Pemetrexed Accord

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



 

2 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion. 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion. 
Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion 
Each vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
Excipient with known effect 
Each vial contains approximately 11 mg sodium. 
 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion 
Each vial contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
Excipient with known effect 
Each vial contains approximately 54 mg sodium. 
 
Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion 
Each vial contains 1000 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
Excipient with known effect 
Each vial contains approximately 108 mg sodium. 
 
After reconstitution (see section 6.6), each vial contains 25 mg/ml of pemetrexed. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
A white to either light yellow or greenish-yellow lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Malignant pleural mesothelioma 
Pemetrexed Accord in combination with cisplatin is indicated for the treatment of chemotherapy naïve 
patients with unresectable malignant pleural mesothelioma. 
 
Non-small cell lung cancer 
Pemetrexed Accord 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 Accord 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 



 

3 

whose disease has not progressed immediately following platinum-based chemotherapy (see section 
5.1). 
 
Pemetrexed Accord 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 
 
Pemetrexed Accord must only be administered under the supervision of a physician qualified in the 
use of anti-cancer chemotherapy. 
 
Posology 
 
Pemetrexed Accord in combination with cisplatin 
The recommended dose of Pemetrexed Accord 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 Accord as single agent 
In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of 
Pemetrexed Accord is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the 
first day of each 21-day cycle. 
 
Premedication 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 



 

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in Tables 1, 2 and 3, which are applicable for Pemetrexed Accord used as a single agent or in 
combination with cisplatin. 
 

Table 1 - Dose modification table for Pemetrexed Accord (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 Accord and 
cisplatin) 

Nadir platelets <50,000 /mm3 regardless of nadir 
ANC 

75 % of previous dose (both Pemetrexed Accord and 
cisplatin) 

Nadir platelets < 50,000 /mm3 with bleedinga, 
regardless of nadir ANC 

50 % of previous dose (both Pemetrexed Accord 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 
Accord 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 Accord (as single agent or in combination) and 
cisplatin– Non-haematologic toxicities a, b 

 Dose of Pemetrexed Accord 
(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 Accord 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 Accord (as single agent or in combination) and 
cisplatin – Neurotoxicity 

CTC a Grade Dose of Pemetrexed Accord (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 Accord 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. 
 
Elderly  
In clinical studies, there has been no indication that patients 65 years of age or older are at increased 
risk of adverse events compared to patients younger than 65 years old. No dose reductions other than 
those recommended for all patients are necessary. 
 
Paediatric population 
There is no relevant use of Pemetrexed Accord in the paediatric population in malignant pleural 
mesothelioma and non-small cell lung cancer. 
 



 

5 

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 
 
For precautions to be taken before handling or administering Pemetrexed Accord, see section 6.6. 
 
Pemetrexed Accord should be administered as an intravenous infusion over 10 minutes on the first day 
of each 21-day cycle. For instructions on reconstitution and dilution of Pemetrexed Accord 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). 
 
Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should 
avoid taking non-steroidal anti-inflammatory drugs (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). 



 

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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. 
 
Excipients 
 
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion 
This medicinal product contains less than 1 mmol sodium (23 mg) sodium per vial, i.e. essentially 
‘sodium-free’. 
 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion 
This medicinal product contains approximately 54 mg of sodium per vial. To be taken into 
consideration by patients on a controlled sodium diet. 
 
Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion 



 

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This medicinal product contains approximately 108 mg of sodium per vial. To be taken into 
consideration by patients on a controlled sodium diet. 
 
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 drugs (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. 
 
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 drugs 
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 drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acidat higher 
dose (> 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence 
of pemetrexed adverse events. 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 drugs 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 
 
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 



 

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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). 
 
Breast-feeding 
It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling 
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 
 
No studies on the effects on the ability to drive and use machines have been performed. 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 below provides the frequency and severity of undesirable effects that have been reported 
in > 5 % of 168 patients with mesothelioma who were randomised to receive cisplatin and pemetrexed 
and 163 patients with mesothelioma randomised to receive single agent cisplatin. In both treatment 
arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12. 
 
Frequency estimate: 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 available data). 
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
System organ 
class 

Frequenc
y 

Event* Pemetrexed/cisplati
n 

Cisplatin 

(N= 168) (N=  163) 
All grades 

toxicity 
(%) 

Grade 
3 - 4 

toxicit
y (%) 

All 
grades 
toxicity 

(%) 

Grade 
3 - 4 

toxicit
y (%)

Blood and Very Neutrophils/ 56.0 23.2 13.5 3.1 



 

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System organ 
class 

Frequenc
y 

Event* Pemetrexed/cisplati
n 

Cisplatin 

lymphatic 
system 
disorders 

common Granulocytes decreased 
Leukocytes decreased 53.0 14.9 16.6 0.6 
Haemoglobin decreased 26.2 4.2 10.4 0.0 
Platelets decreased 23.2 5.4 8.6 0.0 

Metabolism 
and nutrition 
disorders 

Common  Dehydration 6.5 4.2 0.6 0.6 

Nervous 
system 
disorders 

Very 
common 

Neuropathy-Sensory 10.1 0.0 9.8 0.6 

Common Taste disturbance 7.7 0.0*** 6.1 0.0*** 
Eye disorders Common Conjunctivitis  5.4 0.0 0.6 0.0 
Gastrointestina
l disorders 

Very 
common 

Diarrhoea  16.7 3.6 8.0 0.0 
Vomiting  56.5 10.7 49.7 4.3 
Stomatitis/ Pharyngitis 23.2 3.0 6.1 0.0 
Nausea  82.1 11.9 76.7 5.5 
Anorexia  20.2 1.2 14.1 0.6 
Constipation  11.9 0.6 7.4 0.6 

Common Dyspepsia  5.4 0.6 0.6 0.0 
Skin and 
subcutaneous 
tissue disorders 

Very 
common 

Rash  16.1 0.6 4.9 0.0 
Alopecia  11.3 0.0*** 5.5 0.0*** 

Renal and 
urinary 
disorders 

Very 
common 

Creatinine elevation 10.7 0.6 9.8 1.2 
Creatinine clearance 
decreased** 

16.1 0.6 17.8 1.8 

General 
disorders and 
administration 
site conditions 

Very 
common 

Fatigue 47.6 10.1 42.3 9.2 

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity except the term 
“creatinine clearance decreased” 
** which is derived from the term “renal/genitourinary other”. 
*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia 
should only be reported as Grade 1 or 2. 
 
For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter 
considered a possible relationship to pemetrexed and cisplatin. 
 
Clinically relevant CTC toxicities that were reported in ≥ 1 % and < 5 % of the patients that were 
randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile 
neutropenia, increased AST, ALT, and GGT, urticaria and chest pain. 
Clinically relevant CTC toxicities that were reported in < 1 % of the patients that were randomly 
assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy. 
 
The table below provides the frequency and severity of undesirable effects that have been reported in 
> 5 % of 265 patients randomly assigned to receive single agent pemetrexed with folic acid and 
vitamin B12 supplementation and 276 patients randomly assigned to receive single agent docetaxel. All 
patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received 
prior chemotherapy. 
 
System organ 
class 

Frequency Event* Pemetrexed 
N = 265 

Docetaxel 
N = 276 



 

10 

All 
grades 
toxicity 

(%) 

Grade 
3 - 4 

toxicity 
(%) 

All 
grades 
toxicity 

(%) 

Grade 
3 - 4 

toxicity 
(%) 

Blood and 
lymphatic 
system 
disorders 

Very 
common 

Neutrophils/ 
Granulocytes decreased 

10.9 5.3 45.3 40.2 

Leukocytes decreased 12.1 4.2 34.1 27.2 
Haemoglobin decreased 19.2 4.2 22.1 4.3 

Common  Platelets decreased 8.3 1.9 1.1 0.4 
Gastrointestinal 
disorders 

Very 
common 

Diarrhoea  12.8 0.4 24.3 2.5 
Vomiting  16.2 1.5 12.0 1.1 
Stomatitis/ Pharyngitis 14.7 1.1 17.4 1.1 
Nausea  30.9 2.6 16.7 1.8 
Anorexia  21.9 1.9 23.9 2.5 

Common Constipation  5.7 0.0 4.0 0.0 
Hepatobiliary 
disorders 

Common SGPT (ALT) elevation 7.9 1.9 1.4 0.0 
SGOT (AST) elevation 6.8 1.1 0.7 0.0 

Skin and 
subcutaneous 
tissue disorders 

Very 
common 

Rash/ desquamation  14.0 0.0 6.2 0.0 

Common Pruritus 6.8 0.4 1.8 0.0 
Alopecia  6.4 0.4** 37.7 2.2** 

General 
disorders and 
administration 
site conditions 

Very 
common 

Fatigue 34.0 5.3 35.9 5.4 

Common Fever 8.3 0.0 7.6 0.0 

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity. 
**According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as 
Grade 1 or 2. 
 
For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter 
considered a possible relationship to pemetrexed. 
 
Clinically relevant CTC toxicities that were reported in ≥ 1 % and < 5 % of the patients that were 
randomly assigned to pemetrexed include: infection without neutropenia, febrile neutropenia, allergic 
reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema 
multiforme, and abdominal pain. 
 
Clinically relevant CTC toxicities that were reported in < 1 % of the patients that were randomly 
assigned to pemetrexed include supraventricular arrhythmias. 
 
Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated 
Phase 2 results from three single agent pemetrexed studies (n=  164) and the Phase 3 single agent 
pemetrexed study described above, with the exception of neutropenia (12.8 % versus 5.3 %, 
respectively) and alanine aminotransferase elevation (15.2 % versus 1.9 %, respectively). These 
differences were likely due to differences in the patient population, since the Phase 2 studies included 
both chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases 
and/or abnormal baseline liver function tests. 
 
The table below provides the frequency and severity of undesirable effects considered possibly related 
to study drug that have been reported in > 5 % of 839 patients with NSCLC who were randomized to 
receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive 
cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced 
or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid 
and vitamin B12. 
 



 

11 

System organ 
class 

Frequency Event* Pemetrexed/ 
cisplatin (N=  839) 

Gemcitabine/ 
cisplatin (N= 830) 

All 
grades 
toxicity 

(%) 

Grade 
3 - 4 

toxicity 
(%) 

All 
grades 
toxicity 

(%) 

Grade 
3 - 4 

toxicity 
(%) 

Blood and 
lymphatic 
system 
disorders 

Very 
common 

Haemoglobin decreased  33.0* 5.6* 45.7* 9.9* 
Neutrophils/ 
Granulocytes decreased  

29.0* 15.1* 38.4* 26.7* 

Leukocytes decreased 17.8 4.8* 20.6 7.6* 
Platelets decreased 10.1* 4.1* 26.6* 12.7* 

Nervous 
system 
disorders 

Common Neuropathy-Sensory 8.5* 0.0* 12.4* 0.6* 
Taste disturbance 8.1 0.0*** 8.9 0.0*** 

Gastrointestinal 
disorders 

Very 
common 

Nausea  56.1 7.2* 53.4 3.9* 
Vomiting  39.7 6.1 35.5 6.1 
Anorexia  26.6 2.4* 24.2 0.7* 
Constipation  21.0 0.8 19.5 0.4 
Stomatitis/ Pharyngitis 13.5 0.8 12.4 0.1 
Diarrhoea without 
colostomy 

12.4 1.3 12.8 1.6 

Common Dyspepsia/Heartburn 5.2 0.1 5.9 0.0 
Skin and 
subcutaneous 
tissue disorders 

Very 
common 

Alopecia 11.9* 0*** 21.4* 0.5*** 

Common Rash/ desquamation 6.6 0.1 8.0 0.5 
Renal and 
urinary 
disorders 

Very 
common 

Creatinine elevation 10.1* 0.8 6.9* 0.5 

General 
disorders and 
administration 
site conditions 

Very 
common 

Fatigue 42.7 6.7 44.9 4.9 

*P-values < 0.05 comparing pemetrexed/cisplatin to gemcitabine/cisplatin, using Fisher Exact test. 
**Refer to National Cancer Institute CTC (v2.0; NCI 1998) for each Grade of Toxicity. 
***According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia 
should only be reported as Grade 1 or 2. 
 
For the purpose of this table, a cut-off of 5 % was used for inclusion of all events where the reporter 
considered a possible relationship to pemetrexed and cisplatin. 
 
Clinically relevant toxicity that was reported in ≥ 1 % and ≤ 5 % of the patients that were randomly 
assigned to receive cisplatin and pemetrexed include: AST increase, ALT increase, infection, febrile 
neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.  
Clinically relevant toxicity that was reported in < 1 % of the patients that were randomly assigned to 
receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor 
neuropathy. 
 
Clinically relevant toxicities with respect to gender were similar to the overall population in patients 
receiving pemetrexed plus cisplatin. 
 
The table below provides the frequency and severity of undesirable effects considered possibly related 
to study drug that have been reported in > 5 % of 800 patients randomly assigned to receive single 
agent pemetrexed and 402 patients randomly assigned to receive placebo in the single-agent 
pemetrexed maintenance (JMEN: N= 663) and continuation pemetrexed maintenance 
(PARAMOUNT: N=539) studies. All patients were diagnosed with Stage IIIB or IV NSCLC and had 



 

12 

received prior platinum-based chemotherapy. Patients in both study arms were fully supplemented 
with folic acid and vitamin B12. 
 
System organ 
class 

Frequency
* 

Event** Pemetrexed*** 
(N = 800)

Placebo*** 
(N = 402)

All 
grades 
toxicity 

(%) 

Grade 
3 – 4 

toxicity 
(%) 

All 
grades 
toxicity 

(%) 

Grade 
3 – 4 

toxicity 
(%) 

Blood and 
lymphatic system 
disorders 

Very 
common 

Haemoglobin 
decreased 

18.0 4.5 5.2 0.5 

Common Leukocytes decreased  5.8 1.9 0.7 0.2 
Neutrophils decreased 8.4 4.4 0.2 0.0 

Nervous system 
disorders 

Common Neuropathy-Sensory 7.4 0.6 5.0 0.2 

Gastrointestinal 
disorders 

Very 
common 

Nausea  17.3 0.8 4.0 0.2 
Anorexia  12.8 1.1 3.2 0.0 

Common Vomiting  8.4 0.3 1.5 0.0 
Mucositis/ stomatitis 6.8 0.8 1.7 0.0 

Hepatobiliary 
disorders 

Common ALT (SGPT) 
elevation 

6.5 0.1 2.2 0.0 

AST (SGOT) 
elevation 

5.9 0.0 1.7 0.0 

Skin and 
subcutaneous 
tissue disorders 

Common Rash/ desquamation  8.1 0.1 3.7 0.0 

General disorders 
and 
administration 
site conditions 

Very 
common 

Fatigue 24.1 5.3 10.9 0.7 

Common Pain 7.6 0.9 4.5 0.0 
Edema 5.6 0.0 1.5 0.0 

Renal disorders Common Renal disorders**** 7.6 0.9 1.7 0.0 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = 
Common Terminology Criteria for Adverse Event; NCI = National Cancer Institute; SGOT = serum 
glutamic oxaloacectic aminotransferase; SGPT = serum glutamic pyruvic aminotransferase. 
* Definition of frequency terms: Very common - ≥ 10 %; Common - > 5 % and < 10%. . For the 
purpose of this table, a cutoff of 5 % was used for inclusion of all events where the reporter considered 
a possible relationship to pemetrexed. 
** Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of toxicity. The reporting 
rates shown are according to CTCAE version 3.0. 
*** Integrated adverse reactions table combines the results of the JMEN pemetrexed maintenance 
(N=663) and PARAMOUNT continuation pemetrexed maintenance (N=539) studies. 
**** Combined term includes increased serum/blood creatinine, decreased glomerular filtration rate, 
renal failure and renal/genitourinary- other. 
 
Clinically relevant CTC toxicity of any grade that was reported in ≥ 1 % and  5 % of the patients that 
were randomly assigned to pemetrexed include: febrile neutropenia, infection, decreased platelets, 
diarrhoea, constipation, alopecia, pruritis/itching, fever (in the absence of neutropenia), ocular surface 
disease (including conjunctivitis), increased lacrimation, dizziness and motor neuropathy. 
 
Clinically relevant CTC toxicity that was reported in < 1 % of the patients that were randomly 
assigned to pemetrexed include: allergic reaction/hypersensitivity, erythema multiforme, 
supraventricular arrhythmia and pulmonary embolism. 
 
Safety was assessed for patients who were randomised to receive pemetrexed (N=800). The incidence 
of adverse reactions was evaluated for patients who received ≤ 6 cycles of pemetrexed maintenance 
(N=519), and compared to patients who received > 6 cycles of pemetrexed (N=281). Increases in 



 

13 

adverse reactions (all grades) were observed with longer exposure. A significant increase in the 
incidence of possibly study-drug-related Grade 3/4 neutropenia was observed with longer exposure to 
pemetrexed (≤ 6 cycles: 3.3%, > 6cycles: 6.4 %: p=0.046). No statistically significant differences in 
any other individual Grade 3/4/5 adverse reactions were seen with longer exposure. 
 
Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, 
cerebrovascular accident and transient ischaemic attack 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. 
 
Rare cases of hepatitis, potentially serious, have been reported during clinical studies with pemetrexed. 
 
Pancytopenia has been uncommonly reported during clinical trials with pemetrexed. 
 
In clinical trials, cases of colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal 
perforation, intestinal necrosis and typhlitis) have been reported uncommonly in patients treated with 
pemetrexed. 
 
In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, sometimes fatal, have 
been reported uncommonly in patients treated with pemetrexed. 
 
Uncommon cases of oedema have been reported in patients treated with pemetrexed. 
 
Oesophagitis/ radiation oesophagitis has been uncommonly reported during clinical trials with 
pemetrexed. 
 
Sepsis, sometimes fatal, has been commonly reported during clinical trials with pemetrexed. 
 
During post marketing surveillance, the following adverse reactions have been reported in patients 
treated with pemetrexed: 
 
Hyperpigmentation has been commonly reported. 
 
Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association 
with other chemotherapeutic agents (see section 4.4). Nephrogenic diabetes insipidus and renal tubular 
necrosis have been reported in post marketing setting with an unknown frequency. 
 
Uncommon cases of radiation pneumonitis have been reported in patients treated with radiation either 
prior, during or subsequent to their pemetrexed therapy (see section 4.4). 
 
Rare cases of radiation recall have been reported in patients who have received radiotherapy 
previously (see section 4.4). 
 
Uncommon cases of peripheral ischaemia leading sometimes to extremity necrosis have been reported. 
 
Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and Toxic 
epidermal necrolysis which in some cases were fatal. 
 
Rarely, immune-mediated haemolytic anaemia has been reported in patients treated with pemetrexed. 
 
Rare cases of anaphylactic shock have been reported. 
 
Erythematous oedema mainly of the lower limbs has been reported with an unknown frequency. 
Infectious and non-infectious disorders of the dermis, the hypodermis and/or the subcutaneous tissue 
have been reported with an unknown frequency (e.g. acute bacterial dermo-hypodermitis, 
pseudocellulitis, dermatitis). 



 

14 

 
 
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. 
 
 
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 drug 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 drug (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: 
 



 

15 

 
 
 
 
 

Efficacy of pemetrexed plus cisplatin vs. cisplatin in malignant pleural mesothelioma 

 Randomized and treated Fully supplemented 
 patients patients 
Efficacy parameter Pemetrexed / 

cisplatin 
Cisplatin Pemetrexed / 

cisplatin 
Cisplatin 

 (N = 226) (N = 222) (N = 168) (N = 163) 
Median overall survival (months) 12.1  9.3  13.3  10.0  
(95 % CI) (10.0 - 14.4) (7.8 - 10.7) (11.4 - 14.9) (8.4 - 11.9) 
Log Rank p-value* 0.020 0.051 
Median time to tumour progression 
(months) 

5.7  3.9  6.1  3.9  

(95 % CI) (4.9 - 6.5) (2.8 - 4.4) (5.3 - 7.0) (2.8 - 4.5) 
Log Rank p-value* 0.001 0.008 
Time to treatment failure (months) 4.5  2.7  4.7  2.7  
(95 % CI) (3.9 - 4.9) (2.1 - 2.9) (4.3 - 5.6) (2.2 - 3.1) 
Log Rank p-value* 0.001 0.001 
Overall response rate** 41.3 % 16.7 % 45.5 % 19.6 % 
(95 % CI) (34.8 - 48.1) (12.0 - 22.2) (37.8 - 53.4) (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. 
 



 

16 

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). 
 

 
Efficacy of pemetrexed vs docetaxel in NSCLC - ITT population 

 Pemetrexed Docetaxel 
Survival Time (months) 
 Median (m) 
 95 % CI for median 

(n = 283) 
8.3 

(7.0 - 9.4) 

(n = 288) 
7.9 

(6.3 - 9.2) 
 HR 
 95 % CI for HR 
 Non-inferiority p-value (HR) 

0.99 
(.82 - 1.20) 

.226 
Progression free survival (months) 
 Median 

(n = 283) 
2.9 

(n = 288) 
2.9 

 HR (95 % CI) 0.97 (.82 – 1.16) 
Time to treatment failure (TTTF – months) 
 Median 

(n = 283) 
2.3 

(n = 288) 
2.1 

 HR (95 % CI) 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. 
 

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) 

Superiorityp-value

Pemetrexed + cisplatin Gemcitabine + 
cisplatin 

ITT population 10.3 N = 10.3 N = 0.94a 0.259 



 

17 

ITT population 
and histology 

Median overall survival in months 
(95 % CI) 

Adjusted 
Hazard 

Superiorityp-value

(N = 1725) (9.8 – 
11.2) 

862 (9.6 – 
10.9) 

863 (0.84 – 
1.05) 

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 after 
completion of first line (induction) therapy. Patients received a median of 5 cycles of maintenance 

Adenocarcinoma

Survival Time (months)
0 6 12 18 24 30

Su
rv

iv
al

 P
ro

ba
bi

lit
y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

AC
GC

Large Cell Carcinoma

Survival Time (months)
0 6 12 18 24 30

Su
rv

iv
al

 P
ro

ba
bi

lit
y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

AC
GC



 

18 

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 
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 



 

19 

were measured from the time of randomisation after completion of first line (induction) therapy. 
Patients received a median of4 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 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 



 

20 

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. 
 
5.2 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 
 
Mannitol (E421) 
Hydrochloric acid (E507) (for pH adjustment) 
Sodium hydroxide (E524) (for pH adjustment) 
 
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. 
 
6.3 Shelf life 
 
Unopened vial 
3 years. 
 
Reconstituted and infusion solutions 
Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were 
demonstrated for 24 hours at 25°C. 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 normally not be longer than 24 hours at 2°C to 8°C, unless 
reconstitution/dilution has taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 



 

21 

 
This medicinal product does not require any special storage conditions. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion 
Type I glass vial with a grey bromobutyl rubber stopper with lavender flip-off seal containing 100 mg 
of pemetrexed. 
Pack of 1 vial. 
 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion 
Type I glass vial with a grey bromobutyl rubber stopper with royal blue flip-off seal containing 
500 mg of pemetrexed. 
Pack of 1 vial. 
 
Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion 
Type I glass vial with a grey bromobutyl rubber stopper with royal blue flip-off seal containing 
1000 mg of pemetrexed. 
Pack of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration. 
 
2. Calculate the dose and the number of Pemetrexed Accord vials needed. Each vial contains an 
excess of pemetrexed to facilitate delivery of label amount. 
 
3. Reconstitute 100-mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9 %) solution for 
injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.  
 
Reconstitute 500-mg vials with 20 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection, 
without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 
 
Reconstitute 1000-mg vials with 40 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection, 
without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 
 
Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and 
ranges in colour from colourless to yellow or green-yellow without adversely affecting product 
quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required. 
 
4. The appropriate volume of reconstituted pemetrexed solution must be further diluted to 
100 ml with sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, and 
administered as an intravenous infusion over 10 minutes. 
 
5. Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 
chloride and polyolefin lined administration sets and infusion bags. 
 
6. Parenteral medicinal products must be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not administer. 
 
7. 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  



 

22 

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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1071/001 
EU/1/15/1071/002 
EU/1/15/1071/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 January 2016 
 
 
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.  
 

  



 

23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER 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 



 

24 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Accord Healthcare Limited 
Sage House 
319, Pinner Road  
North Harrow 
Middlesex HA1 4HF 
United Kingdom 
 
Wessling Hungary Kft. 
Fòti ùt 56., Budapest, 1047, 
Hungary 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland 
 
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  
 

The requirements for submission of periodic safety update reports 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 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 



 

25 

 

Not applicable 

 

 Obligation to conduct post-authorisation measures  
 

Not applicable 

 
 
  



 

26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 

27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



 

28 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion 
pemetrexed  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution (see package leaflet), each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, hydrochloric acid, sodium hydroxide (see package leaflet for further information). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
For intravenous use after reconstitution and dilution. 
Read the package leaflet before use. 
 
 
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. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
 



 

29 

9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1071/001 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION ON BRAILLE 
 
Justification for not including Braille accepted. 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



 

30 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING 
UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF 
 ADMINISTRATION 
 
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion 
pemetrexed 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg 
 
 
6. OTHER 
 
 
 
 

 
  



 

31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion 
pemetrexed  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution (see package leaflet), each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, hydrochloric acid, sodium hydroxide (see package leaflet for further information). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
For intravenous use after reconstitution and dilution. 
Read the package leaflet before use. 
 
 
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. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 



 

32 

 
 
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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1071/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION ON BRAILLE 
 
Justification for not including Braille accepted. 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



 

33 

PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF 
 ADMINISTRATION 
 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion 
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING (S), IF NECESSARY  
 
CYTOTOXIC. 
 
 
8. EXPIRY DATE   
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
Accord  
 
 
12. MARKETING AUTHORISATION NUMBER (S) 



 

34 

 
EU/1/15/1071/002 
 
 
13. BATCH NUMBER 
 
Lot:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  



 

35 

 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion 
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1000 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution (see package leaflet), each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Mannitol, hydrochloric acid, sodium hydroxide (see package leaflet for further information). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
For intravenous use after reconstitution and dilution. 
Read the package leaflet before use. 
 
 
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. 
 
 
8. EXPIRY DATE   
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 

36 

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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER (S) 
 
EU/1/15/1071/003 
 
 
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 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
 
 
 
 
 
 
 
 
 



 

37 

PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS  
 
VIAL 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion 
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING (S), IF NECESSARY  
 
CYTOTOXIC. 
 
 
8. EXPIRY DATE   
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
Accord  
 
 
12. MARKETING AUTHORISATION NUMBER (S) 
 
EU/1/15/1071/003 



 

38 

 
 
13. BATCH NUMBER 
 
Lot:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
  



 

39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

40 

Package leaflet: Information for the user 
 

Pemetrexed Accord 100 mg powder for concentrate for solution for infusion 
Pemetrexed Accord 500 mg powder for concentrate for solution for infusion 

Pemetrexed Accord 1000 mg powder for concentrate for solution for infusion 
pemetrexed 

 
 
Read all of this leaflet carefully before you start using 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 , pharmacist or nurse. 
-  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
-  If you get any side effects, talk to your doctor or pharmacist or nurse.  This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet:  
 
1. What Pemetrexed Accord is and what it is used for 
2. What you need to know before you use Pemetrexed Accord 
3. How to use Pemetrexed Accord  
4. Possible side effects 
5. How to store Pemetrexed Accord 
6. Contents of the pack and other information 
 
 
1. What Pemetrexed Accord is and what it is used for 
 
Pemetrexed Accord is a medicine used in the treatment of cancer. 
 
Pemetrexed Accord 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.  
 
Pemetrexed Accord is also given in combination with cisplatin for the initial treatment of 
patients with advanced stage of lung cancer. 
 
Pemetrexed Accord 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.  
 
Pemetrexed Accord 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 Pemetrexed Accord 
 
Do not use Pemetrexed Accord 
-  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 

Pemetrexed Accord. 
-  if you have recently received or are about to receive a vaccine against yellow fever.  
  



 

41 

 
Warnings and precautions 
 
Talk to your doctor or hospital pharmacist or nurse before using Pemetrexed Accord. 
 
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 Pemetrexed Accord. 
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 Pemetrexed 
Accord. 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 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 Pemetrexed Accord. 
 
If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects 
with Pemetrexed Accord. 
 
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 Pemetrexed Accord. 
 
Children and adolescents 
There is no relevant use of Pemetrexed Accord in the paediatric population 
 
Other medicines and Pemetrexed Accord 
Please tell your doctor if you are taking any medicines for pain or inflammation (swelling), such as 
medicines called “nonsteroidal anti-inflammatory drugs” (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 Pemetrexed Accord 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. 
 
Please tell your doctor or hospital pharmacist if you are taking or have recently taken any other 
medicines, including medicines obtained without a prescription. 
 
Pregnancy 
If you are pregnant, or think you may be pregnant, or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. The use of Pemetrexed Accord should be avoided 
during pregnancy. Your doctor will discuss with you the potential risk of taking Pemetrexed Accord 
during pregnancy. Women must use effective contraception during treatment with Pemetrexed 
Accord. 
 
Breast-feeding 
If you are breast-feeding, tell your doctor.  
Breast-feeding must be discontinued during Pemetrexed Accord treatment. 
 
Fertility 
Men are advised not to father a child during and up to 6 months following treatment with Pemetrexed 
Accord and should therefore use effective contraception during treatment with Pemetrexed Accord 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 



 

42 

seek counselling on sperm storage before starting your therapy. 
 
Driving and using machines 
Pemetrexed Accord may make you feel tired. Be careful when driving a car or using machines. 
 
Pemetrexed Accord contains sodium 
Pemetrexed Accord 100 mg contains less than 1 mmol sodium (23 mg) sodium per vial, i.e. essentially 
‘sodium-free’. 
Pemetrexed Accord 500 mg contains approximately 54 mg sodium per vial. To be taken into 
consideration by patients on a controlled sodium diet. 
Pemetrexed Accord 1000 mg contains approximately 108 mg sodium per vial. To be taken into 
consideration by patients on a controlled sodium diet. 
 
 
3. How to use Pemetrexed Accord 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose of Pemetrexed Accord 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 may be delayed depending on your blood cell counts and on your general 
condition. A hospital pharmacist, nurse or doctor will have mixed the Pemetrexed Accord powder with 
9 mg/ml (0.9 %) sodium chloride solution for injection before it is given to you. 
 
You will always receive Pemetrexed Accord by infusion into one of your veins. The infusion will last 
approximately 10 minutes. 
 
When using Pemetrexed Accord 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 Pemetrexed Accord 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 Pemetrexed Accord 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 taking 
Pemetrexed Accord. You must take at least 5 doses during the seven days before the first dose of 
Pemetrexed Accord. You must continue taking the folic acid for 21 days after the last dose of 
Pemetrexed Accord. You will also receive an injection of vitamin B12 (1000 micrograms) in the week 
before administration of Pemetrexed Accord and then approximately every 9 weeks (corresponding to 
3 courses of Pemetrexed Accord treatment). Vitamin B12 and folic acid are given to you to reduce the 
possible toxic effects of the anticancer treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 



 

43 

 
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 38ºC 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)  

 
Side effects with Pemetrexed Accord may include: 
 
Very common (may affect more than 1 in 10 people) 
Low white blood cells 
Low haemoglobin level (anaemia) 
Low platelet count 
Diarrhoea  
Vomiting 
Pain, redness, swelling or sores in your mouth 
Nausea 
Loss of appetite 
Fatigue (tiredness) 
Skin rash 
Hair loss 
Constipation 
Loss of sensation 
Kidney: abnormal blood tests 
 
Common (may affect up to 1 in 10 people) 
Allergic reaction: skin rash / burning or prickling sensation  
Infection including sepsis 
Fever 
Dehydration 
Kidney failure 
Irritation of the skin and itching 
Chest pain 
Muscle weakness 
Conjunctivitis (inflamed eye) 
Upset stomach 
Pain in the abdomen 
Taste change 
Liver: abnormal blood tests  
Watery eyes  
Increased skin pigmentation 
 
  



 

44 

Uncommon (may affect up to 1 in 100 people) 
Acute renal failure 
Fast heart rate 
Inflammation of the lining of the oesophagus (gullet) has been experienced with Pemetrexed Accord/ 
radiation therapy. 
Colitis (inflammation of the lining of the large bowel, which may be accompanied by intestinal or 
rectal bleeding) 
Interstitial pneumonitis (scarring of the air sacs of the lung) 
Oedema (excess fluid in body tissue, causing swelling)Some patients have experienced a heart attack, 
stroke or “mini-stroke” while receiving Pemetrexed Accord usually in combination with another 
anticancer therapy. 
Pancytopenia- combined low counts of white cells, red cells and platelets 
Radiation pneumonitis (scarring of the air sacs of the lung associated with radiation therapy) may 
occur in patients who are also treated with radiation either before, during or after their Pemetrexed 
Accord therapy. 
Extremity pain, low temperature and discolouration have been reported. 
Blood clots in the lung blood vessels (pulmonary embolism) 
 
Rare (may affect up to 1 in 1,000 people) 
Radiation recall (a skin rash like severe sunburn) which can occur on skin that has previously been 
exposed to radiotherapy, from days to years after the radiation. 
Bullous conditions (blistering skin diseases)-including Stevens-Johnson syndrome and Toxic 
epidermal necrolysis 
Immune mediated haemolytic anaemia (antibody-mediated destruction of red blood cells) 
Hepatitis (inflammation of the liver) 
Anaphylactic shock (severe allergic reaction) 
 
Not known: frequency cannot be estimated from the available data 
Lower limb swelling with pain and redness 
Increased urine output 
Thirst and increased water consumption 
Hypernatraemia – increased sodium in blood 
Inflammation of the skin, mainly of the lower limb with swelling, pain and redness 
 
 
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. 
 
If you are concerned about any side effects, talk to your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist 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. 
 
 
5. How to store Pemetrexed Accord 
 
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. 
 
This medicine does not require any special storage conditions. 
 



 

45 

Reconstituted and Infusion Solutions: The product should be used immediately. When prepared as 
directed, chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed 
were demonstrated for 24 hours at refrigerated temperature.  
 
Do not use this medicine if you notice any visible signs of deterioration. 
 
This medicine is for single use only. Do not throw away any medicines via wastewater or household 
waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will 
help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Pemetrexed Accord contains 
 
The active substance is pemetrexed.  
 
Pemetrexed Accord 100 mg:  Each vial contains 100 milligrams of pemetrexed (as pemetrexed 
disodium hemipentahydrate). 
Pemetrexed Accord 500 mg:  Each vial contains 500 milligrams of pemetrexed (as pemetrexed 
disodium hemipentahydrate). 
Pemetrexed Accord 1000 mg: Each vial contains 1000 milligrams of pemetrexed (as pemetrexed 
disodium hemipentahydrate). 
 
After reconstitution, the solution contains 25 mg/ml of pemetrexed. Further dilution by a healthcare 
provider is required prior to administration. 
The other ingredients are mannitol, hydrochloric acid and sodium hydroxide (see section 2). 

What Pemetrexed Accord looks like and contents of the pack 
Pemetrexed Accord is a powder for concentrate for solution for infusion in a glass vial. It is a white to 
either light yellow or greenish-yellow lyophilised powder. 
 
Each pack of Pemetrexed Accord consists of one vial.  
 
Marketing Authorisation Holder 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
Manufacturer 
Accord Healthcare Limited 
Sage House 
319, Pinner Road  
North Harrow 
Middlesex HA1 4HF 
United Kingdom 
 
Wessling Hungary Kft. 
Fòti ùt 56., Budapest, 1047, 
Hungary 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland 
 



 

46 

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/ 



 

47 

<--------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for medical or healthcare professionals only: 
 
Instructions for use, handling and disposal. 
 
1. Use aseptic techniques during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration. 
 
2. Calculate the dose and the number of Pemetrexed Accord vials needed. Each vial contains an 
excess of pemetrexed to facilitate delivery of the label amount. 
 
3. Pemetrexed Accord 100 mg: 
Reconstitute each 100 mg vial with 4.2 ml of 9 mg/ml (0.9%) sodium chloride solution for injection, 
without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 

 
Pemetrexed Accord 500 mg: 
Reconstitute each 500 mg vial with 20 ml of 9 mg/ml (0.9%) sodium chloride solution for 
injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 

 
 Pemetrexed Accord 1000 mg: 

Reconstitute each 1000 mg vial with 40 ml of 9 mg/ml (0.9 %) sodium chloride solution for 
injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 
 
Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear 
and ranges in colour from colourless to yellow or green-yellow without adversely affecting 
product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution 
is required. 

 
4. The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml 

with 9 mg/ml (0.9 %) sodium chloride solution for injection, without preservative, and 
administered as an intravenous infusion over 10 minutes. 

 
5. 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. 
 
6. Parenteral medicinal products should be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not administer. 
 
7. Pemetrexed solutions are for single use only. Any unused product or waste material should be 

disposed of in accordance with local requirements. 
 

Storage 
 
Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were 
demonstrated for 24 hours at 25°C. 
 
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 normally not be longer than 24 hours at 2°C- to 8°C, unless reconstitution/dilution has taken 
place in controlled and validated aseptic conditions. 
 
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 



 

48 

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. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET