneous 
tissue 
disorders 

Rash 
Skin 
exfoliation 

Hyperpigment
ation 
Pruritus 
Erythema 
multiforme 
Alopecia 
Urticaria 

 Erythema Stevens-
Johnson 
syndromeb 
Toxic 
epidermal 
necrolysisb 
Pemphigoi
d 

 



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Dermatitis 
bullous 
Acquired 
epidermoly
sis bullosa 
Erythema-
tous 
oedemaf  
Pseudocell
ulitis 
Dermatitis 
Eczema 
Prurigo 

Renal and 
urinary 
disorders 

Creatinine 
clearance 
decreased 
Blood 
creatinine 
increasede 

Renal failure 
Glomerular 
filtration rate 
decreased 

   Nephroge-
nic 
diabetes 
insipidus 
Renal 
tubular 
necrosis 

General 
disorders and 
administration 
site conditions 

Fatigue Pyrexia 
Pain 
Oedema 
Chest pain 
Mucosal 
inflammation 

    

Investigations  Gamma-
glutamyltransf
erase increased 

    

Injury, 
poisoning and 
procedural 
complications 

  Radiation 
oesophagitis 
Radiation 
pneumonitis 

Recall pheno-
menon 

  

a with and without neutropenia  
b in some cases fatal  
c sometimes leading to extremity necrosis  
d with respiratory insufficiency 
eseen only in combination with cisplatin  
f mainly of the lower limbs  
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory 
polyneuropathy and rash. Anticipated complications of overdose include bone marrow suppression as 
manifested by neutropenia, thrombocytopenia and anaemia. In addition, infection with or without 
fever, diarrhoea, and/or mucositis may be seen. In the event of suspected overdose, patients should be 
monitored with blood counts and should receive supportive therapy as necessary. The use of calcium 
folinate / folinic acid in the management of pemetrexed overdose should be considered. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, folic acid analogues, ATC code: L01BA04. 
 
Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial 
folate-dependent metabolic processes essential for cell replication. 
 
In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting 
thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide 
formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of 
thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate 
carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly 
and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The 
polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. 
Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a 
lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life 
resulting in prolonged active substance action in malignant cells. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
pemetrexed in all subsets of the paediatric population in the granted indications (see section 4.2). 
 
Clinical efficacy 
 
Mesothelioma 
 
EMPHACIS, a multicentre, randomised, single-blind phase 3 study of pemetrexed plus cisplatin 
versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients 
treated with pemetrexed and cisplatin had a clinically meaningful 2.8-month median survival 
advantage over patients receiving cisplatin alone. 
 
During the study, low-dose folic acid and vitamin B12 supplementation was introduced to patients 
therapy to reduce toxicity. The primary analysis of this study was performed on the population of all 
patients randomly assigned to a treatment arm who received study medicinal product (randomised and 
treated). A subgroup analysis was performed on patients who received folic acid and vitamin B12 
supplementation during the entire course of study therapy (fully supplemented). The results of these 
analyses of efficacy are summarised in the table below: 



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Table 5. Efficacy of pemetrexed plus cisplatin vs. cisplatin in malignant pleural mesothelioma 
 Randomized and treated 

patients 
Fully supplemented 

Patients 
Efficacy parameter Pemetrexed/ 

cisplatin 
(N=226) 

Cisplatin 
 

(N=222) 

Pemetrexed/ 
cisplatin 
(N=168) 

Cisplatin 
 

(N=163) 
Median overall survival (months) 

(95% CI) 
12.1 

(10.0 - 14.4) 
9.3 

(7.8 - 10.7) 
13.3 

(11.4 - 14.9) 
10.0 

(8.4 - 11.9) 
Log Rank p-value* 0.020 0.051 

Median time to tumour progression 
(months) 
(95% CI) 

5.7 
 

(4.9 - 6.5) 

3.9 
 

(2.8 - 4.4) 

6.1 
 

(5.3 - 7.0) 

3.9 
 

(2.8 - 4.5) 
Log Rank p-value* 0.001 0.008 

Time to treatment failure (months) 
(95% CI) 

4.5 
(3.9 - 4.9) 

2.7 
(2.1 - 2.9) 

4.7 
(4.3 - 5.6) 

2.7 
(2.2 - 3.1) 

Log Rank p-value* 0.001 0.001 
Overall response rate** 

(95% CI) 
41.3% 

(34.8 - 48.1) 
16.7% 

(12.0 - 22.2) 
45.5% 

(37.8 - 53.4) 
19.6% 

(13.8 - 26.6) 
Fisher’s exact p-value* < 0.001 < 0.001 

Abbreviation: CI = confidence interval 
*p-value refers to comparison between arms. 
**In the pemetrexed/cisplatin arm, randomized  and treated (N=225) and fully supplemented (N=167) 

 
A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) 
associated with malignant pleural mesothelioma in the pemetrexed /cisplatin arm (212 patients) versus 
the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale. 
Statistically significant differences in pulmonary function tests were also observed. The separation 
between the treatment arms was achieved by improvement in lung function in the pemetrexed/cisplatin 
arm and deterioration of lung function over time in the control arm. 
 
There are limited data in patients with malignant pleural mesothelioma treated with pemetrexed alone. 
Pemetrexed at a dose of 500 mg/m2 was studied as a single-agent in 64 chemonaive patients with 
malignant pleural mesothelioma. The overall response rate was 14.1%. 
 
NSCLC, second-line treatment 
 
A multicentre, randomised, open label phase 3 study of pemetrexed versus docetaxel in patients with 
locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 
8.3 months for patients treated with pemetrexed (Intent To Treat population n=283) and 7.9 months 
for patients treated with docetaxel (ITT n=288). Prior chemotherapy did not include pemetrexed. An 
analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of 
pemetrexed versus docetaxel for other than predominantly squamous histologies (n = 399, 9.3 versus 
8.0 months, adjusted HR=0.78; 95 % CI = 0 .61-1.00, p=0.047) and was in favour of docetaxel for 
squamous cell carcinoma histology (n=172, 6.2 versus 7.4 months, adjusted HR = 1.56; 95 % CI = 
1.08-2.26, p = 0.018). There were no clinically relevant differences observed for the safety profile of 
pemetrexed within the histology subgroups. 
 
Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy data 
(overall survival, progression free survival) for pemetrexed are similar between patients previously 
pre-treated with docetaxel (n = 41) and patients who did not receive previous docetaxel treatment 
(n = 540). 
 



13 

Table 6. Efficacy of pemetrexed vs docetaxel in NSCLC - ITT population 
 Pemetrexed Docetaxel 

Survival Time (months) 
 Median (m) 

 95 % CI for median 
 HR 

 95 % CI for HR 
 Non-inferiority p-value (HR) 

(n = 283) 
8.3 

(7.0 - 9.4) 

(n = 288) 
7.9 

(6.3 - 9.2) 
0.99 

(.82 - 1.20) 
.226 

Progression free survival (months) 
 Median 

 HR (95 % CI) 

(n = 283) 
2.9 

(n = 288) 
2.9 

0.97 (.82 – 1.16) 

Time to treatment failure (TTTF – months) 
 Median 

 HR (95 % CI) 

(n = 283) 
2.3 

(n = 288) 
2.1 

0.84 (.71 - .997) 

Response (n: qualified for response) 
 Response rate (%) (95 % CI) 

 Stable disease (%) 

(n = 264) 
9.1 (5.9 - 13.2) 

45.8 

(n = 274) 
8.8 (5.7 - 12.8) 

46.4 
Abbreviations:  CI = confidence interval; HR = hazard ratio; ITT = intent to treat; n = total population size. 
 
NSCLC, first-line treatment 
 
A multicentre, randomised, open-label, Phase 3 study of pemetrexed plus cisplatin versus gemcitabine 
plus cisplatin in chemonaive patients with locally advanced or metastatic (Stage IIIb or IV) non-small 
cell lung cancer (NSCLC) showed that pemetrexed plus cisplatin (Intent-To-Treat [ITT] population 
n=862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin 
(ITT n=863) in overall survival (adjusted hazard ratio 0.94; 95 % CI=0.84-1.05). All patients included 
in this study had an ECOG performance status 0 or 1. 
The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy 
endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacy analyses using 
PQ population are consistent with the analyses for the ITT population and support the non-inferiority 
of AC versus GC. 
Progression free survival (PFS) and overall response rate were similar between treatment arms: 
median PFS was 4.8 months for pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus 
cisplatin (adjusted hazard ratio 1.04; 95 % CI = 0.94-1.15), and overall response rate was 30.6% (95 % 
CI = 27.3-33.9) for pemetrexed plus cisplatin versus 28.2% (95 % CI = 25.0-31.4) for gemcitabine 
plus cisplatin. PFS data were partially confirmed by an independent review (400/1725 patients were 
randomly selected for review). The analysis of the impact of NSCLC histology on overall survival 
demonstrated clinically relevant differences in survival according to histology, see table below. 



14 

Table 7. Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-small cell 
lung cancer – ITT population and histology subgroups. 

ITT population 
and histology 

subgroups 

Median overall survival in months 
(95% CI) 

Adjusted 
hazard ratio 

(HR) 
(95% CI) 

 
Superiority 

p-value Pemetrexed + cisplatin Gemcitabine + 
cisplatin 

ITT population 
(N = 1725) 

10.3 
(9.8 – 11.2) 

N=862 10.3 
(9.6 – 10.9) 

N=863 0.94a 
(0.84 – 1.05) 

   

0.259 

Adenocarcinoma 
(N=847) 

12.6 (10.7 – 
13.6) 

N=436 10.9 
(10.2 – 11.9) 

N=411 0.84 
(0.71–0.99) 

0.033 

Large cell 
(N=153) 

10.4 
(8.6 – 14.1) 

N=76 6.7 
(5.5 – 9.0) 

N=77 0.67 
(0.48–0.96) 

0.027 

Other 
(N=252) 

8.6 
(6.8 – 10.2) 

N=106 9.2 
(8.1 – 10.6) 

N=146 1.08 
(0.81–1.45) 

0.586 

Squamous cell 
(N=473) 

9.4 
(8.4 – 10.2) 

N=244 10.8 
(9.5 – 12.1) 

N=229 1.23 
(1.00–1.51) 

0.050 

Abbreviations:  CI = confidence interval; ITT = intent-to-treat; N = total population size. 
a Statistically significant for noninferiority, with the entire confidence interval for HR well below the 1.17645 
noninferiority margin (p <0.001). 
 
Kaplan Meier plots of overall survival by histology 
 

 
 
There were no clinically relevant differences observed for the safety profile of pemetrexed plus 
cisplatin within the histology subgroups. 
Patients treated with pemetrexed and cisplatin required fewer transfusions (16.4% versus 28.9%, 
p<0.001), red blood cell transfusions (16.1% versus 27.3%, p<0.001) and platelet transfusions (1.8% 
versus 4.5%, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin 
(10.4% versus 18.1%, p<0.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations 
(4.3% versus 7.0%, p=0.021). 
 
NSCLC, maintenance treatment 
 
JMEN 
A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the 
efficacy and safety of maintenance treatment with pemetrexed plus best supportive care (BSC) 
(n=441) with that of placebo plus BSC (n=222) in patients with locally advanced (Stage IIIB) or 
metastatic (Stage IV) Non Small Cell Lung Cancer (NSCLC) who did not progress after 4 cycles of 
first line doublet therapy containing Cisplatin or Carboplatin in combination with Gemcitabine, 
Paclitaxel, or Docetaxel. First line doublet therapy containing pemetrexed was not included. All 
patients included in this study had an ECOG performance status 0 or 1. Patients received maintenance 
treatment until disease progression. Efficacy and safety were measured from the time of randomisation 



15 

after completion of first line (induction) therapy. Patients received a median of 5 cycles of 
maintenance treatment with pemetrexed and 3.5 cycles of placebo. A total of 213 patients (48.3%) 
completed ≥ 6 cycles and a total of 103 patients (23.4%) completed ≥ 10 cycles of treatment with 
pemetrexed. 
 
The study met its primary endpoint and showed a statistically significant improvement in PFS in the 
pemetrexed arm over the placebo arm (n=581, independently reviewed population; median of 
4.0 months and 2.0 months, respectively) (hazard ratio=0.60, 95% CI=0.49-0.73, p<0.00001). The 
independent review of patient scans confirmed the findings of the investigator assessment of PFS. The 
median OS for the overall population (n=663) was 13.4 months for the pemetrexed arm and 
10.6 months for the placebo arm, hazard ratio=0.79 (95% CI=0.65-0.95, p=0.01192). 
 
Consistent with other pemetrexed studies, a difference in efficacy according to NSCLC histology was 
observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology 
(n=430, independently reviewed population) median PFS was 4.4 months for the pemetrexed arm and 
1.8 months for the placebo arm, hazard ratio=0.47 (95% CI=0.37-0.60, p=0.00001). The median OS 
for patients with NSCLC other than predominantly squamous cell histology (n=481) was 15.5 months 
for the pemetrexed arm and 10.3 months for the placebo arm, hazard ratio=0.70 (95 % CI = 0.56-0.88, 
p = 0.002). Including the induction phase the median OS for patients with NSCLC other than 
predominantly squamous cell histology was 18.6 months for the pemetrexed arm and 13.6 months for 
the placebo arm, hazard ratio=0.71 (95 % CI=0.56-0.88, p=0.002). 
 
The PFS and OS results in patients with squamous cell histology suggested no advantage for 
pemetrexed over placebo. 
 
There were no clinically relevant differences observed for the safety profile of pemetrexed within the 
histology subgroups. 
 
JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival pemetrexed 
versus placebo in patients with NSCLC other than predominantly squamous cell histology: 
 

 
 
PARAMOUNT 
A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), 
compared the efficacy and safety of continuation maintenance treatment with pemetrexed plus BSC 
(n=359) with that of placebo plus BSC (n=180) in patients with locally advanced (Stage IIIB) or 
metastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progress 
after 4 cycles of first line doublet therapy of pemetrexed in combination with cisplatin. Of the 
939 patients treated with pemetrexed plus cisplatin induction, 539 patients were randomised to 
maintenance treatment with pemetrexed or placebo. Of the randomised patients, 44.9% had a 
complete/partial response and 51.9% had a response of stable disease to pemetrexed plus cisplatin 
induction. Patients randomised to maintenance treatment were required to have an ECOG performance 



16 

status 0 or 1. The median time from the start of pemetrexed plus cisplatin induction therapy to the start 
of maintenance treatment was 2.96 months on both the pemetrexed arm and the placebo arm. 
Randomised patients received maintenance treatment until disease progression. Efficacy and safety 
were measured from the time of randomisation after completion of first line (induction) therapy. 
Patients received a median of 4 cycles of maintenance treatment with pemetrexed and 4 cycles of 
placebo. A total of 169 patients (47.1 %) completed ≥ 6 cycles maintenance treatment with 
pemetrexed, representing at least 10 total cycles of pemetrexed. 
 
The study met its primary endpoint and showed a statistically significant improvement in PFS in the 
pemetrexed arm over the placebo arm (n=472, independently reviewed population; median of 
3.9 months and 2.6 months, respectively) (hazard ratio=0.64, 95 % CI=0.51-0.81, p=0.0002). The 
independent review of patient scans confirmed the findings of the investigator assessment of PFS. For 
randomised patients, as measured from the start of pemetrexed plus cisplatin first line induction 
treatment, the median investigator-assessed PFS was 6.9 months for the pemetrexed arm 
and 5.6 months for the placebo arm (hazard ratio = 0.59 95 % CI=0.47-0.74). 
 
Following pemetrexed plus cisplatin induction (4 cycles), treatment with pemetrexed was statistically 
superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio=0.78, 95 %CI=0.64-
0.96, p=0.0195). At the time of this final survival analysis, 28.7% of patients were alive or lost to 
follow up on the pemetrexed arm versus 21.7% on the placebo arm. The relative treatment effect of 
pemetrexed was internally consistent across subgroups (including disease stage, induction response, 
ECOG PS, smoking status, gender, histology and age) and similar to that observed in the unadjusted 
OS and PFS analyses. The 1 year and 2 year survival rates for patients on pemetrexed were 58% and 
32% respectively, compared to 45% and 21% for patients on placebo. From the start of pemetrexed 
plus cisplatin first line induction treatment, the median OS of patients was 16.9 months for the 
pemetrexed arm and 14.0 months for the placebo arm (hazard ratio=0.78, 95 % CI=0.64-0.96). The 
percentage of patients that received post study treatment was 64.3% for pemetrexed and 71.7% for 
placebo. 
 

PARAMOUNT:Kaplan Meier plot of progression-free survival (PFS) and overall survival 
(OS) for continuation pemetrexed maintenance versus placebo in patients with NSCLC other 
than predominantly squamous cell histology (measured from randomisation) 
 

 
 
The pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNT were 
similar. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetic properties of pemetrexed following single-agent administration have been 
evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 
0.2 to 838 mg/m2 infused over a 10 minute period. Pemetrexed has a steady-state volume of 



17 

distribution of 9 l/m2. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma 
proteins. Binding was not notably affected by varying degrees of renal impairment. Pemetrexed 
undergoes limited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70% to 
90% of the administered dose being recovered unchanged in urine within the first 24 hours following 
administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion 
transporter. Pemetrexed total systemic clearance is 91.8 ml/min and the elimination half-life from 
plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min). 
Between patient variability in clearance is moderate at 19.3%. Pemetrexed total systemic exposure 
(AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics 
of pemetrexed are consistent over multiple treatment cycles. 
 
The pharmacokinetic properties of pemetrexed are not influenced by concurrently administered 
cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the 
pharmacokinetics of pemetrexed. 
 
5.3 Preclinical safety data 
 
Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased foetal 
weight, incomplete ossification of some skeletal structures and cleft palate. 
 
Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by reduced 
fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous bolus injection 
for 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have been 
observed. This suggests that pemetrexed may impair male fertility. Female fertility was not 
investigated. 
 
Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese hamster 
ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in vivo micronucleus 
test in the mouse. 
 
Studies to assess the carcinogenic potential of pemetrexed have not been conducted. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Trometamol (for pH adjustment) 
Citric acid 
Methionine 
Water for injections 
 
6.2 Incompatibilities 
 
Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s 
injection and Ringer’s injection. In the absence of other compatibility studies this medicinal product 
must not be mixed with other medicinal products. 
 
Armisarte contains trometamol as an excipient. Trometamol is incompatible with cisplatin resulting in 
degradation of cisplatin.  
 
Intravenous lines should be flushed after administration of Armisarte. 
 
6.3 Shelf life 
 
Unopened vial 
18 months. 



18 

 
Diluted solution 
Chemical and physical in-use stability of infusion solution of pemetrexed was demonstrated for 
24 hours at room temperature and 7 days at refrigerated temperature. From a microbiological point of 
view, 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 would not be longer than 24 hours at 2 °C-
8 °C, unless dilution has taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store and transport refrigerated (2 °C-8 °C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Colourless glass vial (type I) with type I rubber (bromobutyl) serum stopper and an aluminium cap 
with polypropylene disk. Vials may or may not be sheathed in a protective sleeve. 
 
Pack sizes 
1 x 4 ml vial (100 mg/4 ml) 
1 x 20 ml vial (500 mg/20 ml) 
1 x 34 ml vial (850 mg/34 ml) 
1 x 40 ml vial (1000 mg/40 ml) 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
1. Use aseptic technique during dilution of pemetrexed for intravenous infusion administration. 
 
2. Calculate the dose and the number of Armisarte vials needed. 
 
3. Armisarte must only be diluted with 5% glucose solution, without preservative. The appropriate 

volume of pemetrexed concentrate must be diluted to 100 ml with 5% glucose solution and 
administered as an intravenous infusion over 10 minutes.  

 
4. Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 

chloride and polyolefin lined administration sets and infusion bags. 
 
5. Parenteral medicinal products must be inspected visually for particulate matter and 

discolouration prior to administration. If particulate matter is observed, do not administer. 
 
6. Pemetrexed solutions are for single use only. Any unused medicinal product or waste material 

must be disposed of in accordance with local requirements. 
 
Preparation and administration precautions 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed 
solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If 
pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not 
a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few 
reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. 
Extravasation should be managed by local standard practice as with other non-vesicants. 
 



19 

 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
Reykjavíkurvegi 76-78 
220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1063/001 
EU/1/15/1063/002 
EU/1/15/1063/003 
EU/1/15/1063/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 January 2016 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

  

http://www.ema.europa.eu/


20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



21 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
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. 
RO-011171 Bucharest 
Romania 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
• Additional risk minimisation measures  
 



22 

Not applicable. 
 
• Obligation to conduct post-authorisation measures  
 
Not applicable. 
 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Armisarte 25 mg/ml concentrate for solution for infusion  
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of concentrate contains 25 mg pemetrexed (as pemetrexed diacid). 
 
Each vial of 4 ml contains 100 mg pemetrexed (as pemetrexed diacid). 
Each vial of 20 ml contains 500 mg pemetrexed (as pemetrexed diacid). 
Each vial of 34 ml contains 850 mg pemetrexed (as pemetrexed diacid). 
Each vial of 40 ml contains 1000 mg pemetrexed (as pemetrexed diacid). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: trometamol, citric acid, methionine and water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
 
4 ml vial 
20 ml vial 
34 ml vial 
40 ml vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
Must only be diluted in 5% glucose solution. 
 
Read the package leaflet before use. 
 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 



26 

 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store and transport refrigerated. 
Do not freeze. 
Keep the vial in the outer carton to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1063/001 4 ml vial 
EU/1/15/1063/002 20 ml vial 
EU/1/15/1063/004 34 ml vial 
EU/1/15/1063/003 40 ml vial 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 



27 

2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Armisarte 25 mg/ml sterile concentrate 
pemetrexed 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg/4 ml 
 
 
6. OTHER 
 
Cytotoxic 
  



29 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Armisarte 25 mg/ml concentrate for solution for infusion  
pemetrexed 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 mg/20 ml 
850 mg/34 ml 
1000 mg/40 ml 
 
 
6. OTHER 
 
Cytotoxic 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



31 

Package leaflet: Information for the user 
 

Armisarte 25 mg/ml concentrate for solution for infusion 
pemetrexed 

 
Read all of this leaflet carefully before you start receiving 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 nurse or pharmacist. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Armisarte is and what it is used for 
2. What you need to know before you use Armisarte 
3. How to use Armisarte 
4. Possible side effects 
5. How to store Armisarte 
6. 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 cancer. It contains the active substance pemetrexed. 
Pemetrexed belongs to a group of medicines known as folic acid analogues and disrupts processes that 
are essential for cells to divide. 
 
Armisarte is given in combination with cisplatin, another anti-cancer medicine, as treatment for 
malignant pleural mesothelioma, a form of cancer that affects the lining of the lung, to patients who 
have not received prior chemotherapy. 
 
Armisarte is also given in combination with cisplatin for the initial treatment of patients with advanced 
stage of lung cancer. 
 
Armisarte can be prescribed to you if you have lung cancer at an advanced stage if your disease has 
responded to treatment or it remains largely unchanged after initial chemotherapy. 
 
Armisarte is also a treatment for patients with advanced stage of lung cancer whose disease has 
progressed after other initial chemotherapy has been used. 
 
 
2. What you need to know before you use Armisarte  
 
Do not use Armisarte 
- if you are allergic to pemetrexed or any of the other ingredients of this medicine (listed in 

section 6). 
- if you are breast-feeding; you must discontinue breast-feeding during treatment with Armisarte. 
- if you have recently received or are about to receive a vaccine against yellow fever. 
 
Warnings and precautions 
Talk to your doctor or hospital pharmacist before receiving Armisarte. 
If you currently have or have previously had problems with your kidneys, talk to your doctor or 
hospital pharmacist as you may not be able to receive Armisarte. 
Before each infusion you will have samples of your blood taken to evaluate if you have sufficient 
kidney and liver function and to check that you have enough blood cells to receive Armisarte. Your 
doctor may decide to change the dose or delay treating you depending on your general condition and if 
your blood cell counts are too low. If you are also receiving cisplatin, your doctor will make sure that 



32 

you are properly hydrated and receive appropriate treatment before and after receiving cisplatin to 
prevent vomiting. 
 
If you have had or are going to have radiation therapy, please tell your doctor, as there may be an early 
or late radiation reaction with Armisarte. 
 
If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects 
with Armisarte. 
 
If you have heart disease or a history of heart disease, please tell your doctor. 
 
If you have an accumulation of fluid around your lungs, your doctor may decide to remove the fluid 
before giving you Armisarte. 
 
Children and adolescents 
This medicine should not be used in children or adolescents, since there is no experience with this 
medicine 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 medicine for pain or inflammation (swelling), such as medicines called 
“nonsteroidal anti-inflammatory medicinal products” (NSAIDs), including medicines purchased 
without a doctor’s prescription (such as ibuprofen). There are many sorts of NSAIDs with different 
durations of activity. Based on the planned date of your infusion of Armisarte and/or on the status of 
your kidney function, your doctor needs to 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 NSAIDs. 
 
Like other chemotherapy medicines Armisarte is not recommended with live attenuated vaccines. 
Inactive vaccines should be used where possible. 
 
Pregnancy 
If you are pregnant, think you may be pregnant or are planning to have a baby, tell your doctor. The 
use of Armisarte should be avoided during pregnancy. Your doctor will discuss with you the potential 
risk of taking Armisarte during pregnancy. Women must use effective contraception during treatment 
with Armisarte. 
 
Breast-feeding 
If you are breast-feeding, tell your doctor. 
Breast-feeding must be discontinued during treatment with Armisarte. 
 
Fertility 
Men are advised not to father a child during and up to 6 months following treatment with Armisarte 
and should therefore use effective contraception during treatment with Armisarte and for up to 
6 months afterwards. If you would like to father a child during the treatment or in the 6 months 
following receipt of treatment, seek advice from your doctor or pharmacist. You may want to seek 
counselling on sperm storage before starting your therapy. 
 
Driving and using machines 
Armisarte may make you feel tired. Be careful when driving a car or using machines. 
 
 
3. How to use Armisarte 
 
Armisarte 25 mg/ml concentrate for solution for infusion will always be given to you by a healthcare 
professional. The dose of Armisarte is 500 milligrams for every square metre of your body’s surface 
area. Your height and weight are measured to work out the surface area of your body. Your doctor will 
use this body surface area to work out the right dose for you. This dose may be adjusted, or treatment 



33 

may be delayed depending on your blood cell counts and on your general condition. A hospital 
pharmacist, nurse or doctor will have mixed the Armisarte concentrate with 5% glucose solution for 
injection before it is given to you. 
 
You will always receive Armisarte by infusion into one of your veins. The infusion will last 
approximately 10 minutes. 
 
When using Armisarte in combination with cisplatin: 
The doctor or hospital pharmacist will work out the dose you need based on your height and weight. 
Cisplatin is also given by infusion into one of your veins, and is given approximately 30 minutes after 
the infusion of Armisarte has finished. The infusion of cisplatin will last approximately 2 hours. 
 
You should usually receive your infusion once every 3 weeks.  
 
Additional medicines:  
Corticosteriods: your doctor will prescribe you steroid tablets (equivalent to 4 milligram of 
dexamethasone twice a day) that you will need to take on the day before, on the day of, and the day 
after Armisarte treatment. This medicine is given to you to reduce the frequency and severity of skin 
reactions that you may experience during your anticancer treatment. 
 
Vitamin supplementation: your doctor will prescribe you oral folic acid (vitamin) or a multivitamin 
containing folic acid (350 to 1000 micrograms) that you must take once a day while you are receiving 
Armisarte. You must take at least 5 doses during the seven days before the first dose of Armisarte. 
You must continue taking the folic acid for 21 days after the last dose of Armisarte. You will also 
receive an injection of vitamin B12 (1000 micrograms) in the week before administration of Armisarte 
and then approximately every 9 weeks (corresponding to 3 courses of Armisarte treatment). Vitamin 
B12 and folic acid are given to you to reduce the possible toxic effects of the anticancer treatment. 
 
Your condition will be closely monitored during treatment. This routinely involves blood tests, 
including checks on your liver and kidney function. Your dose may be changed or treatment delayed 
depending on results from these tests. 
 
If you have any further questions on 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 must contact your doctor immediately if you notice any of the following: 
- Fever or infection (common): if you have a temperature of 38 °C or greater, sweating or other 

signs of infection(since you might have less white blood cells than normal which is very 
common). Infection (sepsis) may be severe and could lead to death 

- If you start feeling chest pain (common) or having a fast heart rate (uncommon) 
- If you have pain, redness, swelling or sores in your mouth (very common) 
- Allergic reaction: if you develop skin rash (very common) / burning or prickling sensation 

(common), or fever (common). Rarely, skin reactions may be severe and could lead to death. 
Contact your doctor if you get a severe rash, or itching, or blistering (Stevens-Johnson 
Syndrome or Toxic epidermal necrolysis) 

- If you experience tiredness, feeling faint, becoming easily breathless or if you look pale (since 
you might have less haemoglobin than normal which is very common) 

- If you experience bleeding from the gums, nose or mouth or any bleeding that would not stop, 
reddish or pinkish urine, unexpected bruising (since you might have less platelets than normal 
which is very common) 

- If you experience sudden breathlessness, intense chest pain or cough with bloody sputum 
(uncommon)(may indicate a blood clot in the blood vessels of the lungs) 

 



34 

Other side effects with Armisarte may include: 
 
Very common (may affect more than 1 in 10 people) 
– Infection 
– Pharyngitis (a sore throat) 
– Low number of neutrophil granulocytes (a type of white blood cell) 
– Low white blood cells 
– Low haemoglobin level  
– Pain, redness, swelling or sores in your mouth 
– Loss of appetite 
– Vomiting 
– Diarrhoea 
– Nausea 
– Skin rash 
– Flaking skin 
– Abnormal blood tests showing reduced functionality of kidneys 
– Fatigue (tiredness) 
 
Common (may affect up to 1 in 10 people) 
– Blood infection 
– Fever with low number of neutrophil granulocytes (a type of white blood cell) 
– Low platelet count 
– Allergic reaction 
– Loss of body fluids 
– Taste change 
– Damage to the motor nerves which may cause muscle weakness and atrophy (wasting) primary 

in the arms and legs) 
– Damage to the sensory nerves that may cause lost of sensation, burning pain and unsteady gait 
– Dizziness 
– Inflammation or swelling of the conjunctiva (the membrane that lines the eyelids and covers the 

white of the eye 
– Dry eye 
– Watery eyes 
– Dryness of the conjunctiva (the membrane that lines the eyelids and covers the white of the eye) 

and cornea (the clear layer in front of the iris and pupil. 
– Swelling of the eyelids 
– Eye disorder with dryness, tearing, irritation, and/or pain 
– Cardiac Failure (Condition that affects the pumping power of your heart muscles) 
– Irregular heart rhythm 
– Indigestion 
– Constipation 
– Abdominal pain 
– Liver: increases in the chemicals in the blood made by the liver 
– Increased skin pigmentation 
– Itchy skin 
– Rash on the body where each mark resembles a bullseye 
– Hair loss 
– Hives 
– Kidney stop working 
– Reduced functionality of kidney 
– Fever 
– Pain 
– Excess fluid in body tissue, causing swelling 
– Chest pain 
– Inflammation and ulceration of the mucous membranes lining the digestive tract 
 



35 

Uncommon (may affect up to 1 in 100 people) 
– Reduction in the number of red,white blood cells and platelets 
– Stroke 
– Type of stroke when an artery to the brain is blocked 
– Bleeding inside 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 
– Deficient blood distribution to the limbs 
– Blockage in one of the pulmonary arteries in your lungs 
– Inflammation and scarring of the lining of the lungs with breathing problems 
– Passage of bright red blood from the anus 
– Bleeding in the gastrointestinal tract 
– Ruptured bowel 
– Inflammation of the lining of the oesophagus 
– Inflammation of the lining of the large bowel, which may be accompanied by intestinal or rectal 

bleeding (seen only in combination with cisplatin) 
– Inflammation, edema, erythema, and erosion of the mucosal surface 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 
– Skin rash that develops throughout a previously irradiated area 
 
Very rare (affect up to 1 of 10 000 people) 
– Infections of skin and soft tissues 
– Stevens-Johnson syndrome (a type of severe skin and mucous membranes reaction that may be 

life threatening) 
– Toxic epidermal necrolysis (a type of severe skin reaction that may be life threatening) 
– Autoimmune disorder that results in skin rashes and blistering on the legs, arms, and abdomen 
– Inflammation of the skin characterized by the presence of bullae which are filled with fluid 
– Skin fragility, blisters and erosions and skin scarring 
– Redness, pain and swelling mainly of the lower limbs 
– Inflammation of the skin and fat beneath the skin (pseudocellulitis) 
– Inflammation of the skin (dermatitis) 
– Skin to become inflamed, itchy, red, cracked, and rough 
– Intensely itchy spots 
 
Not known: frequency cannot be estimated from the available data 
– Form of diabetes primarily due to pathology of the kidney 
– Disorder of the kidneys involving the death of tubular epithelial cells that form the renal tubules 
 
You might have any of these symptoms and/or conditions. You must tell your doctor as soon as 
possible when you start experiencing any of these side effects. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

 
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 carton after ‘EXP’. The 
expiry date refers to the last day of that month. 
 
Store and transport refrigerated (2 °C-8 °C). 
 
Do not freeze. 
 
Keep the vial in the outer carton in order to protect from light. 
 
Infusion Solution: Chemical and physical in-use stability of infusion solution of pemetrexed was 
demonstrated for 24 hours at room temperature and 7 days at refrigerated temperature. From a 
microbiological point of view, 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 would not be longer 
than 24 hours at 2 °C-8 °C, unless dilution has taken place in controlled and validated aseptic 
conditions. 
 
Armisarte should not been used if there are any signs of particles. 
 
This medicine is for single use only; any unused solution must be disposed of in accordance with local 
requirements. 
 
 
6. Contents of the pack and other information 
 
What Armisarte contains 
 
The active substance is pemetrexed. Each ml of concentrate contains 25 mg pemetrexed (as 
pemetrexed diacid). 
 
Each vial of 4 ml concentrate contains 100 mg pemetrexed (as pemetrexed diacid) 
Each vial of 20 ml concentrate contains 500 mg pemetrexed (as pemetrexed diacid) 
Each vial of 34 ml concentrate contains 850 mg pemetrexed (as pemetrexed diacid) 
Each vial of 40 ml concentrate contains 1000 mg pemetrexed (as pemetrexed diacid) 
 
The other ingredients are trometamol (for pH adjustment), citric acid, methionine and water for 
injection. 
 
What Armisarte looks like and contents of the pack 
 
Armisarte concentrate for solution for infusion (sterile concentrate) is a clear, colourless to slightly 
yellowish or yellow-greenish solution. 
 
Armisarte is provided in a colourless glass vial with rubber stopper and an aluminium cap with 
polypropylene disk. Vials may or may not be sheathed in a protective sleeve. 
 
Each pack of Armisarte contains one vial. 
 
Pack sizes 
1 x 4 ml vial (100 mg/4 ml) 
1 x 20 ml vial (500 mg/20 ml) 
1 x 34 ml vial (850 mg/34 ml) 
1 x 40 ml vial (1000 mg/40 ml) 



37 

 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegi 76-78 
220 Hafnarfjörður 
Iceland 
 
Manufacturer 
PLIVA CROATIA Ltd. 
10000 Zagreb 
Prilaz baruna Filipovića 25 
Croatia 
 
Actavis Italy S.p.A. 
Viale Pasteur 10 
20014 Nerviano (Milan) 
Italy 
 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd. 
011171 Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Teva Pharma Belgium N.V./S.A./AG 
Tel/Tél: + 32 (0)38 20 73 73 
 

Lietuva 
UAB "Sicor Biotech" 
Tel: +370 5 266 0203 
 

България 
Актавис ЕАД 
Teл.: +359 2 489 95 85 
 

Luxembourg/Luxemburg 
Teva Pharma Belgium N.V./S.A./AG 
Tel/Tél: + 32 (0)38 20 73 73 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel.: +36 1 288 6400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44 98 55 11 
 

Malta 
Actavis Ltd. 
Tel: +35621693533 
 

Deutschland 
ratiopharm GmbH 
Tel: +49 731 402 02 
 

Nederland 
Teva Nederland B.V. 
Tel: +31 (0) 800 0228 400 
 

Eesti 
UAB "Sicor Biotech" Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 210 5401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43(0)1 97007 0 
 

tel:+49


38 

España 
Teva Pharma, S.L.U. 
Tél: +(34) 91 387 32 80  
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 22 345 93 00 
 

France 
Teva Santé 
Tél: +(33) 1 55 91 78 00 
 

Portugal 
Teva Pharma - Produtos Farmacêuticos Lda 
Tel: +351 21 476 75 50 
 

Hrvatska 
Pliva Hrvatska d.o.o.  
Tel: +385 1 37 20 000  
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +4021 230 65 24 
 

Ireland 
Actavis Ireland Limited 
Tel: +353 (0)21 4619040 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 550 3300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o 
Tel: +421 2 57 26 79 11 
 

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

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 (0) 20 180 5900 
 

Κύπρος 
Specifar ABEE  
Τηλ: +30 210 5401500 
Ελλάδα 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB "Sicor Biotech" filiāle Latvijā 
Tel: +371 673 23 666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271 385257 
 

 
This leaflet was last revised in 
 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 
 
  

http://www.ema.europa.eu/


39 

 
--------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for medical or healthcare professionals only: 
 
Instructions for use, handling and disposal 
 
1. Use aseptic techniques during dilution of pemetrexed for intravenous infusion administration. 
 
2. Calculate the dose and the number of Armisarte vials needed.  
 
3. Armisarte must only be diluted with 5% glucose solution, without preservative. The appropriate 

volume of pemetrexed concentrate must be diluted to 100 ml with 5% glucose solution and 
administered as an intravenous infusion over 10 minutes.  

 
4. Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 

chloride and polyolefin lined administration sets and infusion bags. Pemetrexed is incompatible 
with diluents containing calcium, including lactated Ringer’s Injection and Ringer’s Injection.  

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

 
5. Parenteral medicinal products should be inspected visually for particulate matter and 

discolouration prior to administration. If particulate matter is observed, do not administer. 
 
6. Pemetrexed solutions are for single use only. Any unused product or waste material should be 

disposed of in accordance with local requirements. 
 
Preparation and administration precautions 
 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed 
solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If 
pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not 
a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been a few 
reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. 
Extravasation should be managed by local standard practice as with other non-vesicants. 
 
Diluted solution 
 
Chemical and physical in-use stability of infusion solution of pemetrexed was demonstrated for 
24 hours at room temperature and 7 days at refrigerated temperature. From a microbiological point of 
view, 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 would not be longer than 24 hours at 2 °C-
8 °C, unless dilution has taken place in controlled and validated aseptic conditions. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET